Brazilian Journal of Pulmonology - Volume 39, number 2, March/April - 2013

ISSN 1806-3713

Published once every two months

J Bras Pneumol. v.39, number 2, p. 119-256 March/April 2013

PUBLICAÇÃO OFICIAL DA SOCIEDADE BRASILEIRA DE PNEUMOLOGIA E TISIOLOGIA

Highlight

ASTHMA Relationship between exercise capacity and quality of life in adolescents with asthma Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes

PULMONARY CIRCULATION A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)

COPD Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

EMERGENCY Epidemiological aspects of respiratory symptoms treated in the emergency room of a tertiary care hospital

EXPERIMENTAL Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats

CYSTIC FIBROSIS Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis

PULMONARY FUNCTION Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses

INFECTION Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009

INTENSIVE CARE Experimental study on the efficiency and safety of the manual hyperinflation maneuver as a secretion clearance technique

TUBERCULOSIS Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil Completeness of tuberculosis reporting forms in five Brazilian capitals with a high incidence of the disease

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

Editorial: Juliana Guarize

Published once every two months J Bras Pneumol. v.39, number 2, p. 119-256 March/April 2013 Editor-in-Chief Carlos Roberto Ribeiro de Carvalho - University of São Paulo, São Paulo, Brazil

Executive Editors

Associação Brasileira de Editores Científicos

Bruno Guedes Baldi - University of São Paulo, São Paulo, Brazil Carlos Viana Poyares Jardim - University of São Paulo, São Paulo, Brazil Rogério de Souza - University of São Paulo, São Paulo, Brazil Pedro Caruso - University of São Paulo, São Paulo, Brazil

Associate Editors

Publication Indexed in: Latindex, LILACS, SciELO Brasil, Scopus, Index Copernicus, MEDLINE and ISI Web of Science Available in Portuguese and English from: www.jornaldepneumologia.com.br or www.scielo.br/jbpneu.

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Afrânio Lineu Kritski - Federal University of Rio de Janeiro, Brazil Álvaro A. Cruz - Federal University of Bahia, Salvador, Brazil Celso Ricardo Fernandes de Carvalho - University of São Paulo, São Paulo, Brazil Fábio Biscegli Jatene - University of São Paulo, São Paulo, Brazil Geraldo Lorenzi-Filho - University of São Paulo, São Paulo, Brazil Ilma Aparecida Paschoal - State University at Campinas, Campinas, Brazil José Alberto Neder- Federal University of São Paulo, São Paulo, Brazil José Antônio Baddini Martinez - University of São Paulo, Ribeirão Preto, Brazil.

Renato Tetelbom Stein - Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil Sérgio Saldanha Menna Barreto - Federal University of Rio Grande do Sul, Porto Alegre, Brazil

Editorial Council Alberto Cukier - University of São Paulo, São Paulo, Brazil Ana C. Krieger - New York University School of Medicine, New York, NY, USA Ana Luiza de Godoy Fernandes - Federal University of São Paulo, São Paulo, Brazil Antonio Segorbe Luis - University of Coimbra, Coimbra, Portugal Brent Winston - Department of Critical Care Medicine, University of Calgary, Calgary, Canada Carlos Alberto de Assis Viegas - University of Brasília, Brasília, Brazil Carlos M. Luna - Hospital de Clinicas, University of Buenos Aires, Buenos Aires, Argentina Carlos Roberto Ribeiro de Carvalho - University of São Paulo, São Paulo, Brazil Carmem Silvia Valente Barbas - University of São Paulo, São Paulo, Brazil Chris T. Bolliger - University of Stellenbosch, Tygerberg, South Africa Dany Jasinowodolinski - Federal University of São Paulo, São Paulo, Brazil Douglas Bradley - University of Toronto, Toronto, ON, Canada Denis Martinez - Federal University of Rio Grande do Sul, Porto Alegre, Brazil Emílio Pizzichini - Universidade Federal de Santa Catarina, Florianópolis, SC Frank McCormack - University of Cincinnati School of Medicine, Cincinnati, OH, USA Geraldo Lorenzi-Filho - University of São Paulo, São Paulo, Brazil Gustavo Rodrigo- Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevidéu, Uruguay Irma de Godoy - São Paulo State University, Botucatu, Brazil 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 Dirceu Ribeiro - State University at Campinas, Campinas, Brazil José Miguel Chatkin - Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil José Roberto de Brito Jardim - Federal University of São Paulo, São Paulo, Brazil José Roberto Lapa e Silva - Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Kevin Leslie - Mayo Clinic College of Medicine, Rochester, MN, USA Luiz Eduardo Nery - Federal University of São Paulo, São Paulo, Brazil Marc Miravitlles - Hospital Clinic, Barcelona, España Marcelo Alcântara Holanda - Federal University of Ceará, Fortaleza, Brazil Marcos Ribeiro - University of Toronto, Toronto, ON, Canadá Marli Maria Knorst - Federal University of Rio Grande do Sul, Porto Alegre, Brazil Marisa Dolhnikoff - University of São Paulo, São Paulo, Brazil Mauro Musa Zamboni - Brazilian National Cancer Institute, Rio de Janeiro, Brazil.

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 - University of São Paulo, São Paulo, Brazil Peter J. Barnes - National Heart and Lung Institute, Imperial College, London, UK Renato Sotto-Mayor - Hospital Santa Maria, Lisbon, 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 Talmadge King Jr. - University of California, San Francisco, CA, USA Thais Helena Abrahão Thomaz Queluz - São Paulo State University, Botucatu, Brazil Vera Luiza Capelozzi - University of São Paulo, São Paulo, Brazil

BRAZILIAN THORACIC SOCIETY

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The Brazilian Journal of Pulmonology (ISSN 1806-3713) is published once every two months by the Brazilian Thoracic Society (BTS). The statements and opinions contained in the editorials and articles in this Journal are solely those of the authors thereof and not of the Journal’s Editor-in-Chief, peer reviewers, the BTS, its officers, regents, members, or employees. Permission is granted to reproduce any figure, table, or other material published in the Journal provided that the source for any of these is credited.

BTS Board of Directors (2013-2014 biennium): President: Jairo Araujo Sponholz (PR) Secretary-General: Raquel Melo Nunes Carvalho Feitosa (DF) Director, Professional Advocacy: Mário Sérgio Nunes (DF) CFO: John Daniel Rego Bringel (DF) Scientific Director: Emilio Pizzichini (SC) Director, Education and Professional Practice: Alberto Cukier (SP) Director, Communications: Marcelo Alcantara Netherlands (EC) President, BTS Congress 2014: José Miguel Chatkin (RS) President Elect (2015/2016 biennium): Renato Maciel (MG) Chairman of the Board: Roberto Stirbulov (SP) AUDIT COMMITTEE: Active Members: Carlos Alberto Gomes dos Santos (ES), Clovis Botelho (MT), Maia Saul Davila Melo (SE) Alternates: Maurice Meireles Goes (MG), Angelo Ferreira da Silva (SC), Valeria Maria Augusto (MG) COORDINATORS, BTS DEPARTMENTS: Programmatic Initiatives - Alcindo Cerci Neto (PR) Thoracic Surgery - Roberto Saad Junior (SP) Sleep-disordered Breathing - Gleison Marinho Guimaraes (RJ) Respiratory Endoscopy - Viviane Rossi (SP) Pulmonary Function - John Mark Salge (SP) Imaging - Alexandre Dias Mançano Lung Diseases - Rimarcs Gomes Ferreira (SP) Clinical Research - Oliver Augusto Nascimento (SP) Pediatric Pulmonology - Paulo Cesar Kussek (PR) Residency - Alberto Cukier (SP) COORDINATORS, BTS SCIENTIFIC COMMITTEES: Asthma - Marcia Margareth Menezes Pizzichini (SC) Lung Cancer - Ilka Santoro Lopes (SP) Pulmonary Circulation - Daniel Waetge (RJ) Advanced Lung Disease - Valeria Maria Augusto (MG) Interstitial Diseases - Mariana Silva Lima (SP) Environmental and Occupational Respiratory Diseases - Albuquerque Hermano Castro (RJ) COPD - Fernando Luiz Cavalcanti Lundgren (EP) Epidemiology - Ricado Corrêa de Amorim (MG) Cystic Fibrosis - Marcelo Bicalho of Fuccio (MG) Respiratory Infections and Mycoses - Mara Rubia Fernandes de Figueiredo (EC) Pleura - Bernard H. Maranhão (RJ) International Relations - Musa Mauro Zamboni (RJ) Smoking - Luiz Carlos Corrêa da Silva (RS) Intensive Care - Augusto Farias Manoel de Carvalho (BA) Tuberculosis - Eliana Matos Dias (BA) ADMINISTRATIVE SECRETARIAT OF THE BRAZILIAN JOURNAL OF PULMONOLOGY Address: SCS Quadra 01, Bloco K, Asa Sul, salas 203/204. Edifício Denasa, CEP 70398-900, Brasília, DF, Brazil. Tel. +55 61 3245-1030/+55 0800 616218.

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Published once every two months J Bras Pneumol. v.39, number 2, p. 119-256 March/April 2013

EDITORIAL 119 - Endobronchial ultrasound: from lung cancer diagnosis and staging to translational research

Ultrassom endobrônquico: do diagnóstico e estadiamento do câncer de pulmão até a pesquisa translacional Juliana Guarize

ARTIGOS ORIGINAIS / ORIGINAL ARTICLES 121 - Relationship between exercise capacity and quality of life in adolescents with asthma

Relação da capacidade de exercício com a qualidade de vida de adolescentes asmáticos

Renata Pedrolongo Basso, Mauricio Jamami, Ivana Gonçalves Labadessa, Eloisa Maria Gatti Regueiro, Bruna Varanda Pessoa, Antônio Delfino de Oliveira Jr, Valéria Amorim Pires Di Lorenzo, Dirceu Costa 128 - Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes

Comparação temporal das prevalências de asma e rinite em adolescentes em Fortaleza, Brasil Maria de Fátima Gomes de Luna, Gilberto Bueno Fischer, João Rafael Gomes de Luna, Marcelo Gurgel Carlos da Silva, Paulo César de Almeida, Daniela Chiesa

138 - A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country

Sistema de suporte à decisão clínica para um programa para profilaxia de tromboembolia venosa em um hospital geral de um país de renda média Fernanda Fuzinatto, Fernando Starosta de Waldemar, André Wajner, Cesar Al Alam Elias, Juliana Fernándes Fernandez, João Luiz de Souza Hopf, Sergio Saldanha Menna Barreto

147 - Diferencias tomográficas y funcionales entre la EPOC severa relacionada con humo de leña y con cigarrillo

Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease Mauricio González-García, Dario Maldonado Gomez, Carlos A. Torres-Duque, Margarita Barrero, Claudia Jaramillo Villegas, Juan Manuel Pérez, Humberto Varon 155 - Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

Alterações tomográficas pulmonares em mulheres não fumantes com DPOC por exposição à fumaça da combustão de lenha

Maria Auxiliadora Carmo Moreira, Maria Alves Barbosa, Maria Conceição de Castro Antonelli Monteiro de Queiroz, Kim Ir Sen Santos Teixeira, Pedro Paulo Teixeira e Silva Torres, Pedro José de Santana Júnior, Marcelo Eustáquio Montadon Júnior, José Roberto Jardim 164 - Epidemiological aspects of respiratory symptoms treated in the emergency room of a tertiary care hospital

Perfil epidemiológico dos atendimentos de emergência por sintomas respiratórios em um hospital terciário Denise Rossato Silva, Vinícius Pellegrini Viana, Alice Mânica Müller, Ana Cláudia Coelho, Gracieli Nadalon Deponti, Fernando Pohlmann Livi, Paulo de Tarso Roth Dalcin

173 - Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats

Efeitos da metilprednisolona na atividade inflamatória e estresse oxidativo nos pulmões de ratos com morte cerebral Eduardo Sperb Pilla, Raôni Bins Pereira, Luiz Alberto Forgiarini Junior, Luiz Felipe Forgiarini, Artur de Oliveira Paludo, Jane Maria Ulbrich Kulczynski, Paulo Francisco Guerreiro Cardoso, Cristiano Feijó Andrade

181 - Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis

Contribuição da análise molecular do gene regulador da condutância transmembrana na fibrose cística na investigação diagnóstica de pacientes com suspeita de fibrose cística leve ou doença atípica Vinícius Buaes Dal’Maso, Lucas Mallmann, Marina Siebert, Laura Simon, Maria Luiza Saraiva-Pereira, Paulo de Tarso Roth Dalcin

190 - Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses

Valores de referência para o teste de caminhada com carga progressiva em indivíduos saudáveis: da distância percorrida às respostas fisiológicas Victor Zuniga Dourado, Ricardo Luís Fernandes Guerra, Suzana Erico Tanni, Letícia Cláudia de Oliveira Antunes, Irma Godoy

Published once every two months

J Bras Pneumol. v.39, number 2, p. 119-256 March/April 2013

198 - Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009

Mortalidade por doenças respiratórias em idosos após campanhas vacinais contra influenza no Distrito Federal, Brasil, 1996-2009

Francisca Magalhães Scoralick, Luciana Paganini Piazzolla, Liana Laura Pires, Cleudsom Neri, Wladimir Kummer de Paula 205 - Experimental study on the efficiency and safety of the manual hyperinflation maneuver as a secretion clearance technique

Estudo experimental sobre a eficiência e segurança da manobra de hiperinsuflação manual como técnica de remoção de secreção

Tatiana de Arruda Ortiz, Germano Forti, Márcia Souza Volpe, Carlos Roberto Ribeiro Carvalho, Marcelo Brito Passos Amato, Mauro Roberto Tucci 214 - Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil

Prevalência de infecção latente por Mycobacterium tuberculosis e risco de infecção em pacientes com insuficiência renal crônica em hemodiálise em um centro de referência no Brasil Jane Corrêa Fonseca, Waleska Teixeira Caiaffa, Mery Natali Silva Abreu, Katia de Paula Farah, Wânia da Silva Carvalho, Silvana Spindola de Miranda

COMUNICAÇÃO BREVE / BRIEF COMUNICATION 221 - Completeness of tuberculosis reporting forms in five Brazilian capitals with a high incidence of the disease

Completude das fichas de notificações de tuberculose em cinco capitais do Brasil com elevada incidência da doença Normeide Pedreira dos Santos, Monique Lírio, Louran Andrade Reis Passos, Juarez Pereira Dias, Afrânio Lineu Kritski, Bernardo Galvão-Castro, Maria Fernanda Rios Grassi

ARTIGO DE REVISÃO / REVIEW ARTICLE 226 - Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration

Estado atual e aplicabilidade clínica da punção aspirativa por agulha guiada por ultrassom endobrônquico Viviane Rossi Figueiredo, Márcia Jacomelli, Ascédio José Rodrigues, Mauro Canzian, Paulo Francisco Guerreiro Cardoso, Fábio Biscegli Jatene

RELATO DE CASO / CASE REPORT 238 - Pulmonary hypertension and pulmonary artery dissection

Dissecção da artéria pulmonar e hipertensão pulmonar

Ricardo de Amorim Corrêa, Luciana Cristina dos Santos Silva, Cláudia Juliana Rezende, Rodrigo Castro Bernardes, Tarciane Aline Prata, Henrique Lima Silva

CARTAS AO EDITOR / LETTER TO THE EDITOR 242 - Efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in evaluating lung cancer recurrence

Eficácia da tomografia por emissão de pósitrons com 18F fluordesoxiglicose com tomografia computadorizada na avaliação de recidiva de câncer de pulmão Nobuhiro Asai, Yoshihiro Ohkuni, Kazufusa Shoji, Norihiro Kaneko 245 - Impending paradoxical embolism across the interatrial septum

Embolia paradoxal iminente através do septo interatrial

Nilson Lopez Ruiz 248 - Whole-body magnetic resonance imaging for the evaluation of thoracic involvement in disseminated paracoccidioidomycosis

Ressonância magnética de corpo inteiro na avaliação do comprometimento torácico na paracoccidioidomicose disseminada Edson Marchiori, Elisa Carvalho Ferreira, Gláucia Zanetti, Bruno Hochhegger 251 - Successful thoracoscopic thymectomy in an infant

Timectomia toracoscópica bem sucedida em um lactente

Damian Palafox, Brenda Tello-López, Miguel Angel Vichido-Luna, Walid Leonardo Dajer-Fadel, José Palafox 254 - Underdiagnosis of respiratory diseases during an economic downturn and the need for spirometry as a screening test

Subdiagnóstico de doenças respiratórias durante uma desaceleração econômica e necessidade do uso da espirometria como teste de triagem Filio Kotrogianni, Foteini Malli, Konstantinos I Gourgoulianis 256 - Authors’ reply Maria Conceição de Castro Antonelli Monteiro de Queiroz, Maria Auxiliadora Carmo Moreira, Marcelo Fouad Rabahi

Editorial Endobronchial ultrasound: from lung cancer diagnosis and staging to translational research Ultrassom endobrônquico: do diagnóstico e estadiamento do câncer de pulmão até a pesquisa translacional

Juliana Guarize Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is probably the most important advance in thoracic diseases in the last decade. EBUS-TBNA was first applied for the diagnosis of lymph node metastasis in lung cancer patients. Thereafter, its indications quickly evolved, and the method is currently used for the diagnosis of many thoracic diseases, including sarcoidosis, thymomas, tuberculosis, lymphomas, and metastatic diseases.(1) In the oncological setting, EBUS-TBNA soon became a key tool in the evaluation of lung cancer patients. The uses of EBUS ranged from extended and bilateral mediastinal staging to the collection of specimens for molecular analyses—epidermal growth factor receptor (EGFR) mutations, KRAS mutations, and anaplastic lymphoma kinase (ALK) rearrangement—underpinning modern target therapy in lung cancer patients.(2) In the diagnosis of peripheral pulmonary nodules or ground-glass opacities, EBUS-radial probe has improved the diagnostic yield of transbronchial biopsies and dramatically reduced the number of CT-guided transthoracic fine needle aspiration biopsies and their associated complications.

Mediastinal staging is fundamental for the evaluation of resectable lung cancer and indicates the type of treatment (induction chemotherapy, surgery, or definitive chemotherapy/radiotherapy).

For many years, mediastinoscopy was the gold standard for mediastinal staging and was widely used in referral centers. Currently, EBUS-TBNA equals mediastinoscopy in terms of its sensitivity and specificity for the diagnosis of mediastinal lymph node metastasis, and EBUS-TBNA has all of the advantages of a minimally invasive procedure.(3) In 2011, we performed 79 mediastinoscopies for mediastinal staging of lung cancer patients.

In 2012, after the introduction of EBUS into our clinical practice, the number of mediastinoscopies dropped to 17, confirming the central role of EBUS-TBNA at a cancer referral center.

Rapid on-site evaluation (ROSE) and specimen handling are crucial to enhancing the diagnostic yield of EBUS-TBNA and to obtaining all mutational analyses in the final examination. (4) At our center, specimens are collected with a 22G dedicated needle (NA-201SX-4022; Olympus, Tokyo, Japan) and a small amount of material is smeared onto glass slides. Some of the slides are air-dried and stained immediately using MGG quick stain (Bio-Optica, Milan, Italy) so that the cytopathologist can immediately interpret and confirm the adequacy of cell specimens.

“Mirror” slides are alcohol-fixed for H&E staining.

Other needle passages and sustained material are fixed into a formalin-like solution in order to be processed as a cell block for histological evaluation.

In the last 15 months, we have performed 322 EBUS-TBNA procedures (EBUS Convex Probe BF-UC180F; Olympus). The overall sensitivity was 94.5%. The sensitivity among ROSE cases (n = 251) was 98.8%. Molecular analysis was possible in 62 of 71 cases of adenocarcinoma (87.3%). We found EGFR and KRAS mutations in 10 (16.1%) and 15 (24.2%) patients, respectively, whereas ALK rearrangement was detected (by fluorescence in situ hybridization) in 2 of the patients (3.2%).

These data show that the molecular analysis on samples obtained by EBUS-TBNA is feasible and can be incorporated into daily clinical practice.

The proportion of EGFR and KRAS mutations, as well as that of ALK rearrangements, corresponds to those reported in surgically resected specimens.

We have recently implemented a new protocol with EBUS-TBNA specimens for a whole-genome approach (DNA and RNA extraction) in order to identify novel markers of chemoresistance in stage IIIA pN2 non-small cell lung cancer.

In the preliminary phase of this translational research, the harvested samples underwent cell culture (epithelial cell cultures), and samples with little cellularity identified by ROSE did not grow in the culture. This finding confirms the importance of ROSE and the need for a new

J Bras Pneumol. 2013;39(2):119-120

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classification of specimen “adequacy�, taking into account different degrees of cellularity in air-dried smears.

In the current issue of the Brazilian Journal of Pulmonology, Figueiredo et al. published a comprehensive review on EBUS-TBNA. The authors discuss the main aspects, technique, feasibility, and expected results of the procedure.

They also describe the difficulties of using this new technology in Brazil, the extremely high cost of the procedure, and the need for the Brazilian Medical Association to establish a new classification system.(5) Economic concerns also afflict many centers in Europe. EBUS-TBNA is an expensive procedure, and many centers in Italy still use blinded TBNA, with all its limitations. Despite the high cost of EBUS-TBNA, the clear advantages of the procedure should encourage its use in referral centers worldwide. We hope that the spread of the technology will lower the cost of EBUSTBNA, making it available at many more centers.

Juliana Guarize M.D. Interventional Pulmonologist Division of Thoracic Surgery European Institute of Oncology Milan, Italy

J Bras Pneumol. 2013;39(2):119-120

References 1. Eapen GA, Shah AM, Lei X, Jimenez CA, Morice RC, Yarmus L, et al. Complications, Consequences, and Practice Patterns of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: Results of the AQuIRE Registry. Chest. 2012 Nov 1. doi: 10.1378/chest.12-0350.

[Epub ahead of print] 2. Nakajima T, Yasufuku K, Nakagawara A, Kimura H, Yoshino I. Multigene mutation analysis of metastatic lymph nodes in non-small cell lung cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2011;140(5):1319-24.

3. Yasufuku K, Pierre A, Darling G, de Perrot M, Waddell T, Johnston M, et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg. 2011;142(6):1393-400.

4. Nakajima T, Yasufuku K, Saegusa F, Fujiwara T, Sakairi Y, Hiroshima K, et al. Rapid On-Site Cytologic Evaluation During Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Nodal Staging in Patients With Lung Cancer. Ann Thorac Surg. 2012 Dec 12. pii: S00034975(12)02164-9. doi: 10.1016/j.athoracsur.2012.09.074.

[Epub ahead of print] 5. Figueiredo VR, Jacomelli M, Rodrigues AJ, Canzian M, Cardoso PF, Jatene FB. Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration. J Bras Pneumol.

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Original Article Relationship between exercise capacity and quality of life in adolescents with asthma* Relação da capacidade de exercício com a qualidade de vida de adolescentes asmáticos

Renata Pedrolongo Basso, Mauricio Jamami, Ivana Gonçalves Labadessa, Eloisa Maria Gatti Regueiro, Bruna Varanda Pessoa, Antônio Delfino de Oliveira Jr, Valéria Amorim Pires Di Lorenzo, Dirceu Costa

Abstract Objective: To determine whether the quality of life of adolescents with asthma correlates with parameters obtained prior to and after the six-minute step test (6MST); spirometric results after the 6MST; and level of physical activity. Methods: Nineteen adolescents with asthma, ranging from 11-15 years of age, were assessed with spirometry, 6MST, the International Physical Activity Questionnaire (IPAQ), the Pediatric Asthma Quality of Life Questionnaire (PAQLQ), and the 10-point Borg category-ratio scale. Results: Sensation of dyspnea correlated negatively with the total PAQLQ score (r = −0.54) and with the scores of its activity limitation (AL) and symptoms domains (r = −0.64 and r = −0.63, respectively), leg fatigue also correlating negatively with those same domains (r = −0.49 and r = −0.56, respectively). The total IPAQ score correlated with the total PAQLQ score (r = 0.47) and with the PAQLQ AL domain (r = 0.51); IPAQ time spent walking correlated with the PAQLQ symptoms domain (r = 0.45); and IPAQ time spent in vigorous activity correlated with the AL domain (r = 0.50).

In the regression analysis, only sensation of dyspnea remained significantly correlated with the total PAQLQ score and the PAQLQ AL domain; leg fatigue remained significantly correlated with the symptoms domain.

Conclusions: Higher levels of physical activity indicate better quality of life, as do lower perception of dyspnea and less leg fatigue. The 6MST proved to be a viable option for evaluating exercise capacity in adolescents with asthma, because it reflects the discomfort that asthma causes during activities of daily living.

Keywords: Asthma; Quality of life; Dyspnea.

Resumo Objetivo: Determinar se parâmetros obtidos antes e após a realização do teste do degrau de seis minutos (TD6), respostas espirométricas após o TD6 e o nível de atividade física se correlacionam com a qualidade de vida de adolescentes asmáticos. Métodos: Foram avaliados 19 adolescentes asmáticos, com idades variando de 11-15 anos, por meio de espirometria, TD6, International Physical Activity Questionnaire (IPAQ, Questionário Internacional de Atividade Física), Questionário sobre a Qualidade de Vida na Asma Pediátrica (QQVAP) e escala CR10 de Borg.

Resultados: Houve correlações negativas entre sensação de dispneia e pontuação total do QQVAP (r = −0,54) e de seus domínios limitação nas atividades (LA) e sintomas (r = −0,64 e r = −0,63, respectivamente), assim como entre fadiga nos membros inferiores (MMII) e os mesmos domínios (r = −0,49 e r = −0,56, respectivamente). O escore total do IPAQ correlacionou-se com a pontuação total do QQVAP (r = 0,47) e o domínio LA (r = 0,51), enquanto o tempo de caminhada correlacionou-se com o domínio sintomas (r = 0,45), e o tempo de atividade intensa correlacionou-se com o domínio LA (r = 0,50). Na análise de regressão, somente a sensação de dispneia associou-se significativamente ao escore total e o domínio limitação nas atividades do QQVAP, e o mesmo ocorreu entre a fadiga dos MMII e o domínio sintomas. Conclusões: Quanto maior for o nível de atividade física e menor for a dispneia e a fadiga nos MMII, melhor é a qualidade de vida. O TD6 mostrou-se uma opção na avaliação da capacidade ao exercício desses indivíduos por refletir o incômodo que a asma provoca na prática das atividades da vida diária.

Descritores: Asma; Qualidade de vida; Dispneia.

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

Correspondence to: Renata Pedrolongo Basso. Rodovia Washington Luiz, km 235, Laboratório de Espirometria e Fisioterapia Respiratória – DFisio, CEP 13565-905, São Carlos, SP, Brasil.

Tel. 55 16 3351-8343. E-mail: renata.fisio@gmail.com Financial support: This study received financial support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education).

Submitted: 13 September 2012. Accepted, after review: 16 November 2012.

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Basso RP, Jamami M, Labadessa IG, Regueiro EMG, Pessoa BV, Di Lorenzo VAP, Oliveira Jr AD, Costa D

Introduction Asthma is a chronic inflammatory disease that can have a considerable impact on the daily lives of adolescents.(1) Asthma is characterized by recurrent episodes of wheezing, chest tightness, breathlessness, and cough due to a variety of stimuli, the most common of which is physical exercise.(2,3) Exercise-induced bronchospasm (EIB) occurs in 40-90% of all individuals with asthma(3) and can reduce exercise tolerance, leading individuals with asthma to adopt a more sedentary lifestyle than that adopted by those without.(4) Asthma severity and reduced exercise capacity can affect the social, educational, and emotional lives of children and adolescents with asthma, the quality of life of such individuals being significantly worse than that of those without asthma.(5,6) Therefore, it is important to identify and address the factors affecting the quality of life of children and adolescents with asthma in order to provide comprehensive asthma treatment.(7) Clinical parameters such as symptoms, frequency of medication use, and airflow measurements are not strongly related to quality of life and therefore fail to provide a complete picture of how children and adolescents with asthma perceive the disease and of how asthma limits their activities of daily living.(7,8) Therefore, it important to determine whether objective measurements of exercise capacity reflect the impact of asthma on quality of life in order to evaluate such individuals more comprehensively and prescribe a rehabilitation program suited to their limitations and disease severity.

Various tests have been used in order to assess functional capacity in patients with lung disease.

(9-12) However, because submaximal exercise tests are safe, easy to apply, and readily available for routine clinical assessment and because they can predict the ability to perform activities of daily living,(13) submaximal exercise testing has been suggested as an option to evaluate asthma patients, given that it can detect EIB and aid in the early diagnosis of physical activity limitation.

(9,10) However, we found no studies evaluating whether submaximal exercise responses as elicited by a submaximal test such as the six-minute step test (6MST) reflect the impact of asthma on quality of life.

Therefore, the primary objective of the present study was to determine whether the quality of life of adolescents with asthma correlated with J Bras Pneumol. 2013;39(2):121-127

parameters obtained prior to and after the 6MST (i.e., physical performance, cardiorespiratory responses, sensation of dyspnea, and leg fatigue) and with spirometric results after the 6MST. A secondary objective was to determine whether the quality of life of those adolescents correlated with their level of physical activity.

Methods The present study was conducted between March and October of 2010 at the Federal University of São Carlos Respiratory Therapy Unit, located in the city of São Carlos, Brazil. We evaluated 19 adolescents with asthma who were recruited through active community surveillance and who were in the 11-15 year age bracket. The parents or legal guardians of the adolescents who participated in the present study gave written informed consent, and the study was approved by the local research ethics committee (Ruling no. 119/2008).

We included adolescents with a diagnosis of asthma (a clinical diagnosis, a spirometric diagnosis, or both), the diagnosis having been confirmed by pre- and post-bronchodilator spirometry performed under the supervision of a pulmonologist.(14) The participants were clinically stable, having had no respiratory infections or asthma attacks for at least three weeks. We excluded patients who were clinically unstable because of acute respiratory infections or asthma attacks in the three weeks preceding the evaluation, as well as those with other respiratory diseases, heart disease, rheumatic disease, musculoskeletal disease, orthopedic disease, or neurological sequelae that prevented them from performing the proposed tests.

Initially, the adolescents were interviewed.

During the interview, an anamnesis form and the short version of the International Physical Activity Questionnaire (IPAQ)(15) were completed in order to characterize the level of physical activity, the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)(16) being also completed.

Subsequently, the participants underwent general physical examination and respiratory system examination, as well as receiving instructions regarding the proposed protocol.

On the same day, the participants underwent spirometry with a portable spirometer (EasyOne™; ndd Medizintechnik AG, Zurich, Switzerland).

All technical procedures, acceptability criteria,

Relationship between exercise capacity and quality of life in adolescents with asthma

and reproducibility criteria were in accordance with the American Thoracic Society/European Respiratory Society guidelines.(17) We obtained three technically acceptable curves for slow vital capacity, FVC, and maximal voluntary ventilation.

The values obtained were compared with those proposed by Polgar & Promadhat.(18) For functional capacity evaluation, the 6MST was performed on a different day.

The 6MST was performed in accordance with methods described elsewhere.(19) At the end of every minute, standard phrases of encouragement were provided. At the end of every two minutes, SpO2 was measured with a pulse oximeter (Model 2500; Nonin Medical Inc., Minneapolis, MN, USA), HR was measured with an HR monitor (Model Vantage NV™ 1901001; Polar, Kempele, Finland), and sensation of dyspnea and leg fatigue were measured by the 10-point Borg categoryratio scale. Those measurements, together with measurements of systolic blood pressure, diastolic blood pressure, and RR, were performed at rest and immediately after the test, as well as at recovery minutes 1, 3, and 6.

In addition to the abovementioned measurements, FVC maneuvers were performed at various time points: before the test; immediately after the test; and within 5, 10, 15, and 30 minutes after the test, the better of two maneuvers being selected. The participants performed FVC maneuvers at post-test minutes 15 and 30 only if the FEV1 at post-test minute 10 decreased by ≥ 15% in comparison with the pre-test FEV1 value.

(9,20) Performance on the 6MST was determined by the total number of times that the individual being tested went up and down the step, and maximal HR (HRmax) was calculated by the following formula: HRmax = 210 − (0.65 × age in years).(21) For the present study, we chose to use the short version of the IPAQ, previously translated to Portuguese and validated for use in Brazil.(15) The questionnaire consists of 7 open questions, the answers to which provide information that allows us to estimate the weekly time spent in different activities. The questions address the duration and frequency of moderate to vigorous activities and the time spent walking in the previous week. On the basis of the information obtained, the IPAQ allows us to classify individuals as sedentary, insufficiently active, active, or very active.(15)

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We also used the Brazilian Portugueselanguage version of the PAQLQ, previously adapted and validated for use in Brazil.(16) The PAQLQ was developed for children and adolescents in the 7-17 year age bracket and consists of 23 questions distributed into three domains: symptoms, comprising 10 questions; activity limitation, comprising 5 questions; and emotional function, comprising 8 questions. Children are asked to report how they felt in the previous week and to answer each of the 23 questions on a 7-point scale (7 = not bothered at all and 1 = extremely bothered). The score for each of the PAQLQ domains is calculated by summing the scores for each question and dividing the sum by the total number of questions, the total PAQLQ score being calculated by summing the individual domain scores.

In the statistical analysis, we used the ShapiroWilk test in order to evaluate the normality of the data. In addition, we used descriptive statistics for variables with parametric distribution, the data being expressed as mean ± standard deviation, and for those with nonparametric distribution, the data being expressed as median (interquartile range). Subsequently, we used Pearson’s correlation coefficient (for variables with parametric distribution) or Spearman’s correlation coefficient (for variables with nonparametric distribution) and performed backward multiple linear regression analysis of correlated variables in order to find the independent variable determining quality of life, the PAQLQ scores being therefore considered dependent variables.

We used the Statistical Package for the Social Sciences, version 13.0 (SPSS Inc., Chicago, IL, USA). The power of the study was calculated using the GraphPad StatMate software, version 2.0 for Windows (GraphPad Software Inc., San Diego, CA, USA), and the sample corresponded to a power of 80% for the study variables, in accordance with a pilot study involving healthy adolescents. The level of significance was set at 5%.

Results We evaluated 19 asthma patients (15 boys and 4 girls), who were classified as having mild intermittent asthma or mild persistent asthma in accordance with the Global Initiative for Asthma criteria.(14) All of the patients were clinically stable.

Of the 19 patients with asthma, 5 were using J Bras Pneumol. 2013;39(2):121-127

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Basso RP, Jamami M, Labadessa IG, Regueiro EMG, Pessoa BV, Di Lorenzo VAP, Oliveira Jr AD, Costa D

inhaled corticosteroids regularly (mean dose, 200 µg) and 14 used a β2 agonist for symptom relief.

Table 1 shows the following: demographic, anthropometric, and spirometric data at baseline; the level of physical activity, as determined by the time (in min) spent walking, the time (in min) spent in moderate activity, the time (in min) spent in vigorous activity, and the total time spent in physical activity in the previous week; the scores for each PAQLQ domain; and the total PAQLQ scores. The level of physical activity in the study sample was determined on the basis of the answers to the IPAQ.(15) Of the 19 participants, 7 were classified as insufficiently active, 7 were classified as active, and 5 were classified as very active.

There were no significant differences between pre-test FEV1 and post-test FEV1 (as measured immediately after the test and at post-test minutes 5, 10, and 15), and post-test FEV1 did not decrease by ≥ 15% in comparison with pre-test FEV1, Table 1 - Demographic variables, anthropometric variables, spirometric variables, level of physical activity, and quality of life questionnaire scores for 19 adolescents with mild intermittent asthma or mild persistent asthma.a Variable Result Gender, M/F 15/4b Age, years 12.4 ± 1.4 Weight, kg 51.7 ± 14.1 Height, m 1.6 ± 0.1 2.5 ± 0.6 FEV1, L 87.5 ± 8.1 FEV1, % of predicted FVC, L 2.9 ± 0.6 FVC, % of predicted 93.2 ± 6.5 92.8 ± 7.5 FEV1/FVC, % MVV, L/min 77.9 ± 20.6 MVV, % of predicted 80.1 ± 13.9 Weekly time spent walking, min 40 (0-100)c Weekly time spent in moderate 30 (0-120)c activity, min Weekly time spent in vigorous 60 (0-180)c activity, min Total weekly time spent in 225 (90-420)c physical activity, min Total PAQLQ score 5.9 ± 1.0 Symptoms domain 5.8 ± 1.1 Activity limitation domain 5.8 ± 1.0 Emotional function domain 6.0 ± 1.0 MVV: maximal voluntary ventilation; and PAQLQ: Pediatric Asthma Quality of Life Questionnaire. aData expressed as mean ± SD, except where otherwise indicated. bData expressed as n/n. cData expressed as median (interquartile range).

J Bras Pneumol. 2013;39(2):121-127

which would have characterized EIB.(20) Of the 19 participants, 3 had to stop the 6MST for approximately 20 s, on average, because of leg fatigue, resuming the test.

Neither the total PAQLQ score nor the PAQLQ domain scores correlated with the total number of times that the individual being tested went up and down the step during the 6MST or with pre- or post-test RR, HR, systolic blood pressure, diastolic blood pressure, and FEV1. The values obtained at the end of the 6MST are shown in Table 2. Sensation of dyspnea correlated negatively with the total PAQLQ score and with the scores of the PAQLQ activity limitation and symptoms domains, leg fatigue also correlating negatively with those same domains (Table 3).

Regarding the impact of the level of physical activity on quality of life, we found that the time spent in physical activity correlated positively with the total PAQLQ score and the PAQLQ activity limitation domain. Likewise, the time spent walking correlated with the PAQLQ symptoms domain, and the time spent in vigorous activity correlated with the PAQLQ activity limitation domain (Table 3).

In the multiple regression analysis, only sensation of dyspnea remained significantly correlated with the total PAQLQ score (β = −0.27; p = 0.003) and the PAQLQ activity limitation domain (β = −0.33; p ≤ 0.001), sensation of dyspnea having explained 42% of the variation in the total PAQLQ score and 63% of the variation in the activity limitation domain score; leg fatigue remained significantly correlated with the PAQLQ symptoms domain (β = −0.22; p = 0.003), having Table 2 - Physical performance, sensation of dyspnea, leg fatigue, respiratory variables, and cardiovascular variables at the end of the six-minute step test.a Variable Value T-6MST 146.6 ± 30.4 97 (96-97) SpO2, % RR, breaths/min 21.0 ± 2.7 HR, bpm 148.5 ± 21.6 HRmax, % 73.0 ± 10.0 SBP, mmHg 120 (110-130) DBP, mmHg 70 (60-80) Borg scale (dyspnea) 2.0 (0.8-4.3) Borg scale (leg fatigue) 3.0 (1.0-4.3) T-6MST: total number of times that the individual being tested went up and down the step during the six-minute step test; HRmax: maximal HR; SBP: systolic blood pressure; and DBP: diastolic blood pressure. aData expressed as mean ± SD or median (interquartile range).

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Table 3 - Correlations of the quality of life questionnaire with the six-minute step test variables and with the level of physical activity.

PAQLQ Variable Total Symptoms AL EF Borg scale (dyspnea) −0.54* −0.63* −0.64* −0.39 Borg scale (leg fatigue) −0.41 −0.56* −0.49* −0.21 Weekly time spent walking, min 0.44 0.45* 0.37 0.34 Weekly time spent in moderate activity, min 0.22 0.08 0.22 0.17 Weekly time spent in vigorous activity, min 0.30 0.31 0.50* 0.05 Total weekly time spent in physical activity, min 0.47* 0.33 0.51* 0.38 PAQLQ: Pediatric Asthma Quality of Life Questionnaire; AL: activity limitation domain; and EF: emotional function domain. *p ≤ 0.05.

explained 37% of the variation in the symptoms domain score.

Discussion The objective of the present study was to determine whether the quality of life of adolescents with asthma correlated with physical performance, cardiorespiratory responses, sensation of dyspnea, leg fatigue, and spirometric results after the 6MST, as well as with the level of physical activity.

The 6MST has been used and recommended as a method for evaluating patients with lung disease.(12) Because it is a submaximal exercise test, the 6MST assesses functional capacity in terms of the ability to perform activities of daily living.(12,13) The 6MST was found to be a test of moderate intensity for the asthma patients in the present study, having allowed the participants to achieve 73% of their HRmax (Table 2) and having caused, on average, mild dyspnea and moderate leg fatigue or pain, although some of the participants experienced severe dyspnea and leg fatigue or pain.

In the present study, the 6MST was self-paced, meaning that the stepping rate did not remain constant throughout the test. Therefore, a high (> 80%) HR was not achieved or maintained throughout the test. This prevented the occurrence of EIB despite mouth breathing having contributed to turning the inhaled air drier and colder, which can cause EIB.(11,20) In one study,(9) a step test performed at an intensity that was sufficient to maintain an HR > 150 bpm for 5 min caused EIB. In the present study, however, the 6MST was selfpaced in order to be as functional as possible and reflect possible limitations in the ability to perform activities of daily living.

In the present study, we found no correlation between quality of life and cardiorespiratory

responses to the 6MST or between quality of life and spirometric results after the 6MST. This finding is consistent with those of studies showing a weak correlation between clinical variables and quality of life in asthma patients.(7,8) Such a weak correlation is due to the multifaceted nature of quality of life, which has physical, emotional, and social aspects and is therefore difficult to assess by means of objective parameters.

However, sensation of dyspnea and leg fatigue during the 6MST, which are subjective sensations, correlated with the symptoms domain score and the activity limitation domain score, dyspnea having also correlated with the total PAQLQ score. A more intense perception of dyspnea and a greater degree of leg fatigue during the 6MST translated to worse quality of life in our sample of adolescents with asthma.

It is of note that the questions on the quality of life questionnaire used in the present study refer to the previous week, and, because the study participants were clinically stable, the score was high for all domains, especially the emotional function domain. This result is consistent with those of a study showing that patients with controlled asthma have a better quality of life than do those with uncontrolled asthma.(22) However, although the mean score for the activity limitation domain and that for the symptoms domain were equal, the activity limitation domain showed the lowest scores; this constitutes evidence that the asthma patients had lower exercise tolerance, which affected their quality of life.(4-6) Studies have shown that physical activity improves the quality of life of asthma patients.

(23-25) Therefore, we quantified the level of physical activity and classified the adolescents under study in accordance with their level of physical activity, having subsequently determined whether the level of physical activity correlated with quality of life.

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None of the adolescents under study were classified as sedentary, most having been classified as active or insufficiently active.(15) This, together with the fact that the adolescents were clinically stable, might have contributed to the high scores obtained on the quality of life questionnaire. In addition, we found positive correlations between the time spent in physical activity and the score on the questionnaire, a finding that is consistent with those of studies(23-25) showing that physical activity is beneficial to the quality of life of asthma patients. However, our regression analysis showed that the weekly time spent in physical activity was not an independent predictor of quality of life, although sensation of dyspnea and leg fatigue were, underscoring the importance of functional assessment of asthma patients in order to evaluate their symptoms and limitations.

The correlations of sensation of dyspnea and leg fatigue with the PAQLQ variables, together with our regression analysis, showed that the sensation of dyspnea and leg fatigue reported at the end of the 6MST reflected the extent to which patients are bothered (term used in the PAQLQ) by asthma and its symptoms, such as cough, fatigue, breathlessness, and chest tightness, and the extent to which the disease limits their ability to perform activities of daily living. Our findings are also consistent with those of studies showing that sensation of dyspnea is one of the major factors limiting the ability of asthma patients to perform physical activity.(4,26) One limitation of the present study is the fact that the study sample consisted exclusively of adolescents with mild intermittent asthma or mild persistent asthma. Had we evaluated a more diverse sample of asthma patients, the results of the present study might be generalizable.

However, our results are important because those are the most prevalent types in the spectrum of asthma severity.

The quality of life of adolescents with mild intermittent asthma or mild persistent asthma correlates with the level of physical activity, as well as with sensation of dyspnea and leg fatigue during the 6MST. These subjective sensations reflect the extent to which asthma symptoms limit the ability of patients to perform moderate to vigorous activities of daily living, therefore reflecting the impact of asthma on the quality of life of adolescents. In addition, given the relationship between exercise capacity and

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quality of life and the importance of the latter for comprehensive asthma treatment, the 6MST is a viable option for evaluating exercise capacity in asthma patients in clinical practice.

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16. La Scala CS, Naspitz CK, Solé D. Adaptation and validation of the Pediatric Asthma Quality of Life Questionnaire

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(PAQLQ) in Brazilian asthmatic children and adolescents.

[Article in Portuguese] J Pediatr (Rio J). 2005;81(1):54-60.

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18. Polgar C, Promadhat V. Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia: Sanders; 1971.

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Sobre os autores Renata Pedrolongo Basso

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

Mauricio Jamami

Adjunct Professor. Graduate Course in Physical Therapy and Graduate Program in Physical Therapy, Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Ivana Gonçalves Labadessa

Master’s in Physical Therapy. Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Eloisa Maria Gatti Regueiro

Professor. Undergraduate and Graduate Courses in Physical Therapy, UNIFAFIBE University Center, Bebedouro, Brazil, and Claretian University Center, Batatais, Brazil.

Bruna Varanda Pessoa

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

Antônio Delfino de Oliveira Jr

Preceptor. Undergraduate Medical Course, Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Valéria Amorim Pires Di Lorenzo

Adjunct Professor. Graduate Course in Physical Therapy and Graduate Program in Physical Therapy, Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

Dirceu Costa

Professor. Graduate Course in Physical Therapy, Universidade Nove de Julho – UNINOVE, Nove de Julho University – São Paulo, Brazil, and Graduate Program in Physical Therapy, Universidade Federal de São Carlos – UFSCar, Federal University of São Carlos – São Carlos, Brazil.

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Original Article Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes* Comparação temporal das prevalências de asma e rinite em adolescentes em Fortaleza, Brasil

Maria de Fátima Gomes de Luna, Gilberto Bueno Fischer, João Rafael Gomes de Luna, Marcelo Gurgel Carlos da Silva, Paulo César de Almeida, Daniela Chiesa

Abstract Objective: To describe the prevalences of asthma and rhinitis in adolescents (13-14 years of age) in the city of Fortaleza, Brazil, in 2010, comparing the results with those obtained in a prevalence survey conducted in 20062007. Methods: This was a cross-sectional study involving probabilistic samples of 3,015 and 3,020 adolescents in surveys conducted in 2006-2007 and 2010, respectively. The International Study of Asthma and Allergies in Childhood protocol was used on both occasions. Results: Comparing the two periods, there were no significant differences regarding cumulative wheezing, active asthma, four or more wheezing attacks within the last year, sleep disturbed by wheezing more than one night per week, and speech-limiting wheezing. The prevalences of exercise-induced wheezing, dry cough at night, and physician-diagnosed asthma were significantly higher in 2010 than in the 2006-2007 period (p < 0.01 for all). The prevalence of physician-diagnosed rhinitis was significantly lower in 2010 (p = 0.01), whereas there were no significant differences between the two periods regarding cumulative rhinitis, current rhinitis, and rhinoconjunctivitis. In both periods, dry cough at night, current rhinitis, and rhinoconjunctivitis were significantly more prevalent in females than in males (p < 0.01 for all). Also in both periods, active asthma, current rhinitis, and rhinoconjunctivitis were more prevalent in private school students than in public school students (p < 0.01 for all). Conclusions: Our data show that the prevalences of asthma and rhinitis symptoms remain high among 13- and 14-year-olds in Fortaleza, predominantly among females and private school students.

Keywords: Asthma/epidemiology; Rhinitis/epidemiology; Adolescent.

Resumo Objetivo: Descrever as prevalências de asma e rinite em adolescentes de 13-14 anos de idade em Fortaleza (CE) em 2010 e compará-las com as prevalências obtidas em um inquérito em 2006-2007. Métodos: Estudo transversal envolvendo uma amostragem probabilística de 3.015 e 3.020 adolescentes, respectivamente, em 2006-2007 e 2010, utilizando o protocolo do International Study of Asthma and Allergies in Childhood. Resultados: Na comparação entre os dois períodos, não houve diferenças significativas em relação a sibilos cumulativos, asma ativa, quatro ou mais crises de sibilos no último ano, prejuízo do sono por sibilos > 1 noite/semana e crises limitando a fala. Em 2010, houve um aumento significativo na prevalência de sibilos após exercícios, tosse seca noturna e asma diagnosticada (p < 0,01 para todos). Em 2010, houve uma redução significativa na prevalência de rinite diagnosticada (p = 0,01), enquanto não houve diferenças significativas entre os dois períodos nas prevalências de rinite cumulativa, rinite atual e rinoconjuntivite. Em ambos os períodos, tosse seca noturna, rinite atual e rinoconjuntivite foram significativamente mais prevalentes nas mulheres que nos homens (p < 0,01 para todos). Também nos dois períodos, asma ativa, rinite atual e rinoconjuntivite foram significativamente mais prevalentes nos alunos das escolas particulares do que naqueles das escolas públicas (p < 0,01 para todos). Conclusões: Nossos dados mostram que as prevalências de sintomas de asma e rinite continuam altas entre os adolescentes de 13-14 anos em Fortaleza, com predomínio no gênero feminino e em alunos de escolas particulares.

Descritores: Asma/epidemiologia; Rinite/epidemiologia; Adolescente. * Study carried out at the Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Correspondence to: Maria de Fátima Gomes de Luna. Avenida Engenheiro Santana Júnior, 2977, Condomínio Flamboyant du Parc, apto. 401, CEP 60192-205, Fortaleza, CE, Brasil.

Tel. 55 85 3224-3423. E-mail: fatimaluna@terra.com.br 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; Mandate MCT/CNPq/CT-Saúde no. 54/2009 – Doenças Respiratórias na Infância [Respiratory Diseases in Childhood]).

Submitted: 22 August 2012. Accepted, after review: 4 March 2013.

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Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes

Introduction Asthma and rhinitis are chronic inflammatory airway diseases that affect most of the general population and that, in recent decades, have been increasing in prevalence in various parts of the world.(1-3) Although genetic factors are important, they alone cannot explain these increases in prevalence, and it is likely that the environment has greater relevance for the expression of these diseases.(4,5) In this sense, prevalence comparison across populations and over time can be an important source of new clues to understand these conditions.(6,7) The definition of asthma remains vague and inaccurate—given that its pathogenesis remains unclear—and this can hinder the identification of cases in epidemiological studies.(8) Therefore, in 1991, the International Study of Asthma and Allergies in Childhood (ISAAC) protocol was developed with the aim of maximizing the value of research on asthma and allergies in children and adolescents by enabling comparisons of prevalences of these diseases, as well as of their spatial and temporal trends, between populations in different countries and regions.(7) The objectives of the initial phase of the ISAAC (ISAAC phase I) were to describe the prevalence and severity of asthma, rhinitis, and eczema in children (6-7 years of age) and adolescents (13-14 years of age) living in different locations around the world, as well as to make comparisons within and between various countries and regions; to establish baseline values for the assessment of future trends in the prevalence and severity of these diseases; and to provide structure for future etiological studies on genetics, lifestyle, medical care, and environmental factors related to these diseases. Phase II of the ISAAC was aimed at investigating the relative importance of the hypotheses of interest that were raised in phase I by using objective markers, such as the methacholine challenge test; phase III sought to evaluate the trends in the prevalence of asthma, rhinitis, and eczema at the centers participating in phase I, as well as to include new centers that did not participate in phase I and to identify the possible factors related to these trends.(6,7) In ISAAC phase I, the prevalence of asthma symptoms in the last 12 months, considering the two age groups studied, ranged from 1.6% to 36.8%, and the prevalence of allergic rhinitis ranged from 1.4% to 39.7%.(9) More recently,

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the ISAAC phase III findings indicate that the international differences in the prevalence of asthma symptoms have diminished, particularly in the 13-14-year age group, the prevalence decreasing in English-speaking countries, as well as in Western Europe, and increasing in regions where it had previously been low. However, the reported increases in the prevalence of asthma symptoms in Africa, Latin America, and parts of Asia indicate that the global burden of asthma continues to increase.(10) In South America, the mean prevalences of asthma and rhinitis have increased, and there has been a reduction in the differences among centers.(11) In Brazil, the results for the participation of various cities in ISAAC phase III have confirmed the previously observed high prevalences of asthma and rhinitis.(12) In the state of Ceará, Brazil, no studies have yet been conducted in order to evaluate temporal changes in the prevalences of asthma and rhinitis. Therefore, the objective of the present study was to determine the prevalences of asthma and rhinitis in adolescents (13-14 years of age) in the city of Fortaleza, Brazil, in 2010, comparing the results with those obtained in another prevalence survey conducted in 20062007.(13,14)

Methods This was a cross-sectional population-based descriptive study involving public and private school students (13-14 years of age) that was carried out in the city of Fortaleza, Brazil, and comprised two surveys, one conducted in 20062007 and one conducted in 2010. The survey periods were from April to November of each year.

The city of Fortaleza is located on a coastal flat, immediately south of the Equator (between 3°30’S and 4°30’S), at an altitude of 15.49 m above sea level. The city encompasses an area of 4,667.8 km2 and has a population of 2,431,415.

(15) The annual mean temperature ranges from 26°C to 27°C.(16) The air quality is currently classified as fair, and the relative humidity is approximately 82%.(17) In the 2010 Census, 72.9% of the population had a monthly income of only two times the national minimum wage or less.(15) The city is divided into six administrative regions.(18) Among the schools located in those regions and enrolling 50 or more students in the age group of interest, 29 and 27 were randomly selected for analysis in the 2006-2007 period and J Bras Pneumol. 2013;39(2):128-137

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in 2010, respectively. An equal proportion of 13and 14-year-olds was selected from each region, thereby optimizing the representativeness of a sample drawn from a heterogeneous population.

In both surveys, data were collected with the asthma and rhinitis modules of the ISAAC written questionnaire, which have been validated for use in Brazil by Solé et al.(19) and Vanna et al.,(20) respectively. The questionnaires were completed by the adolescents themselves, in the classroom, in the presence of the principal researcher or one the research assistants, the latter having been duly trained by the former and specifically instructed to avoid offering explanations that could influence the responses. Each research assistant received a copy of the ISAAC manual, which describes the field study process in detail.

(6) Each school was visited at least twice in order to minimize the problems related to absenteeism and to optimize the response rate.

The ISAAC questionnaire consists of three modules—asthma, rhinitis, and eczema—and it is suggested that the sample size should be 3,000 subjects per age group.(6,7) We chose the 13-14-year age group because it allows greater ease of operation and high questionnaire return.

The ISAAC asthma module contains four questions on the occurrence of asthma symptoms: wheezing ever (cumulative wheezing); wheezing within the last 12 months (current wheezing or active asthma); exercise-induced wheezing; and dry cough at night in the absence of a cold or respiratory infection within the last 12 months.

In addition, this module contains three questions on symptom severity within the last 12 months: number of wheezing attacks; sleep disturbed by wheezing; and speech-limiting wheezing. There is also one question on physician-diagnosed asthma (asthma ever). Asthma was defined as presence of wheezing within the last 12 months. Individuals with severe asthma were defined as those who had had “four or more wheezing attacks”, “sleep disturbed by wheezing one or more nights per week”, or “speech-limiting wheezing”, or any combination of the three, within the last 12 months. This last question refers to episodes of severe acute asthma.(6,7) The ISAAC rhinitis module, which focuses on eliciting information about symptoms unrelated to influenza or colds, contains six questions related to the following(6,7): sneezing, rhinorrhea, or nasal obstruction ever (cumulative rhinitis); sneezing, J Bras Pneumol. 2013;39(2):128-137

rhinorrhea, or nasal obstruction within the last 12 months (current rhinitis or active rhinitis), used in order to identify adolescents with rhinitis; sneezing, rhinorrhea, or nasal obstruction accompanied by ocular symptoms (watery or itchy eyes) within the last 12 months, used in order to identify adolescents with rhinoconjunctivitis(7); month or months in which nasal problems occurred (not analyzed in the present study); rhinitis-related impairment of daily activities (which measures symptom morbidity/symptom severity), used in order to determine the degree of rhinitis—“severe rhinitis” was defined as choosing “severe” as the response to this question; and rhinitis ever, used in order to identify physician-diagnosed rhinitis.

Data were processed using the Statistical Package for the Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA). The frequencies of positive responses to the questions were obtained by considering the proportion of positive responses to each question in relation to the total number of valid questionnaires. The chi-square test was used in order to test the statistical significance of the comparisons between the results of the two surveys, as well as to analyze potential associations between the variables. The level of significance was set at p < 0.05 for all tests.

The study was approved by the Research Ethics Committee of the Ceará State University (Process no. 09554007-5, FR 31889).

Results In the first survey, conducted in 2006-2007, a total of 3,078 questionnaires were distributed to the adolescents, with a return rate of 98.9% and a response rate of 97.9%. Therefore, we obtained 3,015 valid questionnaires. In the second survey, conducted in 2010, a total of 3,120 questionnaires were distributed, with a return rate of 100% and a response rate of 96.8%, 3,020 valid questionnaires therefore having been obtained. The characteristics of the adolescents who completed the questionnaires correctly are described in Table 1, which shows that, in both surveys, there was greater participation by females.

The proportion of public schools in relation to that of private schools increased in the second survey.

Table 1 shows that the prevalences of exerciseinduced wheezing, dry cough at night, and physician-diagnosed asthma were significantly higher in the second survey than in the first survey

Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes

(p < 0.01 for all). However, the prevalences of physician-diagnosed rhinitis and severe rhinitis were significantly lower (p = 0.01 for both).

There was also a significant difference between the prevalence of active asthma and that of physician-diagnosed asthma, as well as between the prevalence of current rhinitis and that of physician-diagnosed rhinitis.

Table 2 shows that, in both surveys, most symptoms were more prevalent among private school students. The variables for which there were statistically significant differences by type of school (public or private) in the 2006-2007 period, and for which the differences remained statistically significant in 2010, are as follows:

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cumulative wheezing; active asthma; one to three wheezing attacks within the last 12 months; four or more wheezing attacks within the last 12 months; dry cough at night; physician-diagnosed asthma; cumulative rhinitis; current rhinitis; rhinoconjunctivitis; no rhinitis-related impairment of daily activities; and physician-diagnosed rhinitis.

In both periods, “exercise-induced wheezing” was found to be more common among private school students than among public school students, the difference being statistically significant in the 2006-2007 period (p = 0.03) and trending toward statistical significance in 2010 (p = 0.06).

The variable “sleep disturbed by wheezing one or more nights per week” was more common

Table 1 - Comparison of demographic data and prevalence of asthma and rhinitis symptoms in 13- and 14-year-olds between two surveys conducted in the city of Fortaleza, Brazil. 2006-2007 and 2010.

Period 2006-2007 2010 Variable p (n = 3,015) (n = 3,020) n % n % Age 13 years 1,575 52.2 1,614 53.4 0.34 14 years 1,440 47.8 1,406 46.6 School Public 2,165 71.8 2,559 84.7 < 0.01 Private 850 28.2 461 15.3 Gender Male 1,372 45.5 1,369 45.3 0.89 Female 1,643 54.5 1,651 54.7 Cumulative wheezing 1,329 44.1 1,326 44.5 0.74 Current wheezing (active asthma) 682 22.6 708 23.4 0.44 Number of attacks within the last 12 months 1-3 528 17.5 547 18.1 0.54 ≥4 68 2.3 83 2.7 0.22 Sleep disturbed by wheezing < 1 night per week 204 6.8 198 6.6 0.74 ≥ 1 night per week 105 3.5 106 3.5 0.95 Speech-limiting wheezing 105 3.5 109 3.6 0.79 Exercise-induced wheezing 759 25.2 855 28.8 < 0.01 Dry cough at night 1,036 34.4 1,136 37.9 < 0.01 Physician-diagnosed asthma 350 11.6 433 14.5 < 0.01 Cumulative rhinitis 1,710 56.7 1,688 57.1 0.78 Current or active rhinitis 1,303 43.2 1,279 42.4 0.49 Rhinoconjunctivitis (allergic rhinitis) 565 18.7 535 17.7 0.30 Rhinitis-related impairment of daily activities 19.5 0.47 None 567 18.8 590 Mild 581 19.3 582 19.3 0.99 Moderate 81 2.7 81 2.7 0.99 Severe 60 2.0 37 1.2 0.01 Physician-diagnosed rhinitis 609 20.2 520 17.6 0.01

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Table 2 - Distribution of the prevalence of asthma and rhinitis symptoms in 13- and 14-year-olds, of school, in two surveys conducted in the city of Fortaleza, Brazil. 2006-2007 and 2010.

2006-2007 2010 Total Public Private Total Public Private Symptom p (n = 3,015) (n = 2,165) (n = 850) (n = 3,020) (n = 2,559) (n = 461) % % % % n◦ n◦ n◦ % n◦ n◦ n◦ % Cumulative 1,329 44.1 907 41.9 422 49.6 < 0.01 1,326 44.5 1,071 42.4 255 56.3 wheezing Active asthma 682 22.6 442 20.4 240 28.2 < 0.01 708 23.4 548 21.4 160 34.7 Number of attacks within the last 12 months 1-3 528 17.5 334 15.4 194 22.8 < 0.01 547 18.1 424 16.6 123 26.7 ≥4 68 2.3 34 1.6 34 4.0 < 0.01 83 2.7 60 2.3 23 5.0 Sleep disturbed by wheezing < 1 night/week 204 6.8 140 6.5 64 7.5 0.29 198 6.6 162 6.3 36 7.8 ≥ 1 night/week 105 3.5 82 3.8 23 2.7 0.14 106 3.5 80 3.1 26 5.6 Speech-limiting 105 3.5 70 3.2 35 4.1 0.23 109 3.6 87 3.4 22 4.8 wheezing Exercise-induced 759 25.2 522 24.1 237 27.9 0.03 855 28.8 707 28.1 148 32.4 wheezing Dry cough at night 1,036 34.4 721 33.3 315 37.1 0.05 1.136 37.9 941 37.0 195 42.6 Physician350 11.6 220 10.2 130 15.3 < 0.01 433 14.5 353 13.9 80 17.5 diagnosed asthma Cumulative rhinitis 1,710 56.7 1.132 52.3 578 68.0 < 0.01 1,688 57.1 1,378 55.1 310 67.8 Current or active 1,303 43.2 822 38.0 481 56.6 < 0.01 1,279 42.4 1.021 39.9 258 56.0 rhinitis Rhinoconjunctivitis 565 18.7 336 15.5 229 26.9 < 0.01 535 17.7 417 16.3 118 25.6 Rhinitis-related impairment of daily activities None 567 18.8 314 14.5 253 29.8 < 0.01 590 19.5 454 17.7 136 29.5 Mild 581 19.3 404 18.7 177 20.8 0.17 582 19.3 480 18.8 102 22.1 Moderate 81 2.7 52 2.4 29 3.4 0.12 81 2.7 65 2.5 16 3.5 Severe 60 2.0 41 1.9 19 2.2 0.54 37 1.2 29 1.1 8 1.7 Physician609 20.2 326 15.1 283 33.3 < 0.01 520 17.6 365 14.6 155 33.9 diagnosed rhinitis

among private school students only in 2010 (p < 0.01).

Table 3 shows that, at both types of schools, the proportion of students reporting various asthma-related symptoms increased significantly from the first study period to the second.

Among public school students, there was also a temporal increase in the proportion of positive responses to the questions regarding “four or more attacks within the last 12 months” (p = 0.05), “exercise-induced wheezing” (p < 0.01), and “physician-diagnosed asthma” (p < 0.01). Among private school students, there was a significant

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by type

p

< 0.01 < 0.01

< 0.01 0.01

0.23 < 0.01 0.14 0.06 0.02 0.04 < 0.01 < 0.01 < 0.01

< 0.01 0.09 0.25 0.27 < 0.01

increase in the proportion of positive responses to the questions regarding “cumulative wheezing” (p = 0.02), “active asthma” (p = 0.01), and “sleep disturbed by wheezing one or more nights per week” (p < 0.01), as well as an increase trending toward significance in the proportion of positive responses to “exercise-induced wheezing” (p = 0.08). For the variable “dry cough at night”, there was a significant increase among public school students and private school students (p < 0.01 and p = 0.05, respectively).

For rhinitis symptoms, there were significant changes only among public school students.

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Table 3 - Comparison, by type of school, of temporal changes in the prevalence of asthma and rhinitis symptoms in 13- and 14-year-olds between two surveys conducted in the city of Fortaleza, Brazil. 20062007 and 2010.

Public Private 2006-2007 2010 2006-2007 2010 Symptom p p % % % % n◦ n◦ n◦ n◦ Cumulative wheezing 907 41.9 1,071 42.4 0.73 422 49.6 255 56.3 0.02 Active asthma 442 20.4 548 21.4 0.40 240 28.2 160 34.7 0.01 Number of attacks within the last 12 months 1-3 334 15.4 424 16.6 0.28 194 22.8 123 26.7 0.11 ≥4 34 1.6 60 2.3 0.05 34 4.0 23 5.0 0.40 Sleep disturbed by wheezing < 1 night/week 140 6.5 162 6.3 0.84 64 7.5 36 7.8 0.85 ≥ 1 night/week 82 3.8 80 3.1 0.21 23 2.7 26 5.6 < 0.01 Speech-limiting wheezing 70 3.2 87 3.4 0.75 35 4.1 22 4.8 0.57 Exercise-induced wheezing 522 24.1 707 28.1 < 0.01 237 27.9 148 32.4 0.08 Dry cough at night 721 33.3 941 37.0 < 0.01 315 37.1 195 42.6 0.05 Physician diagnosed asthma 220 10.2 353 13.9 < 0.01 130 15.3 80 17.5 0.29 1,378 55.1 0.05 578 68.0 310 67.8 0.95 Cumulative rhinitis 1,132 52.3 Current or active rhinitis 822 38.0 1,021 39.9 0.17 481 56.6 258 56.0 0.82 Rhinoconjunctivitis 336 15.5 417 16.3 0.46 229 26.9 118 25.6 0.59 Rhinitis-related impairment of daily activities None 314 14.5 454 17.7 < 0.01 253 29.8 136 29.5 0.92 Mild 404 18.7 480 18.8 0.93 177 20.8 102 22.1 0.58 Moderate 52 2.4 65 2.5 0.76 29 3.4 16 3.5 0.95 Severe 41 1.9 29 1.1 0.03 19 2.2 8 1.7 0.54 Physician-diagnosed rhinitis 326 15.1 365 14.6 0.66 283 33.3 155 33.9 0.82

Among these students, there were increases in the prevalence of cumulative rhinitis (p = 0.05) and in the proportion of the response “no rhinitisrelated impairment of daily activities” (p < 0.01), whereas there was a significant decrease in the prevalence of severe rhinitis (p = 0.03). There was no significant reduction in the prevalence of physician-diagnosed rhinitis at either type of school (Table 3).

In both surveys, various asthma and rhinitis symptoms were found to be more common among females than among males (Table 4). The variables for which gender-related differences were statistically significant in the two surveys were as follows: cumulative wheezing; sleep disturbed by wheezing less than one night per week; dry cough at night; cumulative rhinitis; current rhinitis; rhinoconjunctivitis; mild rhinitis-related impairment of daily activities; and physiciandiagnosed rhinitis. The variables “active asthma”, “one to three wheezing attacks within the last 12 months”, and “no or moderate rhinitis-related

impairment of daily activities” were found to be more common among females only in the 2006-2007 period (p < 0.01 for all), whereas the variable “exercise-induced wheezing” (p = 0.01) was found to be more common among females only in 2010.

Discussion Questionnaires have been the most widely used instruments in epidemiological surveys, because of their ease of use, low cost, and good acceptability, as well as because they can be self-administered, eliminating interviewer bias, and are considered to be relatively independent of climatic factors. In the ISAAC questionnaire, most questions limit the investigation to the last 12 months in order to reduce memory errors and not to interfere with the month of the study.

However, a concern that arises in questionnairebased surveys is whether the study population is able to understand the questions and provide appropriate responses. To facilitate this process, J Bras Pneumol. 2013;39(2):128-137

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Table 4 - Distribution of the prevalence of asthma and rhinitis symptoms in 13- and 14-year-olds, by gender, in two surveys conducted in the city of Fortaleza, Brazil. 2006-2007 and 2010.

2006/2007 2010 Total Male Female Total Male Female Symptom p p (n = 3,015) (n = 1,372) (n = 1,643) (n = 3,020) (n = 1,369) (n = 1,651) % % % % % % n◦ n◦ n◦ n◦ n◦ n◦ Cumulative 1,329 44.1 561 40.9 768 46.7 < 0.01 1,326 44.5 554 41.1 772 47.3 < 0.01 wheezing Active asthma 682 22.6 275 20.0 407 24.8 < 0.01 708 23.4 303 22.1 405 24.5 0.48 Number of attacks within the last 12 months 1-3 528 17.5 206 15.0 322 19.6 < 0.01 547 18.1 235 17.2 312 18.9 0.21 ≥4 68 2.3 29 2.1 39 2.4 0.63 83 2.7 31 2.3 52 3.1 0.13 Sleep disturbed by wheezing 146 8.9 < 0.01 198 6.6 74 5.4 124 7.5 0.02 < 1 night/week 204 6.8 58 4.2 ≥ 1 night/week 105 3.5 39 2.8 66 4.0 0.08 106 3.5 39 2.8 67 4.1 0.07 Speech-limiting 105 3.5 40 2.9 65 4.0 0.12 109 3.6 46 3.4 63 3.8 0.50 wheezing Exercise-induced 759 25.2 343 25.0 416 25.3 0.84 855 28.8 357 26.1 498 30.2 0.01 wheezing Dry cough at night 1,036 34.4 376 27.4 660 40.2 < 0.01 1,136 37.9 424 31.0 712 43.1 < 0.01 Physician350 11.6 168 12.2 182 11.1 0.31 433 14.5 199 14.5 234 14.2 0.77 diagnosed asthma Cumulative rhinitis 1,710 56.7 676 49.3 1,034 62.9 < 0.01 1,688 57.1 678 49.5 1010 61.2 < 0.01 Current or active 1,303 43.2 494 36.0 809 49.2 < 0.01 1,279 42.4 498 36.4 781 47.3 < 0.01 rhinitis Rhinoconjunctivitis 565 18.7 193 14.1 372 22.6 < 0.01 535 17.7 185 13.5 350 21.2 < 0.01 Rhinitis-related impairment of daily activities None 567 18.8 48 3.5 93 5.7 < 0.01 590 19.5 253 18.5 337 20.4 0.18 Mild 581 19.3 223 16.3 358 21.8 < 0.01 582 19.3 201 14.7 381 23.1 < 0.01 Moderate 81 2.7 25 1.8 56 3.4 < 0.01 81 2.7 39 2.8 42 2.5 0.60 Severe 60 2.0 23 1.7 37 2.3 0.26 37 1.2 13 0.9 24 1.5 0.21 Physician609 20.2 241 17.6 368 22.4 < 0.01 520 17.6 214 15.6 306 18.5 0.03 diagnosed rhinitis

the ISAAC questionnaire consists of objective, well-defined, and easy-to-understand questions.

The ISAAC questionnaire has been validated for use in several countries and is used worldwide, allowing valid comparisons among different cities and countries in terms of the prevalences of asthma and allergies.(6,7,21,22) The prevalences of asthma symptoms and rhinitis symptoms were high in both of our surveys. Although there was an increase in the proportion of public school students who had lower frequencies of asthma symptoms in both surveys, there was a clear increase in the frequencies of exercise-induced wheezing and dry cough at night in the study population as a whole. A

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comparison of the two survey results by type of school, indicating an increase in the frequencies of some symptoms in one group but not in the other, showed that the frequencies of dry cough at night and exercise-induced wheezing increased in the two groups. It is of note that the lower proportional representation of private school students might have decreased the statistical power of our study to demonstrate an increase in the frequency of exercise-induced wheezing in this group, an increase that trended toward statistical significance.

The frequencies of exercise-induced wheezing and dry cough at night also increased in a similar comparative study conducted in the city of Recife,

Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes

Brazil.(22) The findings of the present study are also in accordance with those of the ISAAC phase III, in which the most significant changes were in the mean frequencies of exercise-induced wheezing (an increase of 0.15% per year) and dry cough at night (an increase of 0.51% per year). In that phase, there were small mixed changes in the prevalence of asthma symptoms, but, at most centers, increases were twice as common as were decreases. For instance, the rates of exercise-induced wheezing decreased in the eastern Mediterranean region, on the Indian subcontinent, and in Oceania, whereas they increased in the other regions of the world.(10) The factors involved in the differences in these asthma prevalence trends have yet to be fully elucidated. Environmental aspects associated with the lifestyle of populations and families, such as exposure to allergens, family density, sedentary habits, obesity, socioeconomic status, eating habits, early exposure to infections, etc., have been reported to be highly relevant for explaining these differences and can offer interesting opportunities for prevention.(4,5,23) Underdiagnosis of asthma and rhinitis, which was observed in the two surveys, has also been reported in other studies.(24-26) The responses to the questions “Have you ever had asthma?” and “Have you ever had rhinitis?” depend on whether teenagers recognize these diseases, which, in turn, depends on how their symptoms are perceived by their families, their level of access to the heath care system, the perception of the attending physician in their case, and their level of disease-related morbidity.(22) A previous study found that, as the degree of morbidity decreased, the number of adolescents who did not categorize themselves as having asthma increased.(14) In contrast, the increase in physician-diagnosed asthma observed in our second survey indicates better recognition of the problem by this population or even increased acceptance of the term “asthma”, which contributes to more cases being treated. Corroborating this possibility, our more recent survey showed that the prevalences of the various degrees of asthma severity remained stable, although the prevalences of other symptoms increased.

The frequencies of most rhinitis symptoms remained similar or identical to those previously recorded, suggesting that the prevalence of this disease has reached its peak among these adolescents living in the city of Fortaleza. Some

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studies have demonstrated a parallel increase in the prevalences of asthma and rhinitis, whereas others have not.(25) In the ISAAC phase III, no consistent global temporal trend was identified in the prevalence of rhinoconjunctivitis among children.(26,27) The reduction in the frequency of physiciandiagnosed rhinitis can be attributed to the increase in the proportion of public school students in the second survey, given that, in both surveys, the frequency of this variable was more than twice as high among private school students as among public school students. Corroborating this finding, there was no significant variation in the frequency of physician-diagnosed rhinitis among students attending the same type of school. These data are in accordance with those found for the city of Recife, Brazil, where the prevalence of asthma observed in 2002 was lower than was that reported in a study conducted in 1994-1995, a reduction that was also attributed to an increase in the proportion of public school students in the second survey.(22) Regarding the reduction in the frequency of severe rhinitis, it is supposed that if more cases of asthma are being treated, as presumed on the basis of the increase in the frequency of physician-diagnosed asthma, this could, to some extent, cause a reduction in rhinitis severity, given that patients might be receiving concomitant treatment for rhinitis and given the fact that, by treating asthma, it is possible to relieve rhinitis symptoms. These diseases have similar inflammatory mechanisms and often coexist in the same patient. There are similarities between the nasal and bronchial mucosa, and one of the most important concepts about nose-lung interactions is that there is a functional systemic link between the upper and lower airways.(25) In addition, among public school students, there was an improvement in the perception of milder symptoms of the disease—represented by the increase in the frequency of the response “no rhinitis-related impairment of daily activities”—and this might be contributing to more cases being treated and to a consequent decrease in the frequency of severe cases, a decrease that was found to be significant in this particular group.

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confirms the findings of the first survey and has been previously discussed.(28) In conclusion, the results of our second survey, conducted in 2010, confirm the high prevalences of asthma, rhinitis, and symptoms previously observed in this age group, revealing an increase in the frequency of exercise-induced wheezing and dry cough at night. Underdiagnosis of asthma and rhinitis remains evident, although there was an increase in the frequency of physician-diagnosed asthma and a reduction in the frequency of severe rhinitis. In addition, the present study confirms the predominance of females and private school students among the adolescents reporting symptoms of these diseases. Finally, the present study shows, for the first time, a comparison of the prevalences of asthma and rhinitis between two different periods in the city of Fortaleza, reporting current and relevant data that serve to alert health administrators and planners of the essential need to invest in the quality of primary care focused on the prevention and control of these diseases.

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11. Chong Neto HJ, Rosário NA, Solé D; Latin American ISAAC Group. Asthma and Rhinitis in South America: How Different They are From Other Parts of the World.

Allergy Asthma Immunol Res. 2012;4(2):62-7.

12. Solé D, Wandalsen GF, Camelo-Nunes IC, Naspitz CK; ISAAC - Brazilian Group. Prevalence of symptoms of asthma, rhinitis, and atopic eczema among Brazilian children and adolescents identified by the International Study of Asthma and Allergies in Childhood (ISAAC) Phase 3. J Pediatr (Rio J). 2006:82(5):341-6.

13. Luna MF, Almeida PC, Silva MG. Prevalência de sintomas de rinite em adolescentes de 13 e 14 anos avaliada pelo método ISAAC, na cidade de Fortaleza. Rev Bras Alergia Imunopatol. 2009;32(3):106-11.

14. de Luna Mde F, Almeida PC, Silva MG. Prevalence of asthma among adolescents in the city of Fortaleza, Brazil. J Bras Pneumol. 2009;35(11):1060-7.

15. Instituto Brasileiro de Geografia e Estatística. [homepage on the Internet]. Brasília: Ministério do Planejamento, Orçamento e Gestão [cited 2011 Jan 11]. Censo 2010.

Available from: http://www.censo2010.ibge.gov.br 16. Fundação Cearense de Meteorologia e Recursos Hídricos. [homepage on the Internet]. Fortaleza: Governo do Estado do Ceará. [cited 2011 Apr 17]. Available from: http://www.funceme.br 17. Superintendência Estadual do Meio Ambiente – SEMACE [homepage on the Internet]. Fortaleza: Governo do Estado do Ceará. [cited 2011 Apr 17]. Available from: http://www.semace.ce.gov.br/ 18. Prefeitura de Fortaleza. [homepage on the Internet].

Fortaleza: Prefeitura de Fortaleza. [cited 2010 Mar 02].

Available from: http://www.fortaleza.ce.gov.br 19. Solé D, Vanna AT, Yamada E, Rizzo MC, Naspitz CK. International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire: validation of the asthma component among Brazilian children. J Investig Allergol Clin Immunol. 1998;8(6):376-82.

20. Vanna AT, Yamada E, Arruda LK, Naspitz CK, Solé D. International Study of Asthma and Allergies in Childhood: validation of the rhinitis symptom questionnaire and prevalence of rhinitis in schoolchildren in São Paulo, Brazil. Pediatr Allergy Immunol. 2001;12(2):95-101.

21. Solé D. The International Study of Asthma and Allergies in Childhood (ISAAC): what have we learned? J Bras Pneumol. 2005;31(2):93-4.

22. Pizzichini MM. Defining asthma for epidemiologic studies: can this objective be attained? J Bras Pneumol.

2005;31(6):vi-viii.

23. Mitchell EA, Beasley R, Björkstén B, Crane J, GarcíaMarcos L, Keil U, et al. The association between BMI, vigorous physical activity and television viewing and the risk of symptoms of asthma, rhinoconjunctivitis and eczema in children and adolescents: ISAAC Phase Three. Clin Exp Allergy. 2013;43(1):73-84.

24. Britto MC, Bezerra PG, Brito RC, Rego JC, Burity EF, Alves JG. Asthma in schoolchildren from Recife, Brazil.

Prevalence comparison: 1994-95 and 2002 [Article in Portuguese]. J Pediatr (Rio J). 2004;80(5):391-400.

Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes

25. Jucá SC, Takano OA, Moraes LS, Guimarães LV. Asthma prevalence and risk factors in adolescents 13 to 14 years of age in Cuiabá, Mato Grosso State, Brazil [Article in Portuguese]. Cad Saude Publica. 2012;28(4):689-97.

26. Toledo MF, Rozov T, Leone C. Prevalence of asthma and allergies in 13- to 14-year-old adolescents and the frequency of risk factors in carriers of current asthma in Taubaté, São Paulo, Brazil. Allergol Immunopathol (Madr). 2011;39(5):284-90.

27. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).

Allergy. 2008;63 Suppl 86:8-160.

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28. Björkstén B, Clayton T, Ellwood P, Stewart A, Strachan D; ISAAC Phase III Study Group. Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood. Pediatr Allergy Immunol. 2008;19(2):110-24.

29. Aït-Khaled N, Pearce N, Anderson HR, Ellwood P, Montefort S, Shah J, et al. Global map of the prevalence of symptoms of rhinoconjunctivitis in children: The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three. Allergy. 2009;64(1):123-48.

30. Luna Mde F, Almeida PC, Silva MG. Asthma and rhinitis prevalence and co-morbidity in 13-14-year-old schoolchildren in the city of Fortaleza, Ceará State, Brazil [Article in Portuguese]. Cad Saude Publica.

2011;27(1):103-12.

About the authors Maria de Fátima Gomes de Luna

Pediatrician and Clinical Director. Children’s Hospital of Fortaleza, Fortaleza, Brazil.

Gilberto Bueno Fischer

Professor. Department of Respiratory Diseases, Graduate Program in Pulmonology, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

João Rafael Gomes de Luna

Medical Student. Universidade Federal do Ceará – UFC, Federal University of Ceará – School of Medicine, Fortaleza, Brazil.

Marcelo Gurgel Carlos da Silva

Professor. Universidade Estadual do Ceará – UECE, Ceará State University – Fortaleza, Brazil.

Paulo César de Almeida

Professor. Universidade Estadual do Ceará – UECE, Ceará State University – Fortaleza, Brazil.

Daniela Chiesa

Professor. University of Fortaleza – UNIFOR – Fortaleza, Brazil.

J Bras Pneumol. 2013;39(2):128-137

Original Article A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country*,** Sistema de suporte à decisão clínica para um programa para profilaxia de tromboembolia venosa em um hospital geral de um país de renda média

Fernanda Fuzinatto, Fernando Starosta de Waldemar, André Wajner, Cesar Al Alam Elias, Juliana Fernándes Fernandez, João Luiz de Souza Hopf, Sergio Saldanha Menna Barreto

Abstract Objective: To determine the impact that implementing a combination of a computer-based clinical decision support system and a program of training seminars has on the use of appropriate prophylaxis for venous thromboembolism (VTE). Methods: We conducted a cross-sectional study in two phases (prior to and after the implementation of the new VTE prophylaxis protocol) in order to evaluate the impact that the combined strategy had on the use of appropriate VTE prophylaxis. The study was conducted at Nossa Senhora da Conceição Hospital, a general hospital in the city of Porto Alegre, Brazil. We included clinical and surgical patients over 18 years of age who were hospitalized for ≥ 48 h. The pre-implementation and post-implementation phase samples comprised 262 and 261 patients, respectively. Results: The baseline characteristics of the two samples were similar, including the distribution of patients by risk level. Comparing the pre-implementation and post-implementation periods, we found that the overall use of appropriate VTE prophylaxis increased from 46.2% to 57.9% (p = 0.01). Looking at specific patient populations, we observed that the use of appropriate VTE prophylaxis increased more dramatically among cancer patients (from 18.1% to 44.1%; p = 0.002) and among patients with three or more risk factors (from 25.0% to 42.9%; p = 0.008), two populations that benefit most from prophylaxis. Conclusions: It is possible to increase the use of appropriate VTE prophylaxis in economically constrained settings through the use of a computerized protocol adhered to by trained professionals. The underutilization of prophylaxis continues to be a major problem, indicative of the need for ongoing improvement in the quality of inpatient care.

Keywords: Venous thrombosis/prevention & control; Venous thromboembolism/prevention & control; Heparin/therapeutic use.

Resumo Objetivo: Determinar o impacto da implantação de um sistema informatizado de suporte à decisão clínica combinado com seminários instrucionais na utilização de profilaxia para tromboembolia venosa (TEV) de forma adequada. Métodos: Estudo transversal em duas fases (antes e depois da implantação de um novo protocolo de profilaxia para TEV) para avaliar o impacto que a estratégia combinada teve na utilização adequada da profilaxia para TEV. O estudo foi conduzido no Hospital Nossa Senhora da Conceição, um hospital geral localizado em Porto Alegre (RS). Foram incluídos pacientes clínicos e cirúrgicos com mais de 18 anos com tempo de hospitalização ≥48 h. Nas fases pré e pós-implantação, foram incluídos 262 e 261 pacientes, respectivamente.

Resultados: As características de base das duas amostras foram semelhantes, inclusive em relação à distribuição dos pacientes por nível de risco. Comparando-se os períodos pré e pós-implantação, verificou-se que a adequação da profilaxia para TEV aumentou de 46,2% para 57,9% (p = 0,01). Ao se observar populações específicas de pacientes, o uso adequado da profilaxia para TVE aumentou dramaticamente em pacientes com câncer (de 18,1% para 44,1%; p = 0,002) e em pacientes com três ou mais fatores de risco (de 25,0% para 42,9%; p = 0,008), populações essas que mais se beneficiam da profilaxia. Conclusões: É possível aumentar o uso de profilaxia adequada para TEV em cenários economicamente desfavoráveis através do uso de protocolos informatizados e de profissionais treinados. A subutilização da profilaxia permanece como um problema importante, destacando a necessidade da melhora continuada na qualidade da assistência hospitalar.

Descritores: Trombose venosa/prevenção & controle; Tromboembolia venosa/prevenção & controle; Heparina/uso terapêutico. * Study carried out at the Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil.

Correspondence to: Fernanda Fuzinatto. Hospital Nossa Senhora da Conceição, Serviço de Medicina Interna. Avenida Francisco Trein, 596, Cristo Redentor, CEP 91350-200, Porto Alegre, RS, Brasil.

Tel. 55 51 3357-2000. E-mail: ferfuzi@hotmail.com Financial support: None.

Submitted: 21 October 2012. Accepted, after review: 7 January 2013. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2013;39(2):138-146

A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country

Introduction Venous thromboembolism (VTE) comprises two related conditions—deep-vein thrombosis and pulmonary embolism—and is responsible for a great number of complications in hospitalized patients. Pulmonary embolism accounts for 5-10% of all deaths in hospitalized patients, making VTE the most common preventable cause of in-hospital death.(1,2) Prevention is the most effective strategy to reduce the burden of VTE. There is considerable evidence that primary prophylaxis with heparin significantly reduces the incidence of VTE without increasing the risk of major bleeding. (3,4) In addition, VTE prophylaxis has proven to be cost effective, reducing treatment costs and shortening hospital stays.(5) Over the last decade, several guidelines aimed at improving preventive strategies and increasing their use have been published.(5-7) Although the majority of medical and surgical inpatients have multiple risk factors for VTE, large prospective studies have demonstrated that methods of preventing VTE are underutilized. (8,9) In a multinational cross-sectional study, the proportion of hospital patients at risk for VTE ranged from 36% to 73% and the proportion of patients receiving VTE prophylaxis ranged from 2% to 84%.(10) This illustrates the difficulty of translating into practice knowledge disseminated in the literature. This situation has also stimulated new research to identify possible obstacles that limit the effectiveness of VTE prevention measures and to evaluate strategies to implement changes.(11) Passive strategies and isolated measures, such as the distribution of guidelines and protocols or the staging of one-time trainings, have little impact on practices, whereas the use of multiple strategies with tools that work at the various stages of knowledge dissemination has been shown to be highly effective.(5,12,13) Computer-based clinical decision support systems (CDSSs) and computer reminders are currently in use as strategies to improve the quality of healthcare and have been especially effective for VTE prophylaxis.(14) The objective of the present study was to evaluate the effects that a combined strategy of implementing a CDSS and organizing training seminars has on the use of appropriate VTE prophylaxis. We hypothesized that real-time presentation of VTE prophylaxis guidelines

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through a CDSS would increase the proportion of patients receiving appropriate prophylaxis.

Methods We devised a strategy for improving VTE prophylaxis that involved the creation of a CDSS and the organization of training seminars. We conducted a cross-sectional study in two phases (prior to and after the implementation of the new strategy) in order to assess the proportion of patients receiving appropriate VTE prophylaxis.

The study was conducted at the Nossa Senhora da Conceição Hospital, which is located in the city of Porto Alegre, Brazil, and is the largest general hospital in the southern region of the country. The hospital is affiliated with the Brazilian National Ministry of Health and provides treatment only via the Brazilian Unified Health Care System. It is a teaching hospital, with 750 adult inpatient beds available for use in a number of medical and surgical specialties, except for orthopedics, trauma, and neurosurgery.

In August of 2008, a group of physicians from the internal medicine department was given the challenge of developing a VTE prevention protocol. The group created a protocol, adapted from existing guidelines, to guide the prescription of VTE prophylaxis. The consensus guidelines of the American College of Chest Physicians, published in June of 2008,(5) was selected as the primary source of recommendations for the protocol to be implemented.

We reviewed the current evidence in order to clarify areas of concern, such as major risk factors, contraindications, prophylaxis in post-stroke patients, cancer, and some types of surgery. To incorporate new evidence, we searched the Medline and Cochrane databases, as well as meeting with teams of internists and other specialists to discuss articles pertaining to their practice. To launch the protocol recommendations, physicians from all departments of the hospital were invited to attend a final consensus meeting.

The VTE prevention protocol established risk factors, heparin contraindications, and appropriate prophylaxis measures in accordance with patient risk of VTE. We adopted a model that could be easily followed by the prescribing physician, using a CDSS in which VTE risk was stratified into three levels. Each level of VTE risk was linked to a menu of acceptable prophylaxis options (Chart 1). The protocol did not include trauma, J Bras Pneumol. 2013;39(2):138-146

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Fuzinatto F, Waldemar FS, Wajner A, Elias CAA, Fernandez JF, Hopf JLS

neurosurgery, or orthopedic patients. In addition, we excluded pregnant and postpartum women.

At our hospital, unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH, enoxaparin) are available for VTE prophylaxis.

Because of the higher cost of LMWH, only UFH was included in the VTE prevention protocol, given that UFH is the therapeutic equivalent of LMWH in terms of efficacy and safety in the general medical and surgical population.(5) We estimated that, assuming a 50% prevalence of appropriate prophylaxis in the first phase of the study, two samples of at least 227 patients each would be needed in order to detect differences of at least 15% in that prevalence between the two periods with sufficient precision (two-tailed alpha = 0.05 and beta = 0.10).

In the first phase of the study, conducted between April and July of 2009 (prior to the implementation of the VTE prevention protocol), the patient sample comprised 262 patients, whereas that of the second phase of the study, conducted between December of 2009 and February of 2010 (after the implementation of the protocol), comprised 261 patients. In both phases, the data were collected by six residents in internal medicine, previously trained in the appropriate techniques, who reviewed patient charts and prescription forms in order to obtain the pertinent data. No attending physicians were informed of the study.

We used a two-stage approach in order to implement the strategies and integrate the VTE prevention protocol as a mandatory electronic CDSS. First, one-hour seminars were held to present the protocol, emphasizing the importance of prophylaxis and its indications, as well as to explain how the CDSS would work. Residents and attending physicians from the various medical specialties were invited to attend. The protocol established was then included as a standardized VTE prevention module interfaced with the electronic medical records entry system of the hospital.

The standardized VTE prevention module was activated automatically at the second access of the electronic medical record after an admission or transfer between units, the first access typically being made by the admitting (staff) physician and the second access being by the attending physician. Physicians were prompted to select a VTE risk level for each patient, according to the predetermined risk profiles (Chart 1), and to determine whether there were any contraindications to pharmacologic prophylaxis. When the risk level was selected, the recommended dose of UFH was automatically added to the electronic prescription for that patient. In patients with contraindications, UFH was not included in the prescription and the standardized VTE prevention module was automatically activated every 48 hours in order to identify the persistence or resolution

Chart 1 - Venous thromboembolism prophylaxis protocol.

Risk Level Characteristics Postoperative period following minor surgerya in patients who are not bedridden Low Postoperative period following laparoscopic surgery in patients without risk factors No acute disease or bedridden status in medical patients Postoperative period following major surgery Postoperative period following laparoscopic surgery in patients with risk factors Moderate Acute disease in medical patients Bedridden status and risk factors in medical patients Postoperative period following major surgery in patients with multiple (3 or more) risk factors Postoperative period following bariatric surgery High Postoperative period following major cancer surgery Medical patients with multiple risk factors (3 or more), active cancer, thrombophilia or previous venous thromboembolism episode. a

Prophylaxis

Early ambulation

Unfractionated heparin, 5,000 IU subcutaneously every 12 h

Unfractionated heparin, 5,000 IU subcutaneously every 8 h

Procedures that do not involve the opening of large cavities, risk of severe hemorrhage, or extensive dissections.

J Bras Pneumol. 2013;39(2):138-146

A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country

of the contraindication. The physician could also choose not to use prophylaxis in patients on anticoagulation. Physicians who chose not to follow the protocol recommendations were required to fill out a form justifying that choice.

The main outcome measure was an increase in the proportion of patients receiving appropriate VTE prophylaxis, comparing the pre-implementation and post-implementation periods. In both phases, patients were randomly selected from among those admitted to the medical or surgical wards, including the ICU. Randomization was performed by drawing bed numbers, with the number of beds used in each specialty proportional to the ratio between the number of beds available to that specialty and the total number of beds in the hospital. The inclusion criteria were being over 18 years of age and having been hospitalized for ≥ 48 h on any of the wards. The exclusion criteria were current anticoagulation, pregnancy, puerperium, and a history of acute thromboembolic disease.

The main variables studied, the risk factors, and the contraindications are cited in a previously published article.(15) Each prescription was classified as appropriate or inappropriate on the basis of whether it followed the protocol, after considering the patient risk of VTE and the presence of contraindications to heparin. Two of the authors assessed the appropriateness of prophylaxis, and questionable cases were discussed by the research group as a whole.

Patients were stratified by medical or surgical ward and by the risk of VTE (low, medium, or high). The absolute difference in the proportion of patients receiving appropriate VTE prophylaxis between the two periods and the 95% confidence interval for that difference were calculated for each stratum. Comparisons between the two periods in terms of the clinical characteristics of the patients were tested using the chi-square test or t-test, as appropriate. The analysis included all eligible patients. Values of p < 0.05 were considered statistically significant. All data were analyzed using the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA), and WINPEPI, version 11.4 (http:// www.brixtonhealth.com/pepi4windows.html).

The study was approved by the Research Ethics Committee of the Nossa Senhora da Conceição Hospital, and all of the authors signed a data use agreement.

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Results Except for a few risk factors, the baseline characteristics of the patients were similar in the two phases of the study (Table 1). The distribution of the patients by risk level was also similar between the two phases. In the first and second phases, respectively, 21.4% and 20.3% of patients were postoperative patients, those having undergone major surgery accounting for 66% and 45%, respectively.

Nearly all of the patients included in the study were classified as being at moderate or high risk of VTE (43.4% and 55.4%, respectively).

The main contraindications were coagulopathy, active bleeding, and active peptic ulcer disease.

No other contraindications were identified.

Comparing the pre-implementation and post-implementation data, we found that the use of appropriate VTE prophylaxis increased from 46.2% to 57.9% (Table 2). The absolute difference between the two study periods was 11.7% (95% CI: 3.2% to 20.3%), which was statistically significant (p = 0.01).

In cancer patients, the use of appropriate VTE prophylaxis increased from 18.1% in the pre-implementation phase of the study to 44.1% in the post-implementation phase (absolute difference, 26%; 95% CI: 9.9% to 42.3%; p = 0.002). As can be seen in Table 2, a significant increase was also observed in patients with multiple risk factors (from 25.0% to 42.9%; absolute difference, 17.9%; 95% CI: 4.8-30.9%; p = 0.008). In addition, there was a post-implementation increase in the use of appropriate VTE prophylaxis in patients at high risk of VTE (Table 3). Among surgical patients in the postoperative period (defined as those who had undergone a surgical procedure in the last 30 days), there was a small post-implementation increase in the use of appropriate VTE prophylaxis (from 53.6% to 60.4%), which was not statistically significant (absolute difference, 6.8%; 95% CI: −13.6% to 27.2%; p = 0.6). However, among medical patients, there was a significant improvement (from 44.2% to 57.2%; absolute difference, 13%; 95% CI: 3.0% to 23.1%; p = 0.011).

Discussion Our study demonstrates that the implementation of a CDSS accompanied by training seminars had a positive effect on the J Bras Pneumol. 2013;39(2):138-146

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Table 1 - Characteristics of the patients included in the two phases of the study.

Phase 2b Phase 1a Characteristic (n = 262) (n = 261) Age, mean ± SD 59.1 ± 16.6 52.2 ± 17.1 Male gender, n (%) 137 (52.3) 138 (52.9) Postoperative patients, n (%) 56 (21.4) 53 (20.3) Major specialties, n (%) Internal medicine 58 (22.1) 51 (19.5) Medical specialties 102 (38.9) 110 (42.1) General surgery 35 (13.4) 37 (14.2) Surgical specialties 50 (19.1) 50 (19.2) Gynecology 17 (6.5) 13 (5) VTE risk, n (%) High 143 (54.6) 147 (56.3) Moderate 117 (44.7) 110 (42.1) Low 2 (0.8) 4 (1.5) Risk factors, n (%) Immobilization 185 (70.6) 219 (83.9) Infection 116 (44.3) 136 (52.1) Active cancer 72 (27.5) 68 (26.1) Use of a central venous catheter 35 (13.4) 56 (21.5) Major surgery 37 (14.1) 24 (9.2) Severe lung disease 20 (7.6) 25 (9.6) Heart failure 21 (8) 23 (8.8) Acute myocardial infarction 22 (8.4) 8 (3.1) Stroke 13 (5) 24 (9.2) Limb paralysis/paresis 21 (8) 21 (8) ICU admission 16 (6.1) 17 (6.5) Obesity 45 (17.2) 27 (10.3) BMI 30-35 kg/m2 16 (6.1) 17 (6.5) BMI > 35 kg/m2 Chemotherapy/radiotherapy 7 (2.7) 14 (5.4) History of VTE 3 (1.1) 11 (4.2) Use of oral contraceptives 3 (1.1) 3 (1.1) Use of hormone replacement therapy 2 (0.8) 3 (1.1) Myeloproliferative disease 5 (1.9) 1 (0.4) Inflammatory bowel disease 0 (0) 2 (0.8) Contraindications, n (%) Coagulopathy 10 (3.8) 17 (6.5) Active peptic ulcer disease 2 (0.8) 0 (0) Active bleeding 13 (5) 8 (3.1)

p 0.539 0.963 0.847 0.855

0.626

< 0.0001* 0.88 0.787 0.020* 0.105 0.524 0.864 0.015* 0.86 1 0.991 0.032* 0.991 0.179 0.57 1 0.686 0.216 0.249 0.232 0.499 0.378

VTE: venous thromboembolism; and BMI: body mass index. aFrom April through July of 2009 (prior to the implementation of the VTE prevention protocol). bFrom December of 2009 through February of 2010 (after the implementation of the VTE prevention protocol). *< 0.05 (statistically significant).

practices of physicians, increasing the proportion of patients receiving appropriate prophylaxis for VTE. Our samples were representative of the risk profile of the patients seen at our hospital, most of whom are classified as being at moderate to high risk of VTE, underscoring the need to implement J Bras Pneumol. 2013;39(2):138-146

measures to improve VTE prophylaxis. Neither sample included patients classified as being at very high risk of VTE (orthopedic, neurosurgery, and trauma patients), because such patients are not treated at our hospital. Most of the patients admitted to our hospital are referred from emergency rooms, which leaves few beds

A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country

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Table 2 - Use of appropriate venous thromboembolism prophylaxis in the two phases of the study.

Phase 1a Phase 2b Difference Category All patients Patients with cancer Patients with 3 or more risk factors

N

Total

121 13 26

262 72 104

%

N

Total

%

46.2 18.1 25

151 30 51

261 63 119

57.9 44.1 42.9

Absolute (%) 11.7 26 17.9

95% CI

p

3.2-20.3 9.9-42.3 4.8-30.9

0.01* 0.002* 0.008*

From April through July of 2009 (prior to the implementation of the venous thromboembolism prevention protocol).

From December of 2009 through February of 2010 (after the implementation of the venous thromboembolism prevention protocol). *< 0.05 (statistically significant). a

b

Table 3 - Use of appropriate venous thromboembolism prophylaxis according to patient risk level.

Phase 1 (Before) Phase 2 (After) Difference VTE risk High Moderate Low

N 32 88 1

Total 143 117 2

%

N

Total

%

22.4 75.2 50

63 85 3

147 110 4

42.9 77.3 75

Absolute % 20.5 2.1 25

95% CI

p

9.3 to 31.7 0.0001* â&#x2C6;&#x2019;9.9 to 14.0 0.835 â&#x2C6;&#x2019;93.0 to 100.0 1

VTE: venous thromboembolism. *< 0.05 (statistically significant).

available for elective admissions. This explains the low number of low-risk patients in our samples. The increase in the use of appropriate VTE prophylaxis was most pronounced among patients with cancer and among patients with three or more VTE risk factors, populations that benefit the most from such prophylaxis.

Various health advocacy groups have recommended measures of prophylaxis for VTE. Such recommendations include evaluating VTE risk for every patient at admission and regularly during hospitalization, especially after transfer to the ICU.(16) Considering these recommendations, the CDSS created in our hospital is automatically activated at the second access of the electronic medical record after an admission or transfer between units (i.e., the first access by the attending physician). In addition, it is triggered whenever it detects that heparin has not been prescribed.

There are studies currently underway that are aimed at identifying the characteristics that make a protocol effective. Protocols for VTE prophylaxis should consider many aspects of the decision-making process: VTE risk factors; the primary illness (cause of hospitalization); patient immobilization; and the type of surgery the patient is scheduled to undergo. Considering these aspects, protocols should include many features and yet must keep things efficient

and simple enough for everyday use. Possible errors include listing options for VTE prophylaxis without providing any guidance about which choice is most appropriate or desirable, as well as supplying too much information, making the protocol too complicated. Some order sets offer four to six levels of VTE risk, but the evidence to distinguish the levels of risk, as well as the differences among the types of prophylaxis, is often weak. Two to three levels of VTE risk are sufficient.(17) Another possible error is to offer non-pharmacologic VTE prophylaxis as a firstline option in patients without contraindications to pharmacological methods.

In the creation of our protocol, we considered all these possible errors and built a concise tool that allows physicians to make a quick decision. In addition, because risk level and contraindications change frequently in acutely ill patients, a link to the protocol was permanently available in the electronic record for re-evaluation. When contraindications were reported, the protocol was automatically triggered for reassessment within 48 h.

Several studies have attempted to demonstrate the improvement in the appropriateness of VTE prophylaxis after implementation of various strategies. In a randomized controlled trial involving 6,371 hospitalized patients, the use of

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electronic alerts has increased the use of heparin from 18.9% to 32.2%.(18) In a French study of orthopedic patients, the use of electronic alerts increased the adherence to guidelines from 82.8% to 94.9%.(19) Kucher et al. demonstrated that the application of a CDSS reduces the rates of deep vein thrombosis and pulmonary embolism.(20) To our knowledge, ours is the first study to report testing the effects of a CDSS for VTE prophylaxis in a middle-income country. In Brazil, studies conducted in the cities of SĂŁo Paulo(21) and Salvador(22) showed that the distribution of written guidelines for physicians was not effective in increasing adherence to prophylactic measures.

A meta-analysis that evaluated the effectiveness of different strategies to increase adherence to prophylactic measures for VTE also showed that passive measures, such as the distribution of guidelines, were ineffective.(13) The authors of that study found that the use of multiple strategies is more effective than is that of either strategy in isolation. Among the studies evaluated in that meta-analysis, there were five that had rates of adherence to guidelines of more than 90%. All five of those studies utilized interactive processes of audit and feedback, as well as incorporating warning systems as reminders of VTE risk assessment.(13) Kawamoto et al. identified characteristics of systems that are predictive of effective decision support: generating decision support automatically as part of the normal clinical workflow, at the time and place of decision making; using computers to deliver support; and offering specific recommendations rather than mere assessments. The authors found that 94% of CDSSs presenting those characteristics were successful in improving physician practices.(12) Our strategy involved the use of UFH for two main reasons. First, patients at very high risk of VTE, for whom the evidence of LMWH superiority is more robust, are not admitted to our hospital. Second, although economic analyses have marginally favored the use of enoxaparin,(23,24) there have been no similar analyses of VTE prevention in the context presented hereâ&#x20AC;&#x201D;only studies addressing the treatment of an established thromboembolism.(25) Our local evaluations, focusing on hospital costs, support the use of UFH, mainly due to considerable differences in terms of drug acquisition costs.

Our study has several limitations. The major limitation is inherent in the observational design J Bras Pneumol. 2013;39(2):138-146

and the lack of a control population. We studied two populations sequentially, and it is therefore possible that some unrecognized temporal trend biased our results. We cannot exclude hidden confounding factors. Data were obtained from reviews of patient charts, making it difficult to control for differences in data collection.

In addition, we evaluated the effects of the implementation of the protocol only in terms of the proportional use of appropriate VTE prophylaxis and did not evaluate patient outcomes. However, some authors now consider it preferable to evaluate processes rather than outcomes when assessing quality of care.(26) Although the use of a CDSS increases the use of appropriate VTE prophylaxis, it is still far from optimal. Even with a simple and quick tool, the erroneous evaluation of the risk factors and contraindications can lead the physician to misclassify the level of the patient risk and make an inappropriate choice regarding the prophylaxis.

Another major limitation of our study is the fact that we used a protocol that was developed locally from the current guidelines and was not validated prospectively. In the literature, there are many models to assess VTE risk, most of which have yet to be validated and are complex. (27) Maynard et al. recently published a study validating a model of risk stratification for VTE.(28) The authors demonstrated that a simple model with three levels of risk, implemented through a CDSS, accompanied by educational measures, audit, and feedback, increased the use of appropriate VTE prophylaxis from 58% to 98% over a three-year period and reduced the number of thromboembolic events occurring at the hospital under study.(28) The results of our study show that it is possible to increase the use of appropriate VTE prophylaxis at a general hospital in a middleincome country by implementing a CDSS and by educating the hospital staff. The same CDSS might be useful at other institutions, if the software were adapted to local conditions. Our findings suggest that other hospitals in Brazil should consider implementing a CDSS to increase the use of VTE prophylaxis, given that studies evaluating the use of non-computerized protocols have shown that such protocols provide no benefit.(21,22) The underutilization of VTE prophylaxis remains a major problem. Although the strategy employed in the present study produced significant results, it is still less than ideal and calls for ongoing

A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country

staff training, as well as constant improvement of the CDSS.

Acknowledgments We would like to thank Dr. Paulo Bobek for providing continuous institutional support for this endeavor. We also thank Marco Antonio Fish and his team at our medical information technology office; Dr. Airton Stein for support from the hospital board of teaching and research; and the residents who participated at the outset of the project: Juliana Ferro Schuh, Grasiele Bess, and Josiane França.

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BMJ. 1991;302(6778):709-11.

2. Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis? J R Soc Med. 1989;82(4):203-5.

3. Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med. 2007;146(4):278-88.

4. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin.

Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;318(18):1162-73.

5. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):381S-453S. 6. Scottish Intercollegiate Guidelines Network [homepage on the Internet]. Edinburgh: Scottish Intercollegiate Guidelines Network. [cited 2010 Dec 10]. Prevention and management of venous thromboembolism. [Adobe Acrobat document, 97p.]. Available from: http://www. sign.ac.uk/pdf/sign122.pdf 7. Institute for Clinical Systems Improvement [homepage on the Internet]. Bloomington: Institute for Clinical Systems Improvement. [cited 2003 Nov 30]. Health Care Guideline: Venous Thromboembolism Prophylaxis. [Adobe Acrobat document, 53p.] Available from: https://www. icsi.org/_asset/ht2bhd/VTEProphy-Interactive1112.pdf 8. Deheinzelin D, Braga AL, Martins LC, Martins MA, Hernandez A, Yoshida WB, et al. Incorrect use of thromboprophylaxis for venous thromboembolism in medical and surgical patients: results of a multicentric, observational and cross-sectional study in Brazil. J Thromb Haemost. 2006;4(6):1266-70.

9. Tapson VF, Decousus H, Pini M, Chong BH, Froehlich JB, Monreal M, et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest. 2007;132(3):936-45.

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10. Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study.

Lancet. 2008;371(9610):387-94.

11. Bero LA, Grilli R, Grimshaw JM, Harvey E, Oxman AD, Thomson MA. Closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings. The Cochrane Effective Practice and Organization of Care Review Group. BMJ. 1998;317(7156):465-8.

12. Kawamoto K, Houlihan CA, Balas EA, Lobach DF. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ. 2005;330(7494):765.

13. Tooher R, Middleton P, Pham C, Fitridge R, Rowe S, Babidge W, et al. A systematic review of strategies to improve prophylaxis for venous thromboembolism in hospitals. Ann Surg. 2005;241(3):397-415.

14. Hunt DL, Haynes RB, Hanna SE, Smith K. Effects of computer-based clinical decision support systems on physician performance and patient outcomes: a systematic review. JAMA. 1998;280(15):1339-46.

15. Fuzinatto F, Wajner A, Waldemar FS, Hopf JL, Schuh JF, Barreto SS. Venous thromboembolism prophylaxis in a general hospital. J Bras Pneumol. 2011;37(2):160-7.

16. National Quality Forum [homepage on the Internet].

Washington: National Quality Forum. [cited 2008 Aug 1].

National Voluntary Consensus Standards for Prevention and Care of Venous Thromboembolism: Additional Performance Measures. A consensus Report. 2008. Available from : http://www.qualityforum.org/Publications/2008/10/ National_Voluntary_Consensus_Standards_for_Prevention_ and_Care_of_Venous_Thromboembolism__Additional_ Performance_Measures.aspx 17. Maynard G, Stein J. Designing and implementing effective venous thromboembolism prevention protocols: lessons from collaborative efforts. J Thromb Thrombolysis.

2010;29(2):159-66.

18. Dexter PR, Perkins S, Overhage JM, Maharry K, Kohler RB, McDonald CJ. A computerized reminder system to increase the use of preventive care for hospitalized patients. N Engl J Med. 2001;345(13):965-70.

19. Durieux P, Nizard R, Ravaud P, Mounier N, Lepage E. A clinical decision support system for prevention of venous thromboembolism: effect on physician behavior. JAMA. 2000;283(21):2816-21.

20. Kucher N, Koo S, Quiroz R, Cooper JM, Paterno MD, Soukonnikov B, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352(10):969-77.

21. Maffei FH, Sato AC, Torggler Filho F, Silva SC, Atallah A. Effect of the implementation of a guideline for venous thromboembolism prophylaxis in surgical patients [Article in Portuguese]. Rev Assoc Med Bras. 2009;55(5):587-92.

22. Rocha AT, Paiva EF, AraĂşjo DM, Cardoso DN, Pereira AC, Lopes AA, et al. Impact of a program for venous thromboembolism prophylaxis in hospitalized patients in four hospitals in Salvador [Article in Portuguese].

Rev Assoc Med Bras. 2010;56(2):197-203.

23. Deitelzweig SB, Becker R, Lin J, Benner J. Comparison of the two-year outcomes and costs of prophylaxis in medical patients at risk of venous thromboembolism.

Thromb Haemost. 2008;100(5):810-20.

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24. Leykum L, Pugh J, Diuguid D, Papadopoulos K. Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient. J Hosp Med. 2006;1(3):168-76.

25. Argenta C, Ferreira MA, Sander GB, Moreira LB. Shortterm therapy with enoxaparin or unfractionated heparin for venous thromboembolism in hospitalized patients: utilization study and cost-minimization analysis. Value Health. 2011;14(5 Suppl 1):S89-92.

26. Davies HT, Crombie IK. Assessing the quality of care.

BMJ. 1995;311(7008):766.

27. Caprini JA. Risk assessment as a guide for the prevention of the many faces of venous thromboembolism. Am J Surg. 2010;199(1 Suppl):S3-10.

28. Maynard GA, Morris TA, Jenkins IH, Stone S, Lee J, Renvall M, et al. Optimizing prevention of hospitalacquired venous thromboembolism (VTE): prospective validation of a VTE risk assessment model. J Hosp Med. 2010;5(1):10-8.

About the authors Fernanda Fuzinatto

Preceptor for the Internal Medicine Residency Program. Nossa Senhora da Conceição Hospital and Porto Alegre Hospital de Clínicas, Porto Alegre, Brazil.

Fernando Starosta de Waldemar

Physician Head of Quality Improvement Projects. Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil.

André Wajner

Preceptor for the Internal Medicine Residency Program. Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil.

Cesar Al Alam Elias

Internist. Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil.

Juliana Fernándes Fernandez

Internist. Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil.

João Luiz de Souza Hopf

Internist. Nossa Senhora da Conceição Hospital, Porto Alegre, Brazil.

Sergio Saldanha Menna Barreto

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

J Bras Pneumol. 2013;39(2):138-146

Original Article Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease* Diferencias tomográficas y funcionales entre la EPOC severa relacionada con humo de leña y con cigarrillo

Mauricio González-García, Dario Maldonado Gomez, Carlos A. Torres-Duque, Margarita Barrero, Claudia Jaramillo Villegas, Juan Manuel Pérez, Humberto Varon

Abstract Objective: Wood smoke exposure is a risk factor for COPD. For a given degree of airway obstruction, the reduction in DLCO is smaller in individuals with wood smoke-related COPD than in those with smoking-related COPD, suggesting that there is less emphysema in the former. The objective of this study was to compare HRCT findings between women with wood smoke-related COPD and women with smoking-related COPD. Methods: Twenty-two women with severe COPD (FEV1/FVC ratio < 70% and FEV1 < 50%) were divided into two groups: those with wood smoke-related COPD (n = 12) and those with smoking-related COPD (n = 10).

The two groups were compared regarding emphysema scores and airway involvement (as determined by HRCT); and functional abnormalities—spirometry results, DLCO, alveolar volume (VA), the DLCO/VA ratio, lung volumes, and specific airway resistance (sRaw). Results: There were no significant differences between the two groups in terms of FEV1, sRaw, or lung hyperinflation. Decreases in DLCO and in the DLCO/VA ratio were greater in the smoking-related COPD group subjects, who also had higher emphysema scores, in comparison with the wood smoke-related COPD group subjects. In the wood smoke-related COPD group, HRCT scans showed no significant emphysema, the main findings being peribronchial thickening, bronchial dilation, and subsegmental atelectasis. Conclusions: Female patients with severe wood smoke-related COPD do not appear to develop emphysema, although they do show severe airway involvement. The reduction in DLCO and VA, with a normal DLCO/VA ratio, is probably due to severe bronchial obstruction and incomplete mixing of inspired gas during the determination of single-breath DLCO. Keywords: Pulmonary disease, chronic obstructive; Tomography; Air pollution; Biomass; Smoke; Respiratory function tests.

Resumen Objetivo: La exposición a humo de leña es factor de riesgo para EPOC. A diferencia de la EPOC por cigarrillo (EPOC-C), para un mismo nivel de obstrucción, en la EPOC por leña (EPOC-L), la DLCO está menos disminuida, sugiriendo menos enfisema. Por tanto, el objetivo de este estudio fue comparar los hallazgos en la TCAR en mujeres con EPOC-L y con EPOC- C. Métodos: Veintidós mujeres con EPOC severa (VEF1/CVF < 70% y VEF1 < 50%) fueron divididas en dos grupos: las expuestas a leña (EPOC-L; n = 12) y las expuestas a cigarrillo (EPOC-C; n = 10). Se compararon los dos grupos con respecto al puntaje de enfisema y el compromiso de la vía aérea en la TCAR, las anormalidades funcionales en la espirometría, la DLCO, los volúmenes pulmonares y la resistencia específica de la vía aérea (sRaw). Resultados: Los dos grupos tuvieron VEF1, sRaw e hiperinflación pulmonar similares. En el grupo EPOC-C, hubo mayor disminución de la DLCO y de la DLCO/VA y mayor puntaje de enfisema. En el grupo EPOC-L, no encontramos enfisema significativo en la TCAR. Los hallazgos principales fueron engrosamiento peribronquial, dilataciones bronquiales y atelectasias subsegmentarias. Conclusiones: En pacientes con EPOC-L severa no hay enfisema en la TCAR. El hallazgo más importante es el compromiso severo de la vía aérea. La disminución de la DLCO y del VA con DLCO/VA normal es probablemente determinada por la obstrucción bronquial severa y la mezcla incompleta del gas inspirado en la maniobra de la respiración única de la prueba de difusión Descriptores: Enfermedad pulmonar obstructiva crónica; Tomografía; Contaminación del aire; Biomasa; Humo; Pruebas de función respiratoria. * Study carried out at the Colombian Pulmonology Foundation, Bogotá, Colombia, and at the Department of Radiology and Diagnostic Imaging, Children’s Cardiology Foundation, Cardiology Institute, Bogotá, Colombia.

Correspondence to: Mauricio González-García, Carrera 13B 161-85. Bogotá, Colombia.

Tel. 571 742-8900. Fax. 571 742-8904. E-mail: mgonzalez@neumologica.org Financial support: None.

Submitted: 17 July 2012. Accepted, after review: 18 December 2012.

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Introduction Worldwide, approximately three billion people (half of the global population) use either materials of vegetal or animal origin (biomass) or charcoal as a source of energy in the home.(1) In developing countries, the use of wood, dung, crop residues, and charcoal for cooking and heating homes is quite common. Similarly, in developed countries, there has been an increase in the use of wood for heating as an “energy saving” measure. Household air pollution secondary to burning of these materials is a cause of significant morbidity and mortality.(1,2) Chronic household exposure to wood smoke has been associated with the development of chronic bronchitis and COPD and is now accepted as a risk factor for the development of the latter.(3-6) In the mountainous, rural areas of Colombia, the use of wood for cooking is common. Because of the cold, people in those areas usually cook inside their homes in poorly ventilated spaces and on stoves without chimneys, which causes an increase in household air pollution and is a risk factor for the development of COPD, especially in women. The reported prevalence of COPD in Colombia is 8.9%, and, in 6.7% of the cases, wood smoke exposure was the only COPD risk factor identified.(7) Previous studies have shown that, for a given degree of airway obstruction, the reduction in DLCO is smaller in women with wood smoke-related COPD than in those with smoking-related COPD, and that the DLCO/alveolar volume ratio (DLCO/VA ratio) is normal in the former.(8,9) Although a reduction in DLCO is suggestive of emphysema, this functional behavior has been described in patients with severe obstruction without emphysema and is attributed to involvement of the small airways.(10) The objective of the present study was to describe HRCT findings of emphysema and airway involvement in women with wood smoke-related COPD in terms of severity, and to compare them with those observed in women with smokingrelated COPD.

Methods This was a cross-sectional analytical study involving patients with COPD in which two groups were compared (wood smoke-related COPD group vs. smoking-related COPD group).

The inclusion criteria were as follows: being J Bras Pneumol. 2013;39(2):147-154

female and over 40 years of age; having severe COPD, defined as an FEV1/FVC ratio < 70% and an FEV1 < 50%; and having a history of significant exposure to smoking (smoking history > 20 pack-years) or to wood smoke (> 20 years).

Patients who were exposed to both risk factors were excluded, as were those who experienced exacerbation in the last six weeks and those who had asthma, lung cancer, or tuberculosis sequelae. The study was approved by the local research ethics committee, and all participants gave written informed consent.

The required sample size was calculated to be 8 patients per group, considering a type I error of 0.01 and an accuracy of 10% and using as parameters the values described in a study of subjective assessment of emphysema on HRCT scans in which the mean emphysema score was found to be 9 ± 7 in patients with small airways disease and 74 ± 8 in patients with COPD.(10) Over an 8-month period, we selected a non-random sample of consecutive patients enrolled in the COPD program of the institution who attended outpatient follow-up and met the study inclusion criteria. This COPD program has approximately 580 patients, 40% of whom have severe COPD. The final study simple comprised 22 women with severe COPD, 12 of whom had wood smoke-related COPD and 10 of whom had smoking-related COPD. Spirometry with bronchodilator testing, determination of single-breath DLCO, and plethysmographic measurement of thoracic gas volume and airway resistance (Vmax 229 AutoBox; Sensormedics Inc., Yorba Linda, CA, USA) were performed in accordance with the criteria of the American Thoracic Society and the European Respiratory Society, and the reference equations of Crapo were used.(11-14) Emphysema was quantified by HRCT of the chest, in accordance with a previously described method,(15,16) with a Somatom AR HP CT scanner (Siemens Medical Systems, Munich, Germany).

Six high-resolution slices were performed at 1-mm collimation, in the supine position, during a breath hold: at 3 and 6 cm above the carina; at the level of the carina; and at 3, 6, and 9 cm below the carina. Images were reconstructed with bone algorithm with a level of −600 HU and a window width of 1,500 HU. Emphysema severity was classified on a 0-3 scale: 0 = no emphysema; 1 = areas of low attenuation

Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease

measuring less than 5 mm in diameter; 2 = well-circumscribed areas of low attenuation measuring more than 5 mm, in addition to circumscribed areas measuring less than 5 mm; 3 = diffuse areas of low attenuation (which are not circumscribed) without signs of healthy lung parenchyma or large confluent areas of low attenuation. Emphysema extent was classified on a 1-4 scale on the basis of the degree of involvement on each slice: 1 = below 25%; 2 = from 26% to 50%; 3 = from 51% to 75%; and 4 = above 76%. Each slice was assessed individually, and the right and left lungs were quantified separately. For each of the 12 slices, the severity score was multiplied by the extent score, and, subsequently, summation was performed to calculate the final emphysema score, the maximum possible score being 144 points. A score between 0 and 50 was classified as mild emphysema, a score between 51 and 100 was classified as moderate emphysema, and a score above 101 was classified as severe emphysema.

In order to assess peripheral airway involvement, 5 slices were performed at end-expiration as described previously(17,18): at the level of the aortic arch; at the level of the carina; y at 3, 6, and 9 cm below the carina. The following criteria were used—mosaic pattern: areas of normal-looking lung parenchyma on slices obtained during inhalation that show decreased attenuation coefficient and a decreased artery-to-bronchus ratio on slices obtained during exhalation; peribronchial thickening: linear or branching opacity in the center of the lobule when the bronchiole is parallel to the slice plane; tree-in-bud pattern: obliteration of the terminal bronchioles, which are seen as centrilobular nodules; and cylindrical bronchial dilation (bronchiectasis).

The images were interpreted independently by two radiologists and one pulmonologist, experts in HRCT of the chest, who were blinded to the clinical diagnosis. Subsequently, the images were read jointly by the three observers, also in a blinded fashion, in order to achieve consensus.

Interobserver variability was assessed, as was agreement between the individual readings and the consensus reading.

Qualitative variables are expressed as proportions, whereas quantitative variables are expressed as means and standard deviations or as medians and interquartile ranges. Chi-square statistics were used for categorical variables,

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whereas the Student’s t-test or the nonparametric Mann-Whitney U test was used for continuous variables. We estimated Lin’s concordance correlation coefficient and Bland & Altman limits of agreement between the HRCT scores obtained in the individual readings and those obtained in the consensus reading. All tests were two-tailed, and the level of significance was set at p < 0.05.

We used the STATA statistical program, version 7.0 (Stata Corp., College Station, TX, USA).

Results The patients with wood smoke-related COPD had a history of 41.2 ± 9.8 years of exposure to wood smoke, whereas those with smokingrelated COPD had a smoking history of 47.0 ± 16.2 pack-years. There were no significant differences between the two groups in terms of age or body mass index (Table 1).

All patients had severe obstruction, as well as a significant increase in total lung capacity, functional residual capacity, and airway resistance.

There were no significant differences between the two groups in terms of the degree of impairment.

In the women with wood smoke-related COPD, the DLCO and DLCO/VA ratio were significantly higher, whereas the VA was lower, than in the women with smoking-related COPD (Table 1).

The emphysema scores, expressed as median (interquartile range), were significantly lower in the wood smoke-related COPD group than in the smoking-related COPD group—0 (0-1) vs.

92.5 (73-103); p < 0.001; Figure 1—and the airway involvement was greater in the former: peribronchial thickening (75% vs. 10%; p = 0.008) and bronchial dilation (67% vs. 10%; p = 0.024). In addition, tree-in-bud and subsegmental atelectasis were observed in women with wood smoke-related COPD (in 25% and 33%, respectively), as was severe wall thickening in large bronchi, none of which were found in those with smokingrelated COPD (Figure 2). No mosaic pattern was observed on the slices obtained during exhalation in any patient. The agreement between the initial readings and the consensus readings for emphysema assessment was very good, with a concordance correlation coefficient of 0.937 (p < 0.001), a mean difference of 0.030 ± 15.7 between the scores obtained by the two methods of assessment, and Bland & Altman limits of agreement of −30.77 and 30.83.

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Table 1 - Patient characteristics and pulmonary function test results.a Groups Wood smoke-related Variable Smoking-related COPD COPD (n = 12) (n = 10) Age, years 72.6 ± 8.7 65.9 ± 7.3 23.9 ± 4.6 22.5 ± 3.7 BMI, kg/m2 FVC, % of predicted 62.8 ± 12.7 65.9 ± 25.1 36.0 ± 11.0 32.4 ± 17.7 FEV1, % of predicted 44.3 ± 9.4 37.6 ± 7.2 FEV1/FVC, % TLC, % of predicted 131.5 ± 29.1 137.5 ± 15.5 FRC, % of predicted 189.7 ± 61.9 196.0 ± 26.0 RV, % of predicted 211.3 ± 74.0 226.5 ± 47.6 RV/TLC, % 70.4 ± 9.3 70.1 ± 10.0 sRaw, % of predicted 1,125.3 ± 621.0 1,227.4 ± 569.8 sGaw, % of predicted 10.8 ± 5.6 10.8 ± 6.8 DLCO, % of predicted 57.9 ± 14.2 35.1 ± 10.7 DLCO/VA, % of predicted 94.4 ± 19.9 41.8 ± 11.6 VA, % of predicted 60.0 ± 13.3 85.8 ± 17.8

p 0.07 0.44 0.72 0.57 0.08 0.55 0.75 0.58 0.94 0.69 0.99 < 0.001 < 0.001 0.001

BMI: body mass index; FRC: functional residual capacity; VA: alveolar volume; sRaw: specific airway resistance; and sGaw: specific airway conductance. aValues expressed as mean ± SD.

120.0

Emphysema score

100.0 80.0 60.0 40.0 20.0 0.0 Wood smoke-related COPD group (n = 12)

Smoking-related COPD group (n = 10)

Figure 1 - Emphysema scores (as determined by HRCT) in the wood smoke-related COPD group and in the smoking-related COPD group. The emphysema scores [median (interquartile range)] were significantly higher in women with smoking-related COPD than in women with wood smoke-related COPD [92.5 (73-103) vs. 0 (0-1); p < 0.001].

Discussion In this study based on chest HRCT findings, we demonstrated that, unlike women with smoking-related COPD, those with wood smokerelated COPD and severe obstruction do not J Bras Pneumol. 2013;39(2):147-154

have emphysema, although they have significant airway involvement manifesting as peribronchial thickening, bronchial dilation, and subsegmental atelectasis. These findings correlated with the fact that the change in DLCO and in the DLCO/ VA ratio, as determined by pulmonary function tests, was smaller in women with wood smokerelated COPD than in those with smoking-related COPD, a finding that has been described in cases of severe small airways involvement and little emphysema.(10) Functionally, all patients showed lung volume hyperinflation with a marked increase in functional residual capacity and residual volume, as well as a significant increase in airway resistance as measured by plethysmography, there being no differences between the two groups. Despite the same degree of obstruction, the reduction in DLCO and in the DLCO/VA ratio was significantly smaller in the wood smoke-related COPD group than in the smoking-related COPD group.

The tomographic findings confirmed the absence of significant emphysema in women with wood smoke-related COPD and showed moderate emphysema in women with smoking-related COPD. Previous studies have demonstrated that this subjective quantification of emphysema on HRCT scans correlates significantly with pathologic grading of emphysema on the basis of microscopic

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Figure 2 - HRCT scans showing airway involvement in patients with wood smoke-related COPD. In A, bronchial thickening and bronchiectasis; in B, bronchial dilation; and in C, middle lobe atelectasis.

examination of resected lung specimens.(19,20) Although this subjective quantification might have disadvantages, such as overestimation of the degree of emphysema and, sometimes, low agreement among different observers,(21) we believe that the technique used in our study was adequate, considering the clear differences found between the two groups and the good agreement observed between the individual readings by the three observers and the consensus readings.

Therefore, our results are highly reproducible. As indicated earlier in this article, women exposed to wood smoke, in addition to not having emphysema, were found to have peribronchial thickening, bronchiolar and bronchial dilation, and subsegmental atelectasis, which are evidence of significant airway involvement. The presence of atelectasis is a common finding in individuals with wood smoke-related COPD and has been correlated with endoscopic and histological findings of anthracosis and bronchial inflammation.(9,22)

Although other studies have not found that the frequency of cough and sputum production is higher in women with wood smoke-related COPD than in those with smoking-related COPD,(23,24) probably because of differences in the degree of exposure or disease severity, previous studies conducted in Colombia have found that women exposed to wood smoke have a higher frequency of cough and expectoration, as well as increased bronchial hyperresponsiveness, which suggests greater airway involvement, a finding that is similar to that of the present study.(9,25) A study involving 86 patients with wood smoke-related COPD and 53 patients with smoking-related COPD, with different degrees of obstruction, found that the reduction in DLCO was less severe and was less correlated with the degree of obstruction (reduction in FEV1) in the former than in the latter, and that the DLCO/VA ratio was normal in the former,(9) findings that are similar to those of the present study. This functional behavior,

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i.e., the reduction in DLCO with a normal DLCO/ VA ratio, suggests that there is greater airway involvement and less emphysema, as has been reported in patients with severe obstruction without emphysema, in whom expiratory flow limitation has been attributed to small airways involvement rather than to an emphysemarelated reduction in elastic recoil alone.(10,26,27) Because there were no tomographic findings of emphysema, those authors attributed the reduction in DLCO to a reduction in VA or a spurious reduction in DLCO, and introduced the term pseudophysiologic emphysema, which can be applied to female patients with wood smoke-related COPD. The major determinants of DLCO are the rate of alveolar-capillary gas exchange (permeability factor) and VA, which determines the quantity of gas available for exchange. In individuals with obstructive lung disease, VA measured during the determination of single-breath DLCO is low because of incomplete mixing of inspired gas and residual lung gas during breath holding, which can lead to a reduction in DLCO. In individuals with emphysema, the reduction in alveolar-capillary surface area leads to a proportionally greater reduction in DLCO than does the reduction in VA, which causes a significant reduction in the DLCO/VA ratio.(28,29) We believe that, in women with wood smoke-related COPD, in whom we found little emphysema, maldistribution of inspired gas during the determination of single-breath DLCO, because of the airway disease, can explain the reduction in VA and DLCO and the lesser change in the DLCO/VA ratio, which was normal in some cases.

Airflow limitation in individuals with COPD is attributed to lung parenchymal destruction and reduced elastic recoil, as well as to inflammation and obliteration of the airways. Although we did not measure elastic recoil, we postulate, on the basis of the findings of this study, that the reduced airflow in female patients with severe wood smoke-related COPD is explained mainly by severe airway impairment rather than by loss of elastic recoil due to emphysema. These functional and tomographic findings of no or minimal emphysema correlate with the findings a retrospective study of 103 autopsies of patients exposed to wood smoke. Although clinical and pulmonary function data from those patients were not recorded, the major histological findings J Bras Pneumol. 2013;39(2):147-154

in that group were hypertensive pulmonary vascular disease; peribronchial, perivascular, and interstitial deposition of anthracotic pigment; and no emphysema.(30) One of the limitations of this study was the inclusion of a relatively small number of patients.

However, the selection of consecutive cases, the strict inclusion criteria on the basis of the type of exposure (wood smoke or smoking), and the exclusion of those who were simultaneously exposed to both factors led to the formation of two groups that are clearly comparable. On the basis of the selection criteria, we included only women with severe obstruction, which is why the results obtained cannot be generalized to other degrees of severity or to men with COPD. Further studies involving a large number of patients with different degrees of obstruction are needed in order to confirm the findings of the present study.

In conclusion, in female patients with severe wood smoke-related COPD, HRCT scans showed no significant emphysema, the main finding being severe airway involvement manifesting as peribronchial thickening, bronchial dilation, and subsegmental atelectasis. The reduction in DLCO and VA, with a normal DLCO/VA ratio, is due to severe bronchial obstruction and maldistribution of inspired gas during the determination of single-breath DLCO. We believe that the airflow obstruction in these patients is mainly caused by severe airway involvement rather than by a loss of elastic recoil due to emphysema, a finding that contributes to the understanding of COPD and indicates that pathophysiologically distinct diseases with one shared clinical manifestation (airflow obstruction), which might depend on the type of irritant or contaminant, are being included under the designation of COPD.

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Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc. 2008;5(5):577-90.

2. Arbex MA, Cançado JE, Pereira LA, Braga AL, Saldiva PH. Biomass Burning and Health Effects. J Bras Pneumol.

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3. Dennis RJ, Maldonado D, Norman S, Baena E, Martinez G. Woodsmoke exposure and risk for obstructive airways disease among women. Chest. 1996;109(1):115-9.

4. Hu G, Zhou Y, Tian J, Yao W, Li J, Li B, et al. Risk of COPD from exposure to biomass smoke: a metaanalysis.

Chest. 2010;138(1):20-31.

Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease

5. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55.

6. da Silva LF, Saldiva SR, Saldiva PH, Dolhnikoff M; Bandeira Científica Project. Impaired lung function in individuals chronically exposed to biomass combustion. Environ Res. 2012;112:111-7.

7. Caballero A, Torres-Duque CA, Jaramillo C, Bolívar F, Sanabria F, Osorio P, et al. Prevalence of COPD in five Colombian cities situated at low, medium, and high altitude (PREPOCOL study). Chest. 2008;133(2):343-9.

8. González-García M, Barrero M, Maldonado D. Carbon monoxide diffusing capacity (DLCOSB) and transfer coefficient (DLCO/VA) in wood smoke chronic obstructive pulmonary disease (COPD) in Bogota, Colombia (2640 m). Chest. 2001;120:289S. 9. González M, Páez S, Jaramillo C, Barrero M, Maldonado D. Enfermedad pulmonar obstructiva crónica (EPOC) por humo de leña en mujeres: comparación con la EPOC por cigarrillo. Acta Med Colomb. 2004;29(1):17-25.

10. Gelb AF, Zamel N, Hogg JC, Müller NL, Schein MJ. Pseudophysiologic emphysema resulting from severe small-airways disease. Am J Respir Crit Care Med. 1998;158(3):815-9.

11. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981;123(6):659-64.

12. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720-35.

13. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38.

14. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511-22.

15. Hunsaker A, Ingenito E, Topal U, Pugatch R, Reilly J. Preoperative screening for lung volume reduction surgery: usefulness of combining thin-section CT with physiologic assessment. AJR Am J Roentgenol. 1998;170(2):309-14.

16. Klein JS, Gamsu G, Webb WR, Golden JA, Müller NL. Highresolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology. 1992;182(3):817-21.

17. Müller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology. 1995;196(1):3-12.

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19. Bergin C, Müller N, Nichols DM, Lillington G, Hogg JC, Mullen B, et al. The diagnosis of emphysema. A computed tomographic-pathologic correlation. Am Rev Respir Dis. 1986;133(4):541-6.

20. Kuwano K, Matsuba K, Ikeda T, Murakami J, Araki A, Nishitani H, et al. The diagnosis of mild emphysema.

Correlation of computed tomography and pathology scores. Am Rev Respir Dis. 1990;141(1):169-78.

21. Bankier AA, De Maertelaer V, Keyzer C, Gevenois PA. Pulmonary emphysema: subjective visual grading versus objective quantification with macroscopic morphometry and thin-section CT densitometry. Radiology.

1999;211(3):851-8.

22. Restrepo J, Reyes P, de Ochoa P, Patiño E. Neumoconiosis por inhalación de humo de leña. Acta Med Colomb.

1983;8(4):191-204.

23. Moreira MA, Moraes MR, Silva DG, Pinheiro TF, Vasconcelos Júnior HM, Maia LF, et al. Comparative study of respiratory symptoms and lung function alterations in patients with chronic obstructive pulmonary disease related to the exposure to wood and tobacco smoke. J Bras Pneumol.

2008;34(9):667-74.

24. Ramírez-Venegas A, Sansores RH, Pérez-Padilla R, Regalado J, Velázquez A, Sánchez C, et al. Survival of patients with chronic obstructive pulmonary disease due to biomass smoke and tobacco. Am J Respir Crit Care Med. 2006;173(4):393-7.

25. González-García M, Torres-Duque CA, Bustos A, Jaramillo C, Maldonado D. Bronchial hyperresponsiveness in women with chronic obstructive pulmonary disease related to wood smoke. Int J Chron Obstruct Pulmon Dis. 2012;7:367-73.

26. Gelb AF, Schein M, Kuei J, Tashkin DP, Müller NL, Hogg JC, et al. Limited contribution of emphysema in advanced chronic obstructive pulmonary disease. Am Rev Respir Dis. 1993;147(5):1157-61.

27. Gelb AF, Hogg JC, Müller NL, Schein MJ, Kuei J, Tashkin DP, et al. Contribution of emphysema and small airways in COPD. Chest. 1996;109(2):353-9.

28. Fitting JW. Transfer factor for carbon monoxide: a glance behind the scene. Swiss Med Wkly. 2004;134(29-30):413-8.

29. Hughes JM, Pride NB. In defence of the carbon monoxide transfer coefficient Kco (TL/VA). Eur Respir J. 2001;17(2):168-74.

30. Palacios D, Mendez O. Neumopatía por humo de leña: un estudio en autopsias. Biomédica (Bogota).

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About the authors Mauricio González-García

Internist, Pulmonologist, and Clinical Epidemiologist. Research Department, Colombian Pulmonology Foundation, Bogotá, Colombia.

Dario Maldonado Gomez

Internist, Pulmonologist, and Director. Colombian Pulmonology Foundation, Bogotá, Colombia.

Carlos A. Torres-Duque

Internist and Pulmonologist. Research Department, Colombian Pulmonology Foundation, Bogotá, Colombia.

Margarita Barrero

Physical Therapist. Pulmonary Function Laboratory, Colombian Pulmonology Foundation, Bogotá, Colombia.

Claudia Jaramillo Villegas

Internist and Cardiologist. Research Department, Colombian Pulmonology Foundation, Bogotá, Colombia.

Juan Manuel Pérez

Radiologist. Department of Radiology and Diagnostic Imaging, Children’s Cardiology Foundation, Institute of Cardiology, Bogotá, Colombia.

Humberto Varon

Radiologist. Department of Radiology and Diagnostic Imaging, Children’s Cardiology Foundation, Institute of Cardiology, Bogotá, Colombia.

J Bras Pneumol. 2013;39(2):147-154

Original Article Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure* Alterações tomográficas pulmonares em mulheres não fumantes com DPOC por exposição à fumaça da combustão de lenha

Maria Auxiliadora Carmo Moreira, Maria Alves Barbosa, Maria Conceição de Castro Antonelli Monteiro de Queiroz, Kim Ir Sen Santos Teixeira, Pedro Paulo Teixeira e Silva Torres, Pedro José de Santana Júnior, Marcelo Eustáquio Montadon Júnior, José Roberto Jardim

Abstract Objective: To identify and characterize alterations seen on HRCT scans in nonsmoking females with COPD due to wood smoke exposure. Methods: We evaluated 42 nonsmoking females diagnosed with wood smokerelated COPD and 31 nonsmoking controls with no history of wood smoke exposure or pulmonary disease. The participants completed a questionnaire regarding demographic data, symptoms, and environmental exposure.

All of the participants underwent spirometry and HRCT of the chest. The COPD and control groups were adjusted for age (23 patients each). Results: Most of the patients in the study group were diagnosed with mild to moderate COPD (83.3%). The most common findings on HRCT scans in the COPD group were bronchial wall thickening, bronchiectasis, mosaic perfusion pattern, parenchymal bands, tree-in-bud pattern, and laminar atelectasis (p < 0.001 vs. the control group for all). The alterations were generally mild and not extensive.

There was a positive association between bronchial wall thickening and hour-years of wood smoke exposure.

Centrilobular emphysema was uncommon, and its occurrence did not differ between the groups (p = 0.232).

Conclusions: Wood smoke exposure causes predominantly bronchial changes, which can be detected by HRCT, even in patients with mild COPD. Keywords: Biomass; Smoke; Tomography, X-ray computed; Pulmonary disease, chronic obstructive.

Resumo Objetivo: Identificar e caracterizar alterações na TCAR de tórax em mulheres com DPOC causada por exposição à fumaça da combustão de lenha. Métodos: Foram selecionadas 42 pacientes com DPOC relacionada à exposição à fumaça de lenha, não fumantes, e 31 mulheres não fumantes e sem história de exposição à fumaça de lenha ou de doença pulmonar. Empregou-se um questionário para a obtenção de dados demográficos e informações sobre sintomas e exposições ambientais. Todas as participantes realizaram espirometria e TCAR de tórax. Os grupos DPOC e controle foram ajustados por idade, com 23 pacientes cada. Resultados: A maioria das pacientes do grupo de estudo apresentava DPOC de leve a moderado (83,3%). Os achados de TCAR mais frequentes no grupo DPOC foram espessamento das paredes brônquicas, bronquiectasias, perfusão em mosaico, bandas parenquimatosas, padrão de árvore em brotamento e atelectasias laminares (p < 0,001 para todos na comparação com o grupo controle). As alterações, em geral, foram leves e de pequena extensão. Houve uma associação positiva entre espessamento das paredes brônquicas e duração da exposição à fumaça de lenha em horas-ano.

O achado de enfisema centrolobular foi infrequente e não diferiu entre os grupos (p = 0,232). Conclusões: A exposição à fumaça de lenha provoca alterações predominantemente brônquicas, que podem ser detectadas por TCAR, mesmo nos casos de DPOC leve.

Descritores: Biomassa; Fumaça; Tomografia computadorizada por raios X; Doença pulmonar obstrutiva crônica.

* Study carried out at the Federal University of Goiás School of Medicine Hospital das Clínicas, Goiânia, Brazil.

Correspondence to: Maria Auxiliadora Carmo Moreira. Hospital das Clínicas da Universidade Federal de Goiás, Faculdade de Medicina. Primeira Avenida s/n, Serviço de Pneumologia, 2º andar, Setor Universitário, CEP 74605-020, Goiânia, GO, Brasil.

Tel. 55 62 269-8385. E-mail: helpuol@uol.com.br Financial support: This study received partial financial support from the Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG, Goiás Research Foundation).

Submitted: 4 November 2012. Accepted, after review: 14 February 2013.

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Introduction

Methods

In developing countries, biomass is still widely used as a source of energy for cooking and indoor heating. It is estimated that half of the world population uses biomass, which consists of unprocessed wood (firewood) or processed wood (charcoal), dung, and crop residues.(1) Numerous studies have shown that, among females exposed to biomass smoke, the prevalence of COPD is high and the risk of developing the disease is significantly increased.(2) It is estimated that 25-45% of all COPD patients have never smoked.(3) It is also known that the number of people who are exposed to smoke from biomass combustion is significantly higher than is that of those who are exposed to tobacco smoke (approximately 3 billion vs.

1.01 billion).(3) There is a growing interest in learning more about the structural changes resulting from the inhalation of biomass smoke in order to gain a deeper understanding of the pathophysiology of biomass smoke-related obstructive lung disease. (4) We searched the literature for studies employing HRCT in order to evaluate pulmonary changes caused by biomass smoke exposure and found only ten studies.(5-14) However, nine of those studies are related to the use of a combination of types of biomass (dung, crop residues, and firewood), and only one of those studies examined exposure to wood smoke alone (in 12 women). (9) This heterogeneity of sources of smoke exposure makes it difficult to compare the individuals studied. The abovementioned study showed that bronchial lesions are more common in individuals who inhale wood smoke, whereas alveolar lesions are more common in cigarette smokers. (9) However, to our knowledge, there have been no CT studies of lung lesions in COPD patients exposed to wood smoke, the findings in such patients being compared with those in a control group of nonsmoking females with no history of exposure to biomass smoke.

The objective of the present study was to identify and characterize alterations seen on HRCT scans in nonsmoking females with COPD due to prolonged exposure to wood smoke from cooking.

The present study was conducted in central Brazil between 2008 and 2011. The inclusion criteria for COPD patients were as follows: being ≥ 40 years of age; having been exposed to wood smoke ≥ 80 hour-years for at least 10 years; not being a smoker; and having received a clinical and spirometric diagnosis of COPD. The inclusion criteria for controls were as follows: being ≥ 40 years of age; living in an urban area; not being a smoker; having no history of wood smoke exposure; and having normal spirometry results. All of the females who participated in the present study gave written informed consent. The exclusion criteria for COPD patients and controls were as follows: presenting with clinical findings (of an evaluation performed by a pulmonologist in the present study or of a previous evaluation by a pulmonologist, as reported in the medical records) suggestive of a history of asthma, rhinitis, or any extrapulmonary disease that might affect lung function; and having a positive bronchodilator test, FEV1 increasing by ≥ 12% and 200 mL.(15) We used a shorter version of a questionnaire that was previously used in a population-based study conducted in Brazil(16) in order to collect demographic and clinical data: respiratory symptoms (cough, phlegm, wheezing, and dyspnea), duration (in years and daily hours) of exposure to wood smoke; duration (in years) of exposure to passive smoking by living in a household with smokers; and duration (in years) of residence in a rural area. The degree of dyspnea was quantified by the Medical Research Council (MRC) scale.(17) The cumulative exposure to wood smoke was expressed in hour-years, calculated as the number of years cooking with a wood stove multiplied by the mean number of hours the participant reported to spend, daily, in this activity. The criterion of wood smoke exposure ≥ 80 hour-years for at least 10 years was based on the levels of exposure considered significant in similar studies.(18) The study participants underwent spirometry before and after the use of a bronchodilator (albuterol, 400 µg), FVC, FEV1, and the FEV1/ FVC ratio being measured. The diagnostic criteria for COPD were as follows: being ≥ 40 years of age; having an FEV1/FVC ratio below the lower limit of normality and < 0.70(19,20); having been exposed to smoke from wood stoves; and having

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Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

a history of chronic dyspnea, chronic cough, or both, unrelated to other causes.

The severity of COPD was determined in accordance with the Global Initiative for Chronic Obstructive Lung Disease spirometric classification. (20) The pulmonary function tests were performed in accordance with the Brazilian Thoracic Association guidelines.(21) The predicted values used in the present study were those of Pereira et al.(22) In our analysis of HRCT scans, we used the criteria established by the Brazilian Thoracic Association illustrated Brazilian consensus of terms and fundamental patterns in chest CT scans.(23) In order to locate abnormalities, we used the following criteria: upper lung fields—from the apices to the carina; middle lung fields— from the carina to the mitral valve; and lower lung fields—from the mitral valve to the lung bases. The degree of pulmonary impairment was determined on the basis of the number of lung lobes showing the following changes: parenchymal bands; mosaic perfusion pattern; atelectasis; tree-in-bud pattern; and traction bronchiectasis.

The degree of bronchial wall thickening was classified as follows: grade 1—up to 20% of the diameter of the adjacent pulmonary artery; grade 2—greater than 20% and less than 50% of the diameter of the adjacent pulmonary artery; and grade 3—50-100% of the diameter of the adjacent pulmonary artery. Bronchiectasis was graded as follows: grade 1—the ratio between the internal diameter of the bronchus and the diameter of the adjacent artery was 0.7-1.0; grade 2—the internal diameter of the bronchus was increased but was less than twice the diameter of the adjacent artery; and grade 3—the internal diameter of the bronchus was more than twice the diameter of the adjacent artery. Centrilobular emphysema was classified as follows(24,25): absent; areas of < 5 mm; areas > 5 mm; diffuse areas of low attenuation that were not interspersed with areas of normal lung; and large, confluent areas of low attenuation.

In order to take HRCT scans, we used either a Somatom Emotion™ 6 CT scanner (Siemens, Munich, Germany) or an Aquilion™ 16 CT scanner (Toshiba, Tokyo, Japan). The images were acquired during a maximal inspiratory maneuver, as follows: collimation, 1 mm; 125 kV; 160 mA; and acquisition time, 0.75 s. The intervals between

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images were of 10 mm, with the patient in the supine position. The images were reconstructed with a high-resolution algorithm, with a 512 × 512 pixel matrix. Lung and mediastinal window images were available for analysis. No contrast agent was used.

The images were independently analyzed by three radiologists (one general radiologist with 35 years of experience and two thoracic radiologists, one with 2 years of experience and the other with 12 years of experience). In cases of discordance, the result was based on consensus. (25) All images were evaluated in Digital Imaging and Communications in Medicine format. The radiologists had no information regarding the clinical diagnosis of the study participants or the existence of risk factors for COPD. They were aware of the fact that it was a study aimed at evaluating females exposed to wood smoke.

For the statistical analysis, we used the IBM SPSS Statistics software package, version 15.0 (IBM Corporation, Armonk, NY, USA). We used the Student’s t-test in order to compare the groups in terms of quantitative variables with normal distribution and the Mann-Whitney U test in order to compare the groups in terms of variables with non-normal distribution. The chi-square test and Fisher’s exact test were used in order to compare the frequencies of qualitative variables and calculate the risk that the independent variable represented. By logistic regression analysis, we analyzed the association between abnormal HRCT findings and other variables. We used Pearson’s test in order to detect correlations among variables with normal distribution. In order to balance the sample, the females in the COPD group and those in the control group were matched for age. The oldest females in both groups were excluded, as were the youngest. The odds ratio was calculated with a confidence interval of 95%, and values of p < 0.05 were considered significant.

The present study was approved by the Research Ethics Committee of the Federal University of Goiás Hospital das Clínicas on April 4, 2008 and on September 21, 2010 (Amendment 1), under registration no. 018/08.

Results In the present study, the COPD group comprised 42 females and the control group comprised 31.

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among those living in the region where the study was conducted, particularly elderly females who had never cooked with wood stoves.

The participants were sequentially recruited from among those being treated at either of two general clinical medicine outpatient clinics and from among those being treated at the gynecology outpatient clinic of a university hospital, as well as being recruited from among patients without a confirmed diagnosis of respiratory disease seeking the aforementioned university hospital for spirometry. The females in the control group were selected from among those studying at an open university for the elderly.

The mean age was higher in the COPD group than in the control group (70.8 ± 8.5 years vs. 58.9 ± 7.2 years; p < 0.001), as was the mean duration (in years) of rural residence (40.7 ± 17.7 years vs. 3.61 ± 5.1 years; p = 0.001). All of the females in the COPD group resided in rural areas and worked predominantly as housecleaners or homemakers, sporadically working in the agricultural production of grains. There were no statistically significant differences between the COPD and control groups regarding the mean duration of passive exposure to tobacco smoke (20.6 ± 18.0 years vs. 29.2 ± 21.0 years; p = 0.70; Table 1).

Most of the patients with COPD had one or more of the following respiratory symptoms: cough; Table 1 - Demographic characteristics, clinical characteristics, and data regarding wood smoke exposure in 42 patients with COPD.a Variable Result Age, years 70.8 ± 8.5 Rural residence, years 40.7 ± 17.7 Passive smoking, years 29.2 ± 21.0 Wood smoke exposure, h/day 6.0 ± 1.9 Wood smoke exposure, years 35.1 ±12.5 Wood smoke exposure, hour-years 209.1 ± 98.4 29 (69.9) Chronic coughb 24 (55.8) Expectorationb 29 (67.4) Wheezingb 35 (81.8) Dyspneab COPD severityb Stage I (mild) 9 (21.4) Stage II (moderate) 26 (61.9) Stage III (severe) 7 (16.7) Stage IV (very severe) 0 (0.0) Values expressed as mean ± SD, except where otherwise indicated. bValues expressed as n (%). a

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expectoration; wheezing; and dyspnea. Dyspnea was the most common complaint (Table 1), the Medical Research Council scale scores showing grade 1 or 2 dyspnea in 75% of the cases and grade 3 or 4 in 25%.

The females in the COPD group had mild to moderate airflow limitation (as determined by spirometry); none of the patients had severe obstructive lung disease (Table 1).

Regarding HRCT abnormalities, bronchiectasis, mosaic perfusion pattern, linear atelectasis (lobar atelectasis in one patient), and tree-in-bud pattern were significantly more common in the females in the COPD group than in those in the control group. None of the participants had panlobular emphysema. Lower lobe lesions predominated (Table 2 and Figure 1).

In the COPD group, we found statistically significant associations between bronchial wall thickening and cough (p = 0.013; OR = 6.13; 95% CI: 1.46-25.73) and between bronchial wall thickening and hour-years of wood smoke exposure (p = 0.018; OR = 1.01; 95% CI: 1.011.02). We also found significant associations between centrilobular emphysema and duration of passive smoking (p = 0.033; OR = 1.08; 95% CI: Table 2 - HRCT findings in the COPD and control groups.a COPD Control HRCT finding p (n = 42) (n = 31) Normal 0 (0.0) 1 (3.2) 0.417 Parenchymal bands 33 (78.6) 7 (22.6) < 0.001* Bronchial wall 28 (66.7) 0 (0.0) < 0.001 thickening Nodules 26 (61.9) 23 (74.2) 0.320 Bronchiectasis 23 (54.8) 4 (12.9) < 0.001** Traction 7 (16.7) 0 (0.0) 0.018 bronchiectasis Apical fibrosis/ 21 (50.0) 15 (48.4) 1.000 pleural scarring Mosaic perfusion 19 (45.2) 0 (0.0) < 0.001 pattern Atelectasis 12 (28.6) 0 (0.0) 0.001 Tree-in-bud pattern 9 (21.4) 1 (3.2) 0.037*** Mediastinal 6 (14.3) 2 (6.5) 0.454 lymphadenopathy Centrilobular 5 (11.9) 1 (3.2) 0.232 emphysema Ground-glass opacity 0 (0.0) 2 (6.5) 0.117 Values expressed as n (%). *OR = 12.57 (95% CI: 4.1138.49). **OR = 8.17 (95% CI: 2.43-27.49). ***OR = 8.18 (95% CI: 0.98-68.49). a

Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

A

C

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B

D

Figure 1 - Axial HRCT scans of the chest (lung window) at the level of the lower lung fields. In A, bronchiectasis and bronchial wall thickening (thick arrow), parenchymal bands (thin arrow), and mosaic perfusion pattern (asterisks) in a 66-year-old female patient. In B, middle lobe atelectasis (thick arrow) and bronchial wall thickening (thin arrow) in a 76-year-old female patient. In C, parenchymal bands (thick arrow), moderate bronchial wall thickening (thin arrow), and mosaic perfusion pattern (asterisks) in a 57-year-old female patient. In D, centrilobular micronodules with tree-in-bud pattern in an 81-year-old female patient.

1.01-1.16) and between mosaic perfusion pattern and lower FEV1 values (p = 0.009; ORÂ =Â 0.93; 95% CI: 0.89-0.98).

In order to avoid bias due to possible structural lung changes occurring with age, we divided the participants into two new groups. Each group comprised 23 patients, the two groups being matched for age (Table 3).

After age matching, parenchymal bands, bronchial wall thickening, bronchiectasis, mosaic perfusion pattern, and laminar atelectasis were found to be significantly more common in the COPD group than in the control group. As can be seen in Table 4, those abnormalities occurred predominantly in the lower lung fields (in 76.6%), having occurred in the middle lung fields in 15.6% and in the upper lung fields in 7.8%.

The proportion of nodules on HRCT scans in the COPD group was equal to that of those on HRCT scans in the control group, most of the nodules being micronodules or calcified nodules.

Discussion The present study examined pulmonary changes seen on HRCT scans in females with wood smoke-related COPD and showed that those changes were significantly more severe in those females than in those in the control group, who had no history of wood smoke exposure.

The most common findings were parenchymal bands, bronchial wall thickening, bronchiectasis, mosaic attenuation/perfusion pattern, and linear atelectasis, the differences between the two groups being statistically significant.

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Table 3 - Demographic characteristics, data regarding wood smoke exposure, data regarding passive smoking, and pulmonary function test results in the COPD and control groups after adjustment for age.a COPD Control Variable p (n = 23) (n = 23) Age, years 64.8 ± 6.1 61.6 ± 6.66 0.051 Wood smoke 6.5 ± 2.1 exposure, h/ day Wood smoke 32.8 ±13.4 exposure, years Wood smoke 209.7 ± 110.5 exposure, hour-years Passive 26.5 ± 19.9 21.7 ± 20.3 0.424 smoking FVC, % of 91.8 ± 13.1 99.4 ± 15.3 < 0.001 predicted 65.9 ± 15.1 104.5 ± 12.6 < 0.001 FEV1, % of predicted 0.58 ± 0.1 0.80 ± 0.1 < 0.001 FEV1/FVC a

Values expressed as mean ± SD.

Table 4 - HRCT findings in the COPD and control groups after adjustment for age.a COPD Control HRCT finding p (n = 23) (n = 23) Parenchymal bands 20 (86.9) 4 (17.4) < 0.001* Bronchial wall 14 (60.9) 0 (0.0) < 0.001 thickening Bronchiectasis 10 (43.5) 4 (17.4) 0.047** Mosaic perfusion 7 (30.4) 0 (0.0) 0.009 pattern Atelectasis 7 (30.4) 0 (0.0) 0.009 Tree-in-bud pattern 5 (21.7) 1 (4.3) 0.187 Values expressed as n (%). *OR = 22.56 (95% CI: 4.91103.66). **OR = 5.13 (95% CI: 1.18-22.24). a

It is known that wood combustion produces various substances that are harmful to the lungs, including carbon monoxide, nitrogen oxide, particulate matter, polycyclic aromatic hydrocarbons, and formaldehyde, and that are also present in cigarette smoke; wood smoke exposure can therefore cause changes that are similar to those caused by smoking.(26) In the present study, the most common findings were parenchymal bands, which are changes indicative of parenchymal fibrosis.(23) These changes have been associated with exposure to biomass smoke and wood smoke in pathological and CT

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studies, which have suggested that such changes correspond to an initial interstitial involvement.(5,6) Although we found no areas of significant interstitial involvement in the present study, three studies have described such areas.(5-7) Parenchymal bands and ground-glass opacities were also found in those studies, having been reported to be quite common in one of the studies.(6) In the present study, we found no ground-glass opacities, which are associated with interstitial thickening and alveolar collapse.(23) However, the females investigated in the abovementioned studies(5-7) had been exposed to mixed biomass, which includes dung and wood. Dung combustion generates more pollutants than does wood combustion, ranking lower on the energy scale for being less efficient and more polluting.(27) The differences among the results obtained can be explained by the different types of biomass used and the different purposes for which it is used.

Bronchial wall thickening was the second most common finding in the present study, having remained so after adjustment for age.

This shows that bronchial wall thickening was unrelated to aging.

Bronchiectasis has been found in all studies examining exposure to biomass smoke(5-7) and was the fourth most prevalent type of lesion in the present study, having been found in 54.8% of the females exposed to wood smoke and in 12.5% of those in the control group. Even after adjustment for age, bronchiectasis was significantly more common in the group of females exposed to wood smoke. This shows that bronchiectasis is not associated with lung aging. Unlike bronchiectasis resulting from a specific disease, which tends to accumulate in a localized area of the lung, the bronchiectasis found in the present study was homogeneously distributed in the lungs and was predominantly located in the lower lobes.

Mosaic perfusion pattern, which has been described as a CT manifestation of obstructive lung disease,(23) was found in nearly half of the COPD patients in the present study and was found to be independent of age.

In the present study, atelectasis was found only in the COPD group, having persisted after age matching. The presence of bronchial anthracosis, which causes atelectasis, has been reported in females exposed to biomass smoke.(28)

Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure

A study of women exposed to wood smoke found â&#x20AC;&#x153;pseudoemphysemaâ&#x20AC;? and hyperinflation on CT scans, and it was suggested that those changes were due to pronounced bronchial involvement, given that there were no changes in lung elastic recoil, which are typically seen in cases of emphysema.(9) Emphysema is an unusual finding in individuals exposed to biomass smoke and, when present, is usually less pronounced than is that observed in individuals with smokingrelated COPD.(9) In the present study, we found centrilobular emphysema, which was positively associated with duration of passive smoking. Although it was weak, this association suggests that passive smoking contributes to the development of emphysema.

Another relevant finding of the present study was the association between bronchial wall thickening and chronic cough. We found a weak but positive association between bronchial wall thickening and duration of exposure to biomass smoke. This finding had not been reported in the literature, an association between obstructive functional impairment and duration of exposure to biomass smoke having previously been reported.(6) We found an association between mosaic perfusion pattern, which is suggestive of obstructive lung disease,(23) and lower FEV1 and FEV1/FVC values.

Age-related CT abnormalities, principally bronchial abnormalities, have been reported in individuals over 65 years of age, regardless of their smoking history.(26) However, even after adjustment for age, the difference between the COPD and control groups regarding the frequency of changes persisted, the exception being tree-in-bud pattern. This demonstrated that the changes previously seen in the COPD group were related to wood smoke exposure rather than to aging.

One study established a relationship between various COPD phenotypes and CT findings.(29) One of those phenotypes, reported in nonsmokers, included minimal emphysema, bronchial wall thickening, mild hyperinflation, and high body mass index values. The abovementioned phenotype partly coincides with the phenotype found in the present study.

Most of the patients in the present study had mild to moderate COPD. This can partially explain why those patients had milder HRCT

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abnormalities, which are also seen in patients with smoking-related COPD.(4) The proportion of apical fibrosis/pleural scarring seen in the COPD group was the same as that seen in the control group, as was the proportion of tree-in-bud pattern. Those changes might be due to pulmonary tuberculosis or infectious bronchitis.

However, none of the females investigated in the present study reported a history of tuberculosis, and none had a clinical profile suggestive of active tuberculosis or bronchial infection.

The present study has limitations. Some of the data were collected by means of a questionnaire, and questionnaires depend on the ability of respondents to recollect specific information.

This problem is mitigated by the fact that the questionnaire used in the present study had previously been used in Brazil and by the fact that the interviewers were extensively trained in order to obtain information by objectively referring to specific aspects of the lives of the participants. Another limitation of the present study was the lack of an objective measurement of the degree of pollution at the place of residence of the females who used wood stoves. Finally, we did not take HRCT scans during an expiratory maneuver. Such scans facilitate the visualization of small airway abnormalities. However, blinded individual assessment, followed by consensus among three experienced radiologists, probably minimized this limitation.

Relevant aspects of the present study were the fact that all patients and controls underwent spirometry; we collected data regarding exposure to wood smoke only, data regarding other types of exposure having been excluded; and we established a minimum duration of exposure to wood smoke as a criterion for inclusion in the present study.

Another relevant aspect of the present study is that we found no similar studies in the literature. In our study, we evaluated a control group of nonsmoking females with no history of exposure to biomass smoke, having performed adjustment for age and having used HRCT scans in order to describe the effects of exposure to wood smoke alone on the lungs of nonsmoking females with COPD. We can conclude that wood smoke inhalation causes lung legions predominantly in the airways.

These lesions can be detected by HRCT, even in patients with mild to moderate COPD. This finding is important because it shows that individuals exposed to wood smoke can present with pulmonary J Bras Pneumol. 2013;39(2):155-163

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changes despite being nearly asymptomatic and therefore should be treated early.

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2. Torres-Duque C, Maldonado D, Pérez-Padilla R, Ezzati M, Viegi G; Forum of International Respiratory Studies (FIRS) Task Force on Health Effects of Biomass Exposure.

Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc. 2008;5(5):577-90.

3. Salvi S, Barnes PJ. Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest. 2010;138(1):3-6.

4. Gupta PP, Yadav R, Verma M, Agarwal D, Kumar M. Correlation between high-resolution computed tomography features and patients’ characteristics in chronic obstructive pulmonary disease. Ann Thorac Med. 2008;3(3):87-93.

5. Arslan M, Akkurt I, Egilmez H, Atalar M, Salk I. Biomass exposure and the high resolution computed tomographic and spirometric findings. Eur J Radiol. 2004;52(2):192-9.

6. Kara M, Bulut S, Tas F, Akkurt I, Seyfikli Z. Evaluation of pulmonary changes due to biomass fuels using high-resolution computed tomography. Eur Radiol.

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7. Ozbay B, Uzun K, Arslan H, Zehir I. Functional and radiological impairment in women highly exposed to indoor biomass fuels. Respirology. 2001;6(3):255-8.

8. Amoli K. Bronchopulmonary disease in Iranian housewives chronically exposed to indoor smoke. Eur Respir J. 1998;11(3):659-63.

9. González M, Maldonado D, Pérez J, Varón H. Pseudophysiologic emphysema in women with wood smoke COPD in Bogota (2600 m) [Article in Spanish] Arch Bronconeumol. 2004;40:31.

10. Gupta A, Shah A. Bronchial anthracofibrosis: an emerging pulmonary disease due to biomass fuel exposure. Int J Tuberc Lung Dis. 2011;15(5):602-12.

11. Kim HY, Im JG, Goo JM, Kim JY, Han SK, Lee JK, Song JW. Bronchial anthracofibrosis (inflammatory bronchial stenosis with anthracotic pigmentation): CT findings.

AJR Am J Roentgenol. 2000;174(2):523-7.

12. Torun T, Gungor G, Ozmen I, Maden E, Bolukbasi Y, Tahaoglu K. Bronchial anthracostenosis in patients exposed to biomass smoke. Turkish Respir J. 2007;8(2):48–51.

13. Kala J, Sahay S, Shah A. Bronchial anthracofibrosis and tuberculosis presenting as a middle lobe syndrome. Prim Care Respir J. 2008;17(1):51-5.

14. Kim YJ, Jung CY, Shin HW, Lee BK. Biomass smoke induced bronchial anthracofibrosis: presenting features and clinical course. Respir Med. 2009;103(5):757-65.

15. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-68.

16. Menezes AM, Jardim JR, Pérez-Padilla R, Camelier A, Rosa F, Nascimento O, et al. Prevalence of chronic obstructive pulmonary disease and associated factors:

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the PLATINO Study in São Paulo, Brazil. Cad Saude Publica. 2005;21(5):1565-73.

17. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease.

Thorax. 1999;54(7):581-6.

18. Ramírez-Venegas A, Sansores RH, Pérez-Padilla R, Regalado J, Velázquez A, Sánchez C, et al. Survival of patients with chronic obstructive pulmonary disease due to biomass smoke and tobacco. Am J Respir Crit Care Med. 2006;173(4):393-7.

19. Vollmer WM, Gíslason T, Burney P, Enright PL, Gulsvik A, Kocabas A, et al. Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study.

Eur Respir J. 2009;34(3):588-97.

20. Global Initiative for Chronic Obstructive Disease – GOLD [homepage on the Internet]. Bethesda: Global Initiative for Chronic Obstructive Disease. [cited 2011 Mar 10].

Global Strategy for the Diagnosis, Management, and Prevention of COPD 2010. [Adobe Acrobat document, 117p.]. Available from: http://www.goldcopd.org/uploads/ users/files/GOLDReport_April112011.pdf 21. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38.

22. 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.

23. Silva CI, Marchiori E, Souza Júnior AS, Müller NL; Comissão de Imagem da Sociedade Brasileira de Pneumologia e Tisiologia. Illustrated Brazilian consensus of terms and fundamental patterns in chest CT scans. J Bras Pneumol.

2010;36(1):99-123.

24. Copley SJ, Wells AU, Hawtin KE, Gibson DJ, Hodson JM, Jacques AE, et al. Lung morphology in the elderly: comparative CT study of subjects over 75 years old versus those under 55 years old. Radiology. 2009;251(2):566-73.

25. Roberts HR, Wells AU, Milne DG, Rubens MB, Kolbe J, Cole PJ, et al. Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests. Thorax. 2000;55(3):198-204.

26. Vikgren J, Boijsen M, Andelid K, Ekberg-Jansson A, Larsson S, Bake B, et al. High-resolution computed tomography in healthy smokers and never-smokers: a 6-year follow-up study of men born in 1933. Acta Radiol. 2004;45(1):44-52. Erratum in: Acta Radiol.

2004;45(3):following 663.

27. Junemann A, Legarreta CG. Chronic obstructive pulmonary disease produced by biomass fuels. Clin Pulm Med. 2008;15(6):305-12.

28. González M, Páez S, Jaramillo C, Barrero M, Maldonado D. Enfermedad pulmonar obstructiva crónica (EPOC) por humo de leña en mujeres. Acta Med Colomb.

2004;29(1):17-25.

29. Kitaguchi Y, Fujimoto K, Kubo K, Honda T. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100(10):1742-52.

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About the authors Maria Auxiliadora Carmo Moreira

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

Maria Alves Barbosa

Full Professor. Federal University of Goiás School of Nursing, Goiânia, Brazil.

Maria Conceição de Castro Antonelli Monteiro de Queiroz

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

Kim Ir Sen Santos Teixeira

Adjunct Professor. Department of Diagnostic Imaging and Pathology, Federal University of Goiás School of Medicine, Goiânia, Brazil.

Pedro Paulo Teixeira e Silva Torres

Substitute Professor. Department of Diagnostic Imaging and Pathology, Federal University of Goiás School of Medicine, Goiânia, Brazil.

Pedro José de Santana Júnior

Volunteer Radiologist. Department of Diagnostic Imaging and Pathology, Federal University of Goiás School of Medicine, Goiânia, Brazil.

Marcelo Eustáquio Montadon Júnior

Radiologist. Clínica Multimagem Diagnósticos, Goiânia, Brazil

José Roberto Jardim

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

J Bras Pneumol. 2013;39(2):155-163

Original Article Epidemiological aspects of respiratory symptoms treated in the emergency room of a tertiary care hospital* Perfil epidemiológico dos atendimentos de emergência por sintomas respiratórios em um hospital terciário

Denise Rossato Silva, Vinícius Pellegrini Viana, Alice Mânica Müller, Ana Cláudia Coelho, Gracieli Nadalon Deponti, Fernando Pohlmann Livi, Paulo de Tarso Roth Dalcin

Abstract Objective: To evaluate the prevalence of respiratory symptoms as the motive for emergency room visits by adult and pediatric patients, describing the major clinical syndromes diagnosed and the outcomes of the patients.

Methods: A cross-sectional study conducted in the emergency room of a tertiary care university hospital.

Between November of 2008 and November of 2009, we reviewed the total number of emergency room visits per day. Children and adults who presented with at least one respiratory symptom were included in the study.

The electronic medical records were reviewed, and the major characteristics of the patients were recorded.

Results: During the study period, there were 37,059 emergency room visits, of which 11,953 (32.3%) were motivated by respiratory symptoms. The prevalence of emergency room visits due to respiratory symptoms was 28.7% and 38.9% among adults and children, respectively. In adults, the rates of hospitalization and mortality were 21.2% and 2.7%, respectively, compared with 11.9% and 0.3%, respectively, in children. Among the adults, the time from symptom onset to emergency room visit correlated positively with the need for hospitalization (p < 0.0001), the length of the hospital stay (p < 0.0001), and the mortality rate (p = 0.028). Conclusions: We found a high prevalence of respiratory symptoms as the motive for emergency room visits by adult and pediatric patients. Our results could inform decisions regarding the planning of prevention measures. Further epidemiological studies are needed in order to clarify the risk factors for severe respiratory symptoms.

Keywords: Emergency service, hospital; Respiratory tract diseases; Respiratory tract infections; Signs and symptoms, respiratory.

Resumo Objetivo: Avaliar a prevalência de sintomas respiratórios como motivo para procura de atendimento de emergência por pacientes adultos e pediátricos, descrevendo as principais síndromes clínicas diagnosticadas e o desfecho dos pacientes. Métodos: Estudo transversal, realizado na emergência de um hospital universitário terciário.

Entre novembro de 2008 e novembro de 2009, o número total de atendimentos foi revisado diariamente. Foram incluídos no estudo crianças e adultos com pelo menos um sintoma respiratório. Os prontuários eletrônicos foram revisados e foram registradas as principais características dos pacientes. Resultados: Durante o período do estudo, houve 37.059 admissões na emergência, das quais 11.953 (32,3%) foram motivadas por sintomas respiratórios. A prevalência de atendimentos por sintomas respiratórios foi 28,7% e 38,9% nos adultos e crianças, respectivamente. As taxas de internação hospitalar e de mortalidade nos adultos foram 21,2% e 2,7%, respectivamente, comparadas com 11,9% e 0,3%, respectivamente, nas crianças. Nos adultos, quanto maior o tempo entre o início dos sintomas e a visita à emergência, maiores foram a necessidade de hospitalização (p < 0,0001), o tempo de hospitalização (p < 0,0001) e a mortalidade (p = 0,028). Conclusões: Encontramos uma prevalência elevada de atendimentos por sintomas respiratórios entre os pacientes adultos e pediátricos. Nossos resultados podem contribuir para o planejamento de medidas de prevenção. Futuros estudos epidemiológicos poderão colaborar para a melhor elucidação dos fatores de risco para a presença de sintomas respiratórios nesses pacientes.

Descritores: Serviço hospitalar de emergência; Doenças respiratórias; Infecções respiratórias; Sinais e sintomas respiratórios. * Study carried out at the Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Correspondence to: Denise Rossato Silva. Rua Ramiro Barcelos, 2350, Santa Cecília, CEP 90035-903, Porto Alegre, RS, Brasil.

Tel. 55 51 3359-8241. E-mail: denise.rossato@terra.com.br Financial support: This study received financial support from the Fundo de Incentivo à Pesquisa da Sociedade Brasileira de Pneumologia e Tisiologia (FIPE-SBPT, Research Incentive Fund of the Brazilian Thoracic Association), the Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HPCA, Research Incentive Fund of the Hospital de Clínicas de Porto Alegre), and the Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS, Foundation for the Support of Research in the State of Rio Grande do Sul).

Submitted: 2 October 2012. Accepted, after review: 16 November 2012.

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Epidemiological aspects of respiratory symptoms treated in the emergency room of a tertiary care hospital

Introduction The prevalence of respiratory symptoms in a given population is an indirect indicator of acute and chronic respiratory diseases, an indicator that is quite reliable from an epidemiological standpoint. (1,2) Respiratory diseases are a leading cause of death among adults and children, accounting for 12% of all deaths worldwide.

In low- and middle-income countries, upper respiratory tract infections (URTIs) account for 11.3% and 5.4% of all deaths, respectively.(3) In addition to exerting enormous pressure on health services, respiratory diseases are common causes of school and work absenteeism. In Brazil, chronic and acute respiratory diseases collectively rank second among the leading causes of hospitalization within the Brazilian Unified Health Care System, accounting for approximately 14% of all hospitalizations within the system.

In southern Brazil, respiratory diseases are the leading cause of hospitalization (accounting for 17% of all hospital admissions).(4) Respiratory complaints are the motive for a large proportion of outpatient visits, emergency room visits, and hospitalizations.(5) A study conducted in a developing country(6) showed that 10% of all emergency room visits were due to respiratory diseases. In a two-year study conducted in the city of Gama, Brazil,(7) 641,905 emergency room visits were evaluated, 37,642 (5.8%) of which were found to be due to respiratory complaints.

Studies on the pattern of emergency room visits by individuals with respiratory symptoms are important, because they could inform decisions regarding the organization and planning of health services in order to meet this demand.(6,7) The objective of the present study was to evaluate the prevalence of respiratory symptoms as the motive for emergency room visits by adult and pediatric patients at a tertiary care hospital, describing the major clinical syndromes diagnosed and the patient outcomes.

Methods This was a cross-sectional study conducted in the emergency room of the Hospital de Clínicas de Porto Alegre (HCPA), located in the city of Porto Alegre, southern Brazil. The HCPA is a general tertiary care university hospital with 750 beds and approximately 30,000 admissions per

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year. The city of Porto Alegre has 1,409,939 inhabitants, and the surrounding metropolitan area includes 31 cities, the total population of the greater metropolitan area being 3,979,561.

The Research Ethics Committee of the HCPA granted the researchers access to patient medical records. A waiver of consent was approved, and the researchers signed a confidentiality agreement.

Children and adults who presented to the emergency room with at least one respiratory symptom were included in the study. During the study period (between November of 2008 and November of 2009), we reviewed the total number of visits per day to the pediatric and adult sections of the emergency room of the HCPA. The electronic medical records were reviewed, and the characteristics of the patients treated for respiratory symptoms that were recorded included gender, age, race, smoking history, comorbidities, respiratory symptoms, and familial history of flu symptoms. The respiratory symptoms considered were rhinorrhea, nasal congestion, odynophagia, dysphonia, cough, breathlessness, wheezing, chest pain, and fever.

The patients who presented with fever alone were not included in the study. Clinical findings on admission (axillary temperature, HR, RR, pulmonary auscultation findings, and SpO2— measured by digital pulse oximetry) were also recorded, as were the major clinical syndromes diagnosed and the patient outcomes (ICU admission, ward admission, discharge from the emergency room, and death).

Data were entered into a Microsoft Excel 2007 database, after which they were processed and analyzed with the Statistical Package for the Social Sciences, version 18.0 (SPSS Inc., Chicago, IL, USA). We performed a descriptive analysis of the overall prevalence of visits by patients with respiratory symptoms to the pediatric and adult sectors of the emergency room (for patients < 14 and ≥ 14 years of age, respectively). We stratified the time from symptom onset to emergency room visit (as < 7 days, 7-21 days, and > 21 days), as well as evaluating the major respiratory symptoms, the major clinical diagnoses, the length of the emergency room visit, the rate of admission to the hospital, the rate of ICU admission, the rate of discharge from the emergency room, and the mortality rate.

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Results

Oct. 2009

Sept. 2009

July 2009

Aug. 2009

May 2009

June 2009

Mar. 2009

April 2009

Jan. 2009

Feb. 2009

Dec. 2008

1,400 1,200 1,000 800 600 400 200 0 Nov. 2008

Number of visits

During the 12-month study period, there were 37,059 emergency room visits (24,189 by adults and 12,870 by children), of which 11,953 (32.3%) were motivated by respiratory symptoms. The monthly variation in the number of emergency room visits due to respiratory symptoms is shown in Figures 1 and 2. There was an increase in the number of such visits in April, May, and June. The prevalence of visits due to respiratory symptoms was 28.7% (6,942/24,189) among adult patients and 38.9% (5,011/12,870) among pediatric patients. The

Month

Figure 1 - Monthly variation in the number of visits to the adult sector of the Hospital de Clínicas de Porto Alegre emergency room (for patients ≥ 14 years of age) motivated by respiratory symptoms, between November of 2008 and November of 2009.

Number of visits

1,200 1,000 800 600 400 200 Oct. 2009

Sept. 2009

July 2009

Aug. 2009

May 2009

June 2009

April 2009

Mar. 2009

Feb. 2009

Jan. 2009

Dec. 2008

Nov. 2008

0

Month

Figure 2 - Monthly variation in the number of visits to the pediatric sector of the Hospital de Clínicas de Porto Alegre emergency room (for patients < 14 years of age) motivated by respiratory symptoms, between November of 2008 and November of 2009.

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most common symptoms were cough (in 73.4%), fever (in 56.1%), breathlessness (in 40.9%), chest pain (in 24.5%), and rhinorrhea (20.9%). The median duration of symptoms prior to admission was 3 days (interquartile range: 1-6 days). A total of 2,205 patients (18.5%) admitted to the emergency room required hospitalization. Of those, 242 (2.0%) required ICU admission. The overall mortality rate among all study participants was 2.3% (280/11,953). The demographic and clinical characteristics of the study population (adults and children) are shown in Table 1.

Table 2 shows the characteristics of the adult patients and the analysis of these characteristics on the basis of the time from symptom onset to emergency room visit. Because data on the time from symptom onset to emergency room visit were not available for all patients, the analysis included only 4,434 patients. Of those 4,434 patients, 939 (21.2%) were admitted to the hospital and 120 (2.7%) died. The median (interquartile range) length of emergency room visit and the median (interquartile range) total length of hospital stay were 0.5 day (0.5-1.0 day) and 0.5 day (0.5-3.0 days), respectively. The patients who had a 6-day or shorter history of respiratory symptoms (<7 group) were younger than those who had a 7- to 21-day history (7-21 group) and those who had a 21-day or longer history (>21 group; 44.9 ± 20.4 years vs. 49.4 ± 19.7 years and 49.9 ± 17.6 years; p < 0.0001). A longer time from symptom onset to emergency room visit correlated with a lower level of education of the patients (p < 0.0001).

When the proportion of patients who were residents of the city of Porto Alegre was higher, the time from symptom onset to emergency room visit was shorter (p = 0.012). Rhinorrhea, odynophagia, and fever were most common in the patients in the <7 group, whereas cough and breathlessness were most common in those in the 7-21 group. The number of patients with asthma was highest in the <7 group (p = 0.002), and the number of patients with HIV infection was highest in the >21 group (p < 0.0001).

Among the patients who underwent chest X-ray, normal results were more common in those in the <7 group (p < 0.0001), and a consolidation pattern was more common in those in the 7-21 group (p = 0.002). Pleural effusion and diffuse infiltrates were most common in the >21 group (p = 0.008 and p = 0.003, respectively). The

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Table 1 - Principal characteristics of the patients.a Characteristic Age, yearsb Male gender White > 8 years of schooling Place of residence Porto Alegre Greater metropolitan area of Porto Alegre Interior of the state of Rio Grande do Sul Symptom upon arrival at the emergency room Cough Breathlessness Chest pain Rhinorrhea Nasal congestion Odynophagia Dysphonia Wheezing Fever Hemoptysis Duration of symptoms prior to arrival at the emergency room, days Comorbidity Systemic arterial hypertension Asthma COPD Ischemic heart disease Heart failure Diabetes mellitus HIV infection Cancer Chronic renal failure Smoking status Nonsmoker Former smoker Current smoker

Adults (n = 6,942) 50.0 (30.0-55.0) 3,125 (45.0) 5,941 (85.6) 3,129 (51.2)

Children (n = 5,011) 2.0 (0.8-5.0) 2,795 (55.8) 4,007 (80.0) -

4,815 (69.4) 1,851 (26.7) 276 (3.9)

3,635 (72.5) 1,247 (24.9) 129 (2.6)

4,553 (65.6) 3,521 (50.7) 2,697 (38.9) 676 (9.7) 263 (3.8) 897 (12.9) 102 (1.5) 264 (3.8) 2,986 (43.0) 186 (2.7) 3.0 (1.0-7.0)c

4,214 (84.1) 1,363 (27.2) 229 (4.6) 1.821 (36.3) 673 (13.4) 472 (9.4) 60 (1.2) 760 (15.2) 3,718 (74.2) 4 (0.1) 2.0 (1.0-4.0)c

1,730 (24.9) 603 (8.7) 730 (10.5) 567 (8.2) 554 (8.0) 900 (13.0) 400 (5.8) 632 (9.1) 231 (3.3) 143 (2.1) 712 (10.3) 611 (8.8)

0 777 (15.5) 0 0 0 6 (0.1) 32 (0.6) 48 (1.0) 0 0 0 0

Values expressed as n (%), except where otherwise indicated. bValue expressed as mean Âą SD. cValues expressed as median (interquartile range). a

most common diagnoses in the <7 group were influenza (in 18.2%), pneumonia (in 12.6%), and URTI (in 12.2%). In the 7-21 group, the most common diagnoses were pneumonia (in 17.8%), URTI (in 10.7%), and COPD exacerbation (in 9.6%); whereas the most common diagnoses in the >21 group were pneumonia (in 9.1%), COPD exacerbation (in 5.2%), and sinusitis (in 4.3%). The length of emergency room visit was shortest among the patients in the <7 group (p < 0.0001). A longer time from symptom onset to

emergency room visit correlated with a greater need for hospitalization (p < 0.0001), longer hospital stays (p < 0.0001), and higher mortality (p = 0.028).

Table 3 shows the characteristics of the pediatric patients and the analysis of those characteristics on the basis of the time from symptom onset to emergency room visit. Because, as was true for adults, data on the time from symptom onset to emergency room visit were not available for the entire group of pediatric patients,

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Table 2 - Characteristics of the adult patients and analysis based on the time from onset of respiratory symptoms to emergency room visit.a Time from symptom onset to emergency room visit Total p Characteristic < 7 days 7-21 days > 21 days (n = 4,434) (n = 3,024) (n = 1,179) (n = 230) Age, yearsb 46.4 ± 20.2 44.9 ± 20.4*,** 49.4 ± 19.7* 49.9 ± 17.6** < 0.0001 Male gender 1,961 (44.2) 1,355 (44.8) 500 (42.4) 106 (46.1) 0.317 White 3,791 (85.5) 2,600 (86.0) 598 (84.6) 193 (83.9) 0.438 > 8 years of schooling 2,103 (53.5) 1,506 (55.8)*,** 498 (48.4)*,*** 99 (48.1)**,*** < 0.0001 Place of residence Porto Alegre 3,110 (70.1) 2,162 (71.5)*,** 799 (67.8)*,** 149 (64.8)**,*** 0.012 Greater metropolitan area of 1,174 (26.5) 777 (25.7) 329 (27.9) 68 (29.6) 0.189 Porto Alegre Interior of the state of Rio 150 (3.4) 86 (2.8)*,** 51 (4.3)*,** 13 (5.7)**,*** 0.009 Grande do Sul Symptom upon arrival at the emergency room Cough 3,132 (70.6) 2,069 (68.4)*,** 906 (76.8)*,*** 157 (68.3)**,*** < 0.0001 Expectoration 1,946 (28.0) 795 (26.3)* 445 (37.7)*,*** 60 (26.1)*** < 0.0001 Breathlessness 2,071 (46.7) 1,335 (44,1)*,** 621 (52.7)*,*** 115 (50.0)**,*** < 0..001 Chest pain 1,841 (41.5) 1,249 (41.3) 495 (42.0) 97 (42.2) 0.900 Rhinorrhea 538 (12.1) 422 (14.0)*,** 102 (8.7)*,*** 14 (6.1)**,*** < 0.0001 Nasal congestion 203 (4.6) 148 (4.9) 49 (4.2) 6 (2.6) 0.201 Odynophagia 683 (15.4) 547 (18.1)*,** 124 (10.5)*,*** 12 (5.2)**,*** < 0.0001 Dysphonia 75 (1.7) 49 (1.6) 25 (2.1) 1 (0.4) 0.167 Wheezing 166 (3.7) 113 (3.7) 47 (4.0) 6 (2.6) 0.602 Fever 2,240 (50.5) 1,645 (54.4)*,** 518 (43.9)*,*** 77 (33.5)**,*** < 0.0001 Hemoptysis 118 (2.7) 75 (2.5) 35 (3.0) 8 (3.5) 0.494 Comorbidity Systemic arterial hypertension 1,071 (24.2) 698 (23.1)*,** 316 (26.8)*,*** 57 (24.8)**,*** 0.039 Asthma 389 (8.8) 291 (9.6)*,** 90 (7.6)*,*** 8 (3.5)**,*** 0.002 COPD 381 (8.6) 249 (8.2)*,** 122 (10.3)*,*** 10 (4.3)**,*** 0.006 Ischemic heart disease 357 (8.1) 261 (8.6) 83 (7.0) 13 (5.7) 0.092 Heart failure 310 (7.0) 212 (7.0) 90 (7.6) 8 (3.5) 0.078 Diabetes mellitus 542 (12.2) 376 (12.4) 136 (11.5) 30 (13.0) 0.675 HIV infection 278 (6.3) 150 (5.0)*,** 95 (8.1)*,*** 33 (14.3)**,*** < 0.0001 Cancer 302 (6.8) 202 (6.7) 88 (7.5) 12 (5.2) 0.407 Chronic renal failure 133 (3.0) 95 (3.1) 32 (2.7) 6 (2.6) 0.720 Smoking status Nonsmoker 107 (45.0) 64 (43.5) 32 (49.2) 11 (42.3) 0.714 Former smoker 452 (81.7) 299 (88.5) 124 (87.9) 29 (76.3) 0.112 Current smoker 405 (87.4) 248 (81.0) 128 (85.3) 29 (72.5) 0.160 Radiological pattern Normal 881 (38.7) 593 (41.8)*,** 241 (34.2)*,*** 47 (30.9)**,*** < 0.0001 Consolidation 498 (21.9) 298 (21.0)*,** 180 (25.5)*,*** 20 (13.2)**,*** 0.002 Diffuse infiltrate 114 (5.0) 57 (4.0)*,** 42 (6.0)*,*** 15 (9.9)**,*** 0.003 Pleural effusion 176 (7.7) 91 (6.4)*,** 68 (9.7)*,*** 17 (11.2)**,*** 0.008 Primary diagnosis URTI 503 (11.3) 368 (12.2)*,** 126 (10.7)*,*** 9 (3.9)**,*** 0.001 Pneumonia 612 (13.8) 381 (12.6)*,** 210 (17.8)*,*** 21 (9.1)**,*** < 0.0001 Influenza 614 (13.8) 550 (18.2)*,** 64 (5.4)*,*** 0 (0)**,*** < 0.0001 Asthma 204 (4.6) 156 (5.2)*,** 43 (3.6)* 5 (2.2)** 0.022 COPD 331 (7.5) 206 (6.8)*,** 113 (9.6)*,*** 12 (5.2)**,*** 0.004 Sinusitis 227 (5.1) 134 (4.4)*,** 83 (7.0)*,*** 10 (4.3)**,*** 0.002 Pulmonary tuberculosis 42 (0.9) 13 (0.4)*,** 13 (1.1)* 16 (7.0)** < 0.0001 Length of emergency room visit, , 0.5 (0.5-1) 0.5 (0.5-1)* ** 0.5 (0.5-2)* 0.5 (0.5-2)** < 0.0001 daysc , , ‡ , Need for hospitalization 939 (21.2) 560 (18.5)* ** 303 (25.7)* *** 76 (33.0)** *** <0.0001 Need for ICU admission 119 (2.7) 70 (2.3) 39 (3.3) 10 (4.3) 0.056 0.5 (0.5-3.0) 7 (3-14)*,**† 10 (6-19)*,*** 14 (6-24)**,*** < 0.0001 Length of hospital stay, daysc 39 (3.3)*,*** 11 (4.8)**,*** 0.028 Death 120 (2.7) 70 (2.3)*,** URTI: upper respiratory tract infection. aValues expressed as n (%), except where otherwise indicated. bValue expressed as mean ± SD. cValues expressed as median (interquartile range). *Comparison between the < 7 days and 7-21 days. **Comparison between the < 7 days and > 21 days. ***Comparison between the 7-21 days and > 21 days.

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Table 3 - Characteristics of the pediatric patients and analysis based on the time from onset of respiratory symptoms to emergency room visit.

Time from symptom onset to emergency room visit Total Characteristic p < 7 days 7-21 days > 21 days (n = 3,860) (n = 3,242) (n = 574) (n = 44) b Age, years 2.0 (0.8-5.0) 2.0 (0.8-5.0)** 1.0 (0.7-5.0)*** 0.9 (0.5-3.0)**,*** 0.023 Male gender 2,116 (54.8) 1,771 (54.6) 322 (56.1) 23 (52.3) 0.762 White 3,085 (79.9) 2,602 (80.3) 447 (77.9) 36 (81.8) 0.401 Place of residence Porto Alegre 2,806 (72.7) 2,352 (72.5) 420 (73.2) 34 (77.3) 0.754 Greater metropolitan area of 963 (24.9) 815 (25.1) 138 (24.0) 10 (22.7) 0.806 Porto Alegre Interior of the state of Rio 91 (2.4) 75 (2.3) 16 (2.8) 0 (0) 0.461 Grande do Sul Symptom upon arrival at the emergency room Cough 3,311 (85.8) 2,765 (85.3) 507 (88.3) 39 (88.6) 0.136 Breathlessness 988 (25.6) 837 (25.8) 140 (24.4) 11 (25.0) 0.767 Chest pain 181 (4.7) 151 (4.7) 30 (5.2) 0 (0) 0.280 Rhinorrhea 1,459 (37.8) 1,213 (37.4) 233 (40.6) 13 (29.5) 0.184 Nasal congestion 544 (14.1) 442 (13.6) 95 (16.6) 7 (15.9) 0.170 39 (6.8)*,*** 1 (2.3)**,*** 0.008 Odynophagia 374 (9.7) 334 (10.3)*,** Dysphonia 47 (1.2) 37 (1.1) 9 (1.6) 1 (2.3) 0.563 Wheezing 575 (14.9) 488 (15.1) 77 (13.4) 10 (22.7) 0.203 25 (56.8)**,*** < 0.0001 Fever 2,985 (77,3) 2,554 (78.8)*,** 406 (70.7)*,*** Comorbidity Asthma 587 (15.2) 506 (15.6) 74 (12.9) 7 (15.9) 0.246 0 (0) 0.857 HIV infection 25 (0.6) 21 (0.6) 4 (0.7) Cancer 35 (0.9) 30 (0.9) 5 (0.9) 0 (0) 0.809 History of bronchiolitis 117 (3.0) 98 (3.0) 18 (3.1) 1 (2.3) 0.947 Radiological pattern Normal 651 (47.7) 539 (48.8) 98 (43.8) 14 (60.9) 0.210 64 (28.4)*,*** 4 (17.4)**,*** 0.035 Consolidation 300 (22.0) 232 (20.8)*,** Diffuse infiltrate 137 (10.0) 115 (10.3) 19 (8.4) 3 (13.0) 0.623 Primary diagnosis URTI 980 (25.4) 816 (25.2) 155 (27.0) 9 (20.5) 0.487 76 (13.2)*,*** 4 (9.1)**,*** 0.014 Pneumonia 381 (9.9) 301 (9.3)*,** 28 (4.9)*,*** 2 (4.5)**,*** < 0.0001 Influenza 356 (9.2) 326 (10.1)*,** Asthma 486 (12.6) 426 (13.1) 56 (9.8) 4 (9.1) 0.062 Bronchiolitis 366 (9.5) 303 (9.3) 57 (9.9) 6 (13.6) 0.580 18 (3.1)*,*** 2 (4.5)**,*** 0.002 Sinusitis 63 (1.6) 43 (1.3)*,** Length of emergency room visit, 0.5 (0.5-0.5) 0.5 (0.5-0.5) 0.5 (0.5-0.5) 0.5 (0.5-0.5) 0.182 daysc Need for hospitalization 458 (11.9) 376 (11.6) 73 (12.1) 9 (20.5) 0.156 Need for ICU admission 27 (0.7) 22 (0.7) 5 (0.9) 0 (0) 0.751 0.5 (0.5-0.5) 6 (3-11) 5 (3-10) 11 (4.5-20.5) 0.179 Length of hospital stay, daysc Mortality rate 12 (0.3) 9 (0.3) 3 (0.5) 0 (0) 0.582 URTI: upper respiratory tract infection. aValues expressed as n (%), except where otherwise indicated. bValue expressed as mean Âą SD. cValues expressed as median (interquartile range). *Comparison between the < 7 days and 7-21 days. **Comparison between the < 7 days and > 21 days. ***Comparison between the 7-21 days and > 21 days.

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the analysis included only 3,860 patients. Of those 3,860 patients, 458 (11.9%) were admitted to the hospital and 12 (0.3%) died. The median length of the emergency room visit and median length of hospital stay were equal: 0.5 days (range, 0.5-0.5 days). The pediatric patients in the >21 group were younger than were those in the <7 and 7-21 groups (p = 0.023). Fever and odynophagia were most common in the patients in the <7 group (p < 0.0001 and p = 0.008, respectively). In all three of those groups, the most common diagnoses were influenza (p < 0.0001), pneumonia (p = 0.014), and sinusitis (p = 0.002). Among the pediatric patients, the type of symptom(s) presented did not correlate significantly with the length of emergency room visit, length of hospital stay, or mortality.

Discussion In this cross-sectional study, we have described the characteristics of adult and pediatric patients presenting to the emergency room of a tertiary care hospital with respiratory symptoms. In one year, the prevalence of emergency room visits due to respiratory symptoms was 28.7% and 38.9% among adult and pediatric patients, respectively. In adults, the rates of hospitalization and mortality were 21.2% and 2.7%, respectively, compared with 11.9% and 0.3%, respectively, in children.

In a study conducted at various emergency rooms in a city in Italy,(8) only 5% of all visits by adults were motivated by respiratory symptoms.

The same percentage was found by another group of authors,(9) who also reported that 47% of patients presenting to primary care did so because of respiratory symptoms. At 77 basic health care facilities in Algeria, the presence of respiratory symptoms was the motive for seeking medical attention in up to 31.6% of the cases.(10) In our sample, the number of patients who sought treatment because of respiratory symptoms might have been overestimated because of the influenza A (H1N1) pandemic, which occurred during the study period. This also explains the high prevalence of diagnoses of influenza and URTI in patients treated at the emergency room of the tertiary care hospital. Likewise, upper respiratory tract symptoms, such as rhinorrhea and odynophagia, as well as fever, were more common in the adult patients presenting to the emergency room with a â&#x2030;¤ 6-day history of J Bras Pneumol. 2013;39(2):164-172

respiratory symptoms, perhaps out of concern regarding the possibility of having A (H1N1) influenza.

The adult patients who had a â&#x2030;¤ 6-day history of respiratory symptoms were younger than were the other patients. It is known that elderly patients with pneumonia have lower body temperature and that it can take them longer to seek medical attention, increasing the likelihood of delayed diagnosis and delayed treatment.(11) In fact, the higher number of patients diagnosed with pneumonia in the 7-21 and >21 groups corroborates this finding.

A higher level of education was found in the group of adult patients who presented to the emergency room earlier (<7 group). Studies have demonstrated that individuals with a higher level of education have a healthier behavior, have more information about their health, and clearly understand the instructions provided at discharge from the emergency room.(12) In general, those with a higher level of education tend to make better health-related decisions. Therefore, considering the context of the influenza A (H1N1) epidemic, it is possible that these patients sought medical attention earlier for fear of this pathology.

In the adult patients, we found that a longer time from symptom onset to emergency room visit correlated with a greater need for hospitalization, longer hospital stays, and higher mortality.

Respiratory symptoms are associated with various diseases and are considered significant predictors of mortality.(13) Among respiratory symptoms, breathlessness is the most closely associated with mortality.(14) In fact, in our study, we found that breathlessness was more common in the 7-21 and >21 groups than in the <7 group, probably indicating greater severity and chronicity of symptoms in the first two groups.

The present study has some methodological limitations. We included only patients presenting to the emergency room, and those probably represented cases that were more severe than those treated in primary care. In addition, the diagnoses were syndromic (i.e., the etiologic agent was not identified). However, despite these limitations, the study achieved its objective of showing the characteristics of patients with respiratory symptoms and is relevant for the evaluation of these patients in the context of emergency care.

Epidemiological aspects of respiratory symptoms treated in the emergency room of a tertiary care hospital

In conclusion, we have described the epidemiological profile of adult and pediatric patients presenting to an emergency room with respiratory symptoms. We found a high prevalence of respiratory symptoms as the motive for emergency room visits by adult and pediatric patients (in 28.7% and 38.0%, respectively).

In addition, we found that a longer time from symptom onset to emergency room visit correlated with a greater need for hospitalization, longer hospital stays, and higher mortality among adults.

Similar studies could inform decisions regarding the planning of prevention measures. Further longitudinal epidemiological studies are needed in order to clarify the risk factors for severe respiratory symptoms.

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influenza-associated pneumonia. Arch Gerontol Geriatr.

2009;49(2):322-5.

12. Cutler DM, Lleras-Muney A. Understanding differences in health behaviors by education. J Health Econ.

2010;29(1):1-28.

13. Frostad A, Søyseth V, Andersen A, Gulsvik A. Respiratory symptoms as predictors of all-cause mortality in an urban community: a 30-year follow-up. J Intern Med. 2006;259(5):520-9.

14. Knuiman MW, James AL, Divitini ML, Ryan G, Bartholomew HC, Musk AW. Lung function, respiratory symptoms, and mortality: results from the Busselton Health Study.

Ann Epidemiol. 1999;9(5):297-306.

References 1. Pivetta ABDA, Botelho C. Prevalência de sintomas respiratórios e avaliação espirométrica em trabalhadores de marmorarias. J Pneumol. 1997;23(4):179-188.

2. Ruffino-Neto A, Carvalheiro JR. Doenças do aparelho respiratório e doenças infecciosas e parasitárias na morbidade referida pela população, Ribeirão Preto, SP, 1975. Medicina (Ribeirão Preto) 1982;15:79-83.

3. World Health Organization [homepage in the Internet].

Geneva: World Health Organization. [cited 2012 Oct 10]. The top 10 causes of death - Fact sheet N°310, Updated June 2011. Available from: http://www.who. int/mediacentre/factsheets/fs310/en/index.html 4. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Oct 10]. Sistema de informações hospitalares do SUS (SIH/SUS). Available from: http://portal.saude.gov.br/portal/saude/profissional/ visualizar_texto.cfm?idtxt=29939&janela=1 5. Greenberg SB. Respiratory viral infections in adults.

Curr Opin Pulm Med. 2002;8(3):201-8.

6. Desalu OO, Ojo OO, Busari OA, Fadeyi A. Pattern of respiratory diseases seen among adults in an emergency room in a resource-poor nation health facility. Pan Afr Med J. 2011;9:24.

7. Valença LM, Restivo PC, Nunes MS. Seasonal variations in emergency room visits for asthma attacks in Gama, Brazil. J Bras Pneumol. 2006;32(4):284-9.

8. Tramuto F, Cusimano R, Cerame G, Vultaggio M, Calamusa G, Maida CM, et al. Urban air pollution and emergency room admissions for respiratory symptoms: a case-crossover study in Palermo, Italy. Environ Health. 2011;10:31.

9. Backman AS, Blomqvist P, Lagerlund M, Carlsson-Holm E, Adami J. Characteristics of non-urgent patients. Crosssectional study of emergency department and primary care patients. Scand J Prim Health Care. 2008;26(3):181-7.

10. Zidouni N, Baough L, Laid Y, Chaulet P. Practical approach to lung health strategy in Algeria [Article in French].

Int J Tuberc Lung Dis. 2009;13(8):1029-37.

11. Matsuno O, Kataoka H, Takenaka R, Okubo F, Okamoto K, Masutomo K, et al. Influence of age on symptoms and laboratory findings at presentation in patients with

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About the authors Denise Rossato Silva

Adjunct Professor of Pulmonology. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

Vinícius Pellegrini Viana

Physician. Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Alice Mânica Müller

Master’s Student. Graduate Program in Pulmonology, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

Ana Cláudia Coelho

Physical Therapist. Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Gracieli Nadalon Deponti

Master’s Student. Graduate Program in Pulmonology, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

Fernando Pohlmann Livi

Professor. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Geography, Porto Alegre, Brazil.

Paulo de Tarso Roth Dalcin

Associate Professor of Pulmonology. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

J Bras Pneumol. 2013;39(2):164-172

Original Article Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats*,** Efeitos da metilprednisolona na atividade inflamatória e estresse oxidativo nos pulmões de ratos com morte cerebral

Eduardo Sperb Pilla, Raôni Bins Pereira, Luiz Alberto Forgiarini Junior, Luiz Felipe Forgiarini, Artur de Oliveira Paludo, Jane Maria Ulbrich Kulczynski, Paulo Francisco Guerreiro Cardoso, Cristiano Feijó Andrade

Abstract Objective: To evaluate the effects that early and late systemic administration of methylprednisolone have on lungs in a rat model of brain death. Methods: Twenty-four male Wistar rats were anesthetized and randomly divided into four groups (n = 6 per group): sham-operated (sham); brain death only (BD); brain death plus methylprednisolone (30 mg/kg i.v.) after 5 min (MP5); and brain death plus methylprednisolone (30 mg/kg i.v.) after 60 min (MP60). In the BD, MP5, and MP60 group rats, we induced brain death by inflating a balloon catheter in the extradural space. All of the animals were observed and ventilated for 120 min. We determined hemodynamic and arterial blood gas variables; wet/dry weight ratio; histological score; levels of thiobarbituric acid reactive substances (TBARS); superoxide dismutase (SOD) activity; and catalase activity. In BAL fluid, we determined differential white cell counts, total protein, and lactate dehydrogenase levels. Myeloperoxidase activity, lipid peroxidation, and TNF-α levels were assessed in lung tissue. Results: No significant differences were found among the groups in terms of hemodynamics, arterial blood gases, wet/dry weight ratio, BAL fluid analysis, or histological score—nor in terms of SOD, myeloperoxidase, and catalase activity. The levels of TBARS were significantly higher in the MP5 and MP60 groups than in the sham and BD groups (p < 0.001).

The levels of TNF-α were significantly lower in the MP5 and MP60 groups than in the BD group (p < 0.001).

Conclusions: In this model of brain death, the early and late administration of methylprednisolone had similar effects on inflammatory activity and lipid peroxidation in lung tissue.

Keywords: Rats; Brain death; Oxidative stress; Lung; Hydroxycorticosteroids.

Resumo Objetivo: Avaliar os efeitos da administração sistêmica precoce e tardia de metilprednisolona nos pulmões em um modelo de morte encefálica em ratos. Métodos: Vinte e quatro ratos Wistar machos foram anestesiados e randomizados em quatro grupos (n = 6 por grupo): sham, somente morte encefálica (ME), metilprednisolona i.v. (30 mg/kg) administrada 5 min após a morte encefálica (MP5) e 60 min após a morte encefálica (MP60). Os grupos ME, MP5 e MP60 foram submetidos à morte encefálica por insuflação de um balão no espaço extradural.

Todos os animais foram observados e ventilados durante 120 min. Foram determinadas variáveis hemodinâmicas e gasométricas, relação peso úmido/seco, escore histológico, thiobarbituric acid reactive substances (TBARS, substâncias reativas ao ácido tiobarbitúrico), atividade de superóxido dismutase (SOD) e de catalase, assim como contagem diferencial de células brancas, proteína total e nível de desidrogenase lática no LBA. A atividade da mieloperoxidase, peroxidação lipídica e níveis de TNF-α foram avaliados no tecido pulmonar. Resultados: Não foram observadas diferenças significativas nas variáveis hemodinâmicas e gasométricas, relação peso úmido/ seco, análises do LBA, escore histológico, SOD, mieloperoxidase e catalase entre os grupos. Os níveis de TBARS foram significativamente maiores nos grupos MP5 e MP60 do que nos grupos sham e ME (p < 0,001). Os níveis de TNF-α foram significativamente menores nos grupos MP5 e MP60 do que no grupo ME (p < 0,001).

Conclusões: Neste modelo de morte cerebral, a administração precoce e tardia de metilprednisolona apresentou efeitos semelhantes sobre a inflamação e a peroxidação lipídica no tecido pulmonar.

Descritores: Ratos; Morte encefálica; Estresse oxidativo; Pulmão; Hidroxicorticosteroides. *Study carried out at the Porto Alegre Hospital de Clínicas, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Correspondence to: Cristiano Feijó Andrade. Hospital de Clínicas de Porto Alegre, Departamento de Cirurgia Torácica, Rua Ramiro Barcelos, 2350, Santa Cecília, CEP 90035-903, Porto Alegre, RS, Brasil.

Tel. 55 51 3359-8839. E-mail: cristianofa@gmail.com Financial support: This study received financial support from the Fundo de Incentivo à Pesquisa (FIPE, Research Incentive Fund) of Porto Alegre Hospital de Clínicas and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development).

Submitted: 18 September 2012. Accepted, after review: 22 January 2013. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Pilla ES, Pereira RB, Forgiarini Junior LA, Forgiarini LF, Paludo AO, Kulczynski JMU, Cardoso PFG, Andrade CF

Introduction Lung transplantation is an established therapeutic option for patients with end-stage lung disease. In the last decade, there has been a significant increase in the number of lung transplant centers.(1) As a result, the number of patients on waiting lists has been increasing.

In contrast, the donor pool has remained fairly constant, the proportion of available lungs that are suitable for transplantation ranging from 4.9% to 27%.(1-4) Recently, with the use of lungs from marginal donors and the encouraging results of ex vivo lung perfusion for lung reconditioning, there has been a trend toward an increase in the number of lung transplants.(5,6) Brain-dead donors still represent the major source of organs for transplantation. In the ICU, the lungs of potential donors are exposed to direct damage caused by the process related to the occurrence of brain death. In addition, the lungs are at risk for acute lung injury secondary to trauma, prolonged mechanical ventilation, transfusion, ischemia, aspiration, and infection.(7,8) Brain death is defined as the death of all central neurological tissue, resulting in the loss of cerebral function.(9) The pathophysiology of brain death is complex, involving sympathetic, hemodynamic, and inflammatory mechanisms that can injure the lung.(7,10) Significant endocrine changes result in a decrease in the plasma levels of adrenocorticotropic hormone, cortisol, triiodothyronine, thyroxine, insulin, and vasopressin.(7) Currently, there is a consensus that organ grafts should not be considered immunologically inert.

Donor risk factors, such as previous diseases, age, cause of death, donor management, and, most importantly, brain death itself, can reprogram the graft, making it an immunologically active organ.(8,11) New strategies for the treatment of potential brain-dead donors represent a promising approach to reducing the immunogenicity of the graft and improving the quality of the organ before transplantation.(12) The administration of systemic corticosteroids to brain-dead donors is known to be beneficial mostly because of its ability to modulate the systemic inflammatory response caused by brain death. This modulation improves graft viability by reducing the release of pro-inflammatory molecules and the production of leukocyte adhesion molecules, thus increasing alveolar fluid clearance.(13,14) J Bras Pneumol. 2013;39(2):173-180

The optimal timing for the administration of corticosteroids in the setting of brain death is controversial. The aim of the present study was to evaluate the effects that early and late systemic administration of methylprednisolone have on the lungs in a rat model of brain death.

Methods The Animal Care Committee and the Research Ethics Committee of the Porto Alegre Hospital de Clínicas, Federal University of Rio Grande do Sul, Porto Alegre, Brazil, approved the protocols used in the present study.

Twenty-four male Wistar rats, weighing 170-200 g, underwent general anesthesia, induced by intraperitoneal administration of ketamine (100 mg/kg) and xylazine (15 mg/kg).

Anesthesia was followed by a tracheostomy with an indwelling 14-gauge cannula (Abbocath® #14; Abbott Laboratories, Abbott Park, IL, USA). The rats were ventilated with room air at 70-80 breaths/min with a tidal volume of 10 mL/kg (Harvard Rodent Ventilator, model 683; Harvard Apparatus Co., Millis, MA, USA). The right carotid artery was dissected and cannulated with a 24-gauge cannula (Becton Dickinson, Franklin Lakes, NJ, USA) for mean arterial pressure and HR recordings on an ink-jet recorder (Sirecust 730; Siemens-Elema, Solna, Sweden). The right jugular vein was dissected and cannulated in the same fashion. Normal saline was used to flush the lines, with a total volume of 5 mL/kg per hour in all animals, and a heated surgical table was used to maintain the body temperature at 37°C during the procedure.

After the initial procedures, the animals were randomly allocated to one of the following four groups (6 animals per group): • Sham (sham-operated): a craniotomy was performed, but no balloon catheter was introduced into the extradural space.

• BD (brain death only): brain death was induced; at 5 min after brain death had been confirmed, 0.2 mL of normal saline was administered intravenously.

• MP5 (methylprednisolone after 5 min of brain death): brain death was induced; at 5 min after brain death had been confirmed, an intravenous bolus of methylprednisolone (30 mg/kg) diluted in 0.2 mL of normal saline was administered .

Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats

• MP60 (methylprednisolone after 60 min of brain death): brain death was induced; at 60 min after brain death had been confirmed, an intravenous bolus of methylprednisolone (30 mg/kg) diluted in 0.2 mL of normal saline was administered.

The brain death model has previously been described in detail.(15,16) In brief, through a frontolateral trepanation (1 × 1 mm with a dental drill), a 14G Fogarty balloon catheter (Baxter Healthcare Corp., Irvine, CA, USA) was introduced into the extradural space with the tip pointed caudally. The balloon was inflated with 1.5 mL of water for 1 min, producing a sudden rise in intracranial pressure, which resulted in rapidly progressive brain injury, leading to immediate brain death. A sharp rise and then a subsequent drop of blood pressure and HR defined the initiation of brain death. The state of brain death was confirmed by the absence of corneal reflexes and by the apnea test.

The animals were monitored for 120 min, during which the pre-procedure ventilation parameters were maintained. Arterial blood samples were drawn for blood gas analyses: at the time of the insertion of the arterial line (baseline); and at 60 and 120 min after the procedures.

Upon completion of the assessment, a median sternotomy was performed, and the animals were sacrificed by exsanguination. The heart-lung blocks were excised, the right main bronchus was clamped, and the left lung was submitted to BAL three times (3 mL of normal saline each time). The right lung was then separated from the heart-lung block and divided into two parts.

Most of the right lung was snap frozen in liquid nitrogen and stored at −80°C for subsequent analyses of lipid peroxidation, catalase activity, superoxide dismutase activity, and TNF-α levels.

The remainder of the lung was fixed in formalin for histopathology. The mediastinal lobe was excised and weighed (wet weight) on a precision scale. Samples were then placed in a vacuum oven (at 70°C for 72 h) until a stable dry weight had been achieved. The wet-to-dry ratio of the lung weight was then calculated and used as an indicator of lung edema.(17) The BAL fluid (BALF) was centrifuged at 300 × g for 5 min, and the resulting cell pellet was separated from the supernatant. After preparation, the differential white cell count was determined with Romanowsky staining. The total protein

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concentration was determined using the biuret method (Modular Analytics; Roche Diagnostics, Penzberg, Germany), whereas the lactate dehydrogenase concentration was determined using the UV kinetic method (Modular Analytics).

After the samples had thawed, a 96-well plate was coated with monoclonal antibody for the determination of TNF-α levels. The wells were filled with either 100 µL of homogenized lung (dilution 1:2), 100 µL of positive control, 100 µL of negative control, or 100 µL of recombinant TNF-α, in concentrations established by the manufacturer of the antibody (Creative Biomart, New York, NY, USA). To each well, we then added 100 μL of polyclonal anti-TNF-α conjugated with peroxidase and incubated the plates for 3 h at room temperature. After the incubation period, the plate was washed four times with a detergent solution. A color change was then induced by adding hydrogen peroxide (0.02%) and tetramethylbenzene (2%). The reaction was interrupted 30 min later with sulfuric acid (1 M). Color intensity was measured in an automated ELISA reader (Titertek Multiskan®; Flow Laboratories, McLean, VA, USA), at a wavelength of 450 nm, and is expressed as optical density.

The TNF-α concentration in the homogenized lung was calculated from the results obtained with a standard curve.

The products generated by lipid peroxidation were quantified by the thiobarbituric acid reactive substance (TBARS) method using 3 mg of protein per sample. The samples were incubated at 90°C for 30 min, and 500 µL of 0.37% thiobarbituric acid and 15% trichloroacetic acid were then added to the samples, which were centrifuged at 2,000 x g at 4°C for 15 min. Absorbance was determined using spectrophotometry at 535 nm.(18) The activity of superoxide dismutase was determined by pulse radiolysis based on the autooxidation of epinephrine in accordance with the method described by Misra & Fridovich.(19) Catalase activity was determined by the spectrophotometry method described by Maehly & Chance.(20) Myeloperoxidase activity was used as an indicator of polymorphonuclear leukocyte accumulation. The rate of change in absorbance was measured by spectrophotometry at 650 nm. Myeloperoxidase activity was defined as the quantity of enzyme degrading 1 μmol of peroxide/min at 37°C and was expressed in mU/g of wet tissue.

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The fragment of lung fixed in formalin was embedded in paraffin, cut into 3-mm sections and stained with H&E. A pathologist blinded to the experimental protocol performed the quantitative examination by light microscopy. Each lung sample was examined at low and high magnifications, and 20 fields were randomly selected and analyzed. The severity of histological lesions was assessed using a five-parameter score that included intra-alveolar edema; hyaline membrane formation; hemorrhage; focal alveolar collapse or consolidation; and epithelial desquamation or necrosis of airways or alveoli. Each parameter was evaluated semi-quantitatively using the following scale: 0 = absent; 1 = mild; 2 = moderate; and 3 = prominent. For each animal, the parameter scores were summed in order to obtain the final score.(21) All of the data collected were coded, recorded, and analyzed using the Statistical Package for the Social Sciences, version 16.0 (SPSS Inc., Chicago, IL, USA). We used ANOVA for comparisons among the groups. When ANOVA showed a significant difference, Tukey’s post hoc test for multiple comparisons was applied in order to evaluate that difference. We used repeated measures ANOVA for intergroup comparisons related to dependent variables that were measured more than once during the observation period. For each test, the data were expressed as means and standard errors, and the level of significance was set at p < 0.05.

Results There were no differences among the groups regarding the duration of the procedure; wet/dry weight ratio; arterial blood gas measurements; myeloperoxidase activity; superoxide dismutase activity; catalase activity; or (in the BALF) differential white cell count, total protein content, and lactate dehydrogenase levels. Nor were there any differences among the groups in terms of mean arterial pressure during the observation period.

The levels of TBARS were significantly higher in the two groups treated with methylprednisolone than in the sham and BD groups (p < 0.001; Figure 1). There were no significant differences in the histological scores among the groups (Figure 2).

Lung injury, represented by intra-alveolar hemorrhage or hyaline membrane formation, was not observed in any samples. The predominant J Bras Pneumol. 2013;39(2):173-180

finding was mild focal alveolar collapse, which was present in the majority of the samples, at similar intensity across the groups (Figure 2).

The levels of TNF-α were significantly lower in the MP5 and MP60 groups when compared with the BD group (p < 0.001 for both; Figure 3).

Discussion The vast majority of experimental studies have shown a significant increase in inflammatory molecules and interleukins immediately after the induction of brain death.(22,23) The pro-inflammatory cytokine TNF-α has been shown to be significantly up-regulated in the lung tissue after brain death(12,24) and plays an important role in the development of lung injury.(22) In the present study, brain death resulted in a systemic inflammatory response and the administration of methylprednisolone was associated with reduced TNF-α expression in lung tissue. McLean et al. obtained similar results in a study of the effects that a glucocorticoid has on myocardial function in a porcine model of brain death.(25) To our knowledge, the present study is the first to investigate the role of the administration of methylprednisolone in a rat model of brain death and its influence on TNF-α expression and oxidative stress in the lungs.(22) Our study demonstrated that the administration of methylprednisolone has no effect on arterial blood gas and hemodynamic parameters. The lack of differences in these findings might be related to the short period of observation. The administration of methylprednisolone immediately after brain death in a rat model of lung transplantation has been shown to modulate the inflammatory injury of the donor lung, resulting in better graft performance after transplantation.(14) Clinically, the use of corticosteroids in multiorgan donors is still controversial. However, various clinical studies using different hormone resuscitation protocols have shown promising results. Nevertheless, a standard protocol has yet to be established, especially with respect to lung retrieval.(26-29) The use of glucocorticoids in brain-dead donors probably has dual beneficial effects, because it reduces inflammatory activity and replaces cortisol levels in the blood. Although we studied TNF-α activity after brain death, it would have been interesting to have also measured the cortisol levels after brain death in this model.

In a baboon model, Faropoulos & Apostolakis

Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats

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U/mg of protein

0.5

*

*

MP5

MP60

0.4 0.3 0.2 0.1 0 BD

sham Group

Figure 1 - Oxidative stress and brain death. There was a significant increase in lipid peroxidation using the thiobarbituric acid reactive substance method in the groups that received methylprednisolone at 5 and 60 min after brain death (MP5 and MP60, respectively) when compared with the sham and brain death (BD) groups.

Values are expressed as mean ± SE. *p < 0.001.

3 2.5

Score

2 1.5 1 0.5 0 BD

sham

MP5

MP60

Group

Figure 2 - Histological score and microscopic optical analysis (H&E; magnification, ×400). No significant differences were observed among the groups. The predominant finding was mild focal alveolar collapse.

Groups: sham; brain death (BD); methylprednisolone at 5 min after brain death (MP5), and methylprednisolone at 60 min after brain death (MP60). Values are expressed as mean ± SE.

found that cortisol levels rise within 5 min after the induction of brain death, declining steadily thereafter (over the next 15-45 min) and becoming undetectable at 4 h after brain death.(30) In our experiments, we found no differences in the differential white cell count in BALF or in histology. We suppose that lung inflammatory changes can be assessed up to 120 min of ventilation after brain death induction in

lungs that are still suitable for transplantation.

However, there have been reports based on other experimental models of lung injury and brain death that advocate for the analysis of pulmonary inflammation within the first 6 h after brain death.(11) The present study has limitations, and care must be taken when extrapolating its results to a clinical situation. We used a standardized,

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* 700 600

pg/dL

500 400 300 200 100 0 BD

sham

MP5

MP60

Group

Figure 3 - TNF-α levels in lung tissue. There was a significant increase in TNF-α levels in the brain death (BD) group when compared with the methylprednisolone at 5 min after brain death (MP5) and methylprednisolone at 60 min after brain death (MP60) groups. Values are expressed as mean ± SE. *p < 0.001.

small animal model of brain death that includes a sudden rise in intracranial pressure, which differs from what is often found in patients evolving to brain death, in whom intracranial pressure rises at a slower pace. Another difference is that the time from brain death to organ harvest is typically much longer in the clinical scenario than it was in our model. A brain death model in which intracranial pressure is gradually induced by the inflation of a subdural balloon catheter has been developed.

This improved model allows for the study of donor organ quality without the use of an inotropic infusion. Regarding corticosteroid administration, there is evidence that methylprednisolone given every 24 h (at 15 mg/kg i.v.) during brain death improves the effectiveness of the subsequent lung transplantation.(13) Therefore, we decided to use a higher dose of methylprednisolone in an attempt to potentiate the anti-inflammatory effects. The ideal period for the administration of the corticosteroid is still controversial in the literature. In the clinical scenario, it is expected that treatment with corticosteroids will be introduced as soon as possible in order to reduce the inflammatory activity. We considered 60 min after brain death to be late administration, given that, in a controlled animal model of brain death, the inflammatory activity at 60 min after brain

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death would be considerably higher than at 5 min after brain death.

The results of the present study show that the early administration of methylprednisolone after acute brain death does not improve oxygenation indices or hemodynamic parameters in lungs ventilated for 120 min. We also demonstrated an increase in the generation of lipid peroxidation products in the groups treated with methylprednisolone after 5 and 60 min of brain death. As previously demonstrated, traumatic brain injury significantly increases lipid peroxidation levels in lung tissue only 24 h after the trauma,(22) which could explain our lipid peroxidation results. However, the exact causes of these findings cannot be determined from our experiments.

We conclude that, in this model of brain death, early and late administration of methylprednisolone have similar effects on inflammatory and lipid peroxidation activity in lung tissue. We suggest that late administration of methylprednisolone can be used in settings of brain death, because of its potential anti-inflammatory effect. Further studies investigating the effects of late administration of methylprednisolone in the setting of lung transplantation following brain death are needed in order to confirm its beneficial effects.

Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats

References 1. Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, Taylor DO, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart-lung transplantation report-2007.

J Heart Lung Transplant. 2007;26(8):782-95.

2. Fernandes PM, Samano MN, Junqueira JJ, Waisberg DR, Noleto GS, Jatene FB. Lung donor profile in the State of S達o Paulo, Brazil, in 2006. J Bras Pneumol.

2008;34(7):497-505.

3. Organ and tissue donation and transplantation (update 2000). Canadian Medical Association [Article in English, French]. CMAJ. 2000;163(2):206-11.

4. Chakinala MM, Kollef MH, Trulock EP. Critical Care Aspects of Lung Transplant Patients. J Intensive Care Med. 2002;17:8-33.

5. Yeung JC, Cypel M, Waddell TK, van Raemdonck D, Keshavjee S. Update on donor assessment, resuscitation, and acceptance criteria, including novel techniques-non-heart-beating donor lung retrieval and ex vivo donor lung perfusion. Thorac Surg Clin. 2009;19(2):261-74.

6. Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364(15):1431-40.

7. Avlonitis VS, Fisher AJ, Kirby JA, Dark JH. Pulmonary transplantation: the role of brain death in donor lung injury. Transplantation. 2003;75(12):1928-33.

8. de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemiareperfusion-induced lung injury. Am J Respir Crit Care Med. 2003;167(4):490-511.

9. Power BM, Van Heerden PV. The physiological changes associated with brain death--current concepts and implications for treatment of the brain dead organ donor. Anaesth Intensive Care. 1995;23(1):26-36.

10. Rosenberg RN. Consciousness, coma, and brain death-2009. JAMA. 2009;301(11):1172-4.

11. de Perrot M, Bonser RS, Dark J, Kelly RF, McGiffin D, Menza R, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part III: donorrelated risk factors and markers. J Heart Lung Transplant.

2005;24(10):1460-7.

12. Pratschke J, Neuhaus P, Tullius SG. What can be learned from brain-death models? Transpl Int. 2005;18(1):15-21.

13. Follette DM, Rudich SM, Babcock WD. Improved oxygenation and increased lung donor recovery with high-dose steroid administration after brain death. J Heart Lung Transplant. 1998;17(4):423-9.

14. Wigfield C, Golledge H, Shenton B, Kirby J, Dark J. Ameliorated reperfusion injury in lung transplantation after reduction of brain death induced inflammatory graft damage in the donor. J Heart Lung Transplant.

2002;21(1):57.

15. van Der Hoeven JA, Ter Horst GJ, Molema G, de Vos P, Girbes AR, Postema F, et al. Effects of brain death

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and hemodynamic status on function and immunologic activation of the potential donor liver in the rat. Ann Surg. 2000;232(6):804-13.

16. Herijgers P, Leunens V, Tjandra-Maga TB, Mubagwa K, Flameng W. Changes in organ perfusion after brain death in the rat and its relation to circulating catecholamines.

Transplantation. 1996;62(3):330-5.

17. Pearce ML, Yamashita J, Beazell J. Measurement Of Pulmonary Edema. Circ Res. 1965;16:482-8.

18. Buege JA, Aust SD. Microsomal lipid peroxidation.

Methods Enzymol. 1978;52:302-10.

19. Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170-5.

20. Maehly AC, Chance B. The assay of catalases and peroxidases: methods of biochemical analysis. In: Glick D, editor. Methods of Biochemical Analysis. New York: Interscience Publishers; 1954. p. 357-424.

21. Fujino Y, Goddon S, Chiche JD, Hromi J, Kacmarek RM. Partial liquid ventilation ventilates better than gas ventilation. Am J Respir Crit Care Med. 2000;162(2 Pt 1):650-7.

22. Barklin A. Systemic inflammation in the brain-dead organ donor. Acta Anaesthesiol Scand. 2009;53(4):425-35.

23. Takada M, Nadeau KC, Hancock WW, Mackenzie HS, Shaw GD, Waaga AM, et al. Effects of explosive brain death on cytokine activation of peripheral organs in the rat. Transplantation. 1998;65(12):1533-42.

24. Skrabal CA, Thompson LO, Potapov EV, Southard RE, Joyce DL, Youker KA, et al. Organ-specific regulation of pro-inflammatory molecules in heart, lung, and kidney following brain death. J Surg Res. 2005;123(1):118-25.

25. McLean KM, Duffy JY, Pandalai PK, Lyons JM, Bulcao CF, Wagner CJ, et al. Glucocorticoids alter the balance between pro- and anti-inflammatory mediators in the myocardium in a porcine model of brain death. J Heart Lung Transplant. 2007;26(1):78-84.

26. Van Bakel AB, Pitzer S, Drake P, Kay NA, Stroud M, Sade RM. Early hormonal therapy stabilizes hemodynamics during donor procurement. Transplant Proc. 2004;36(9):2573-8.

27. Venkateswaran RV, Patchell VB, Wilson IC, Mascaro JG, Thompson RD, Quinn DW, et al. Early donor management increases the retrieval rate of lungs for transplantation.

Ann Thorac Surg. 2008;85(1):278-86; discussion 286.

28. Rosendale JD, Kauffman HM, McBride MA, Chabalewski FL, Zaroff JG, Garrity ER, et al. Aggressive pharmacologic donor management results in more transplanted organs.

Transplantation. 2003;75(4):482-7.

29. Kutsogiannis DJ, Pagliarello G, Doig C, Ross H, Shemie SD. Medical management to optimize donor organ potential: review of the literature. Can J Anaesth. 2006;53(8):820-30.

30. Faropoulos K, Apostolakis E. Brain death and its influence on the lungs of the donor: how is it prevented? Transplant Proc. 2009;41(10):4114-9.

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About the authors Eduardo Sperb Pilla

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

Raôni Bins Pereira

Physician. Department of Thoracic Surgery, Porto Alegre Hospital de Clínicas, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Luiz Alberto Forgiarini Junior

Professor of Physiotherapy. Methodist University Center, Porto Alegre Institute, Porto Alegre, Brazil.

Luiz Felipe Forgiarini

Biologist. Department of Thoracic Surgery, Porto Alegre Hospital de Clínicas, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.

Artur de Oliveira Paludo

Medical Student. Federal University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil.

Jane Maria Ulbrich Kulczynski

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

Paulo Francisco Guerreiro Cardoso

Professor. Department of Cardiorespiratory Diseases, University of São Paulo School of Medicine Hospital das Clínicas Heart Institute, São Paulo, Brazil.

Cristiano Feijó Andrade

Thoracic Surgeon. Porto Alegre Hospital de Clínicas, Federal University of Rio Grande do Sul, and Santo Antônio Children’s Hospital, Santa Casa Hospital Complex, Porto Alegre, Brazil.

J Bras Pneumol. 2013;39(2):173-180

Original Article Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis* Contribuição da análise molecular do gene regulador da condutância transmembrana na fibrose cística na investigação diagnóstica de pacientes com suspeita de fibrose cística leve ou doença atípica

Vinícius Buaes Dal’Maso, Lucas Mallmann, Marina Siebert, Laura Simon, Maria Luiza Saraiva-Pereira, Paulo de Tarso Roth Dalcin

Abstract Objective: To evaluate the diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suspected of having mild or atypical cystic fibrosis (CF). Methods: This was a cross-sectional study involving adolescents and adults aged ≥ 14 years. Volunteers underwent clinical, laboratory, and radiological evaluation, as well as spirometry, sputum microbiology, liver ultrasound, sweat tests, and molecular analysis of the CFTR gene. We then divided the patients into three groups by the number of mutations identified (none, one, and two or more) and compared those groups in terms of their characteristics.

Results: We evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation.

The mean age of the patients was 32.5 ± 13.6 years, and females predominated (75.7%). The molecular analysis contributed to the definitive diagnosis of CF in 3 patients (8.1%), all of whom had at least two mutations.

There were 7 patients (18.9%) with only one mutation and 26 patients (70.3%) with no mutations. None of the clinical characteristics evaluated was found to be associated with the genetic diagnosis. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H, and p.T351S. Conclusions: The molecular analysis of the CFTR gene coding region showed a limited contribution to the diagnostic investigation of patients suspected of having mild or atypical CF. In addition, there were no associations between the clinical characteristics and the genetic diagnosis.

Keywords: Cystic fibrosis/diagnosis; Cystic fibrosis/genetics; Cystic fibrosis transmembrane conductance regulator.

Resumo Objetivo: Avaliar a contribuição da análise molecular do gene cystic fibrosis transmembrane conductance regulator (CFTR, regulador da condutância transmembrana na fibrose cística) na investigação diagnóstica da fibrose cística em pacientes com suspeita de fibrose cística (FC) leve ou atípica. Métodos: Estudo transversal em adolescentes e adultos (idade ≥ 14 anos). Os voluntários foram submetidos à avaliação clínica, laboratorial e radiológica; espirometria, microbiologia do escarro, ecografia hepática, teste do suor e análise molecular do gene CFTR. Compararam-se as características dos pacientes divididos em três grupos, segundo o número de mutações identificadas (duas ou mais, uma e nenhuma). Resultados: Foram avaliados 37 pacientes com achados fenotípicos de FC, com ou sem confirmação pelo teste do suor. Houve predomínio do sexo feminino (75,7%), e a média de idade dos participantes foi de 32,5 ± 13,6 anos. A análise molecular contribuiu para o diagnóstico de FC em 3 casos (8,1%), todos esses com pelo menos duas mutações. Houve a identificação de uma e nenhuma mutação, respectivamente, em 7 (18,9%) e 26 pacientes (70,3%). Nenhuma característica clínica estudada se associou com o diagnóstico genético.

A mutação p.F508del foi a mais comum, encontrada em 5 pacientes. A associação de p.V232D e p.F508del foi encontrada em 2 pacientes. Outras mutações encontradas foram p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H e p.T351S. Conclusões: A análise molecular da região codificadora do gene CFTR apresentou uma contribuição limitada para a investigação diagnóstica desses pacientes com suspeita de FC leve ou atípica.

Além disso, não houve associações entre as características clínicas e o diagnóstico genético.

Descritores: Fibrose cística/diagnóstico; Fibrose cística/genética; Regulador de condutância transmembrana em fibrose cística. * Study carried out at the Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Correspondence to: Vinícius Buaes Dal’Maso. Rua Uruguai, 1953, CEP 99010-115, Passo Fundo, RS, Brasil.

Tel. 55 54 3311-6711. E-mail: dalmaso@upf.br Financial support: This study received financial support from the Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA, Research Incentive Fund of the Porto Alegre Hospital de Clínicas) and, in the form of donations, from United Medical and Roche.

Submitted: 23 October 2012. Accepted, after review: 4 March 2013.

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Introduction

Methods

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in a gene that is located on the long arm of chromosome 7 and that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein.(1,2) Although CF is usually diagnosed in childhood (in the first year of life in 70% of cases), the number of cases of CF diagnosed in adolescence and adulthood has increased as a result of a higher level of clinical suspicion and the availability of diagnostic techniques.(3) The phenotypic expression of CF varies among CF patients. The diagnosis is based on phenotypic findings, family history, newborn screening test results, and quantitative pilocarpine iontophoresis sweat test results.(4) The sweat test is considered the gold standard for the diagnosis of CF,(5) which is confirmed by two or more determinations of sweat chloride concentrations greater than 60 mEq/L at different time points. In cases in which sweat chloride concentrations are found to be borderline or normal, additional diagnostic tests are needed, molecular analysis being performed in order to identify mutations in the CFTR gene.(6,7) Although the method is highly specific for CF, its sensitivity is low. This is due to the fact that the number of known mutations is quite large (over 1,900), although only a minority is included in commercially available panels.(2,8) Despite its shortcomings, analysis of mutations in the CFTR gene has been increasingly used as a diagnostic method for CF. The identification of two CF-causing mutations confirms the diagnosis of atypical CF. The identification of one mutation is inconclusive. The absence of mutations means that the diagnosis of CF is highly unlikely, and differential diagnoses, such as ciliary dyskinesia and immunodeficiency, should be considered.(9) The objective of the present study was to evaluate the contribution of molecular analysis of the CFTR gene coding region to the diagnostic investigation of adolescents and adults suspected of having mild or atypical CF, as well as to compare the characteristics of three groups of patients, divided according to the number of CFTR gene mutations identified (none, one, or two or more, the last of the three confirming the diagnosis of CF).

This was a single-center cross-sectional study. We sought to evaluate the contribution of molecular analysis of the CFTR gene to the diagnostic investigation of adolescents and adults suspected of having mild CF (diagnosis confirmed by sweat test results and mild lung disease without pancreatic insufficiency) or atypical CF (clinical phenotype consistent with CF without sweat test confirmation).

The study protocol was approved by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre (HCPA, Porto Alegre Hospital de Clínicas; Protocol no. 08-549). All of the participants gave written informed consent.

Although we received donations from private companies (Roche and United Medical), those sponsors had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

The study population consisted of patients selected from among those treated at the HCPA Department of Pulmonology outpatient clinic for adolescents and adults with CF, located in the city of Porto Alegre, Brazil. We included individuals ≥ 14 years of age with phenotypic findings of CF (digital clubbing, bronchiectasis, chronic infection with typical bacteria, and exocrine pancreatic insufficiency), with or without sweat test confirmation.

We excluded patients in whom the phenotypic findings were attributable to other diseases, such as ciliary dyskinesia and primary immunodeficiency; pregnant patients; and patients who declined to participate in the study or who declined to give written informed consent.

Volunteers were selected from among patients attending the abovementioned outpatient clinic for routine medical visits between 2009 and 2010. The selected patients were interviewed by one of the members of our study group. The interviewer used a data collection form in order to gather information on the following variables: age; gender; marital status; race; family history of CF; presence of digital clubbing; and body mass index (BMI), in kg/m2.

All of the patients underwent 2-h oral glucose tolerance tests, with the exception of those with a previous diagnosis of diabetes mellitus based on fasting blood glucose levels, in accordance with the American Diabetes Association criteria. (10,11)

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Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis

The evaluation of chronic sinus disease was complemented by CT of the sinuses.

The Shwachman-Kulczycki score(12) was used in order to assess overall disease severity. This clinical scoring system is based on four different aspects (general activity, physical examination, nutrition, and chest X-ray findings). Each is scored on a 5-25 point scale, a better performance translating to a higher score. A final score of 100 points indicates optimal clinical condition.

We reviewed the bacteriological tests performed on sputum samples collected during routine clinical visits in the last 12 months. Identification of mucoid and nonmucoid Pseudomonas aeruginosa, methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Burkholderia cepacia, and Haemophilus influenzae was recorded when they were identified at least twice in sputum samples collected during routine clinical visits at intervals longer than 30 days.

Spirometry was performed in the HCPA Department of Pulmonology with a MasterScreen spirometer and the program v4.31 (Jaeger, Würzburg, Germany) in accordance with the Brazilian Thoracic Association technical acceptability criteria.(13) We recorded FVC, FEV1, and the FEV1/FVC ratio. Three acceptable maneuvers were performed, the values obtained on the best test being recorded. All parameters were expressed as a percentage of the predicted values for age, height, and gender.(14) For the diagnosis of liver disease in CF, we used the ultrasound scoring system developed by Williams.(15) The scoring system is based on three ultrasound features: liver parenchyma—normal (1 point), coarse (2 points), or irregular (3 points); liver edge—smooth (1 point) or nodular (3 points); and periportal fibrosis—absent (1 point), moderate (2 points), or severe (3 points). A final score of 3 is consistent with normal liver, higher scores being suggestive of progressive liver disease.

A score of 8-9 is consistent with established liver cirrhosis. This ultrasound scoring system is routinely used at the HCPA. The sonographer at the HCPA interpreted and scored the findings of routine ultrasound examinations.

Molecular analysis was performed in the HCPA Department of Genetics. A sample of 5 mL of peripheral blood was collected for DNA extraction. The CFTR gene coding region was amplified by polymerase chain reaction.

Sequencing of the fragments was performed using

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the Big Dye™ Terminator v3.1 Ready Reaction Cycle Sequencing (Applied Biosystems, Foster City, CA, USA) and fluorescent dye terminator sequencing on a genetic analyzer (ABI PRISM™ 3130xl, Applied Biosystems). The analyses were performed with the DNA Sequencing Software v5.2 (Applied Biosystems). All 27 CFTR gene exons were sequenced. The flanking regions and exon-intron organization were also included in the sequencing. The intron 8 polymorphism was also analyzed.

For the statistical analysis, the data were processed and analyzed with the aid of the IBM SPSS Statistics software package, version 18.0 (IBM Corporation, Armonk, NY, USA).

Descriptive analysis was performed, quantitative data being presented as mean ± SD or median (interquartile range). Qualitative data were expressed as n (%).

In the statistical analysis, the patients were divided into three groups by the number of known CF-causing mutations identified (two or more, one, or none).

The three groups were compared by one-way ANOVA for continuous variables with normal distribution; by the Kruskal-Wallis test for ordinal variables or for continuous variables without normal distribution; and by the chi-square test for categorical variables, Yates’ correction or Fisher’s exact test being used when necessary.

The level of significance was set at 5%, and all tests were two-tailed.

Results Between May of 2009 and November of 2010, we evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation. None of the selected patients declined to participate in the study. All of the patients completed the study protocol.

Table 1 shows the general characteristics of the patients. Females predominated in the study sample, which consisted of 28 females (75.7%) and 9 males (24.3%). The mean age was 32.5 ± 13.6 years (range, 14-67 years). Most of the patients were White (only 1 patient was non-White), and 16 patients (43.2%) reported having relatives (firstand second-degree relatives) with a confirmed diagnosis of CF. Five patients (13.5%) had been diagnosed with exocrine pancreatic insufficiency.

The mean BMI was 22.4 ± 3.85 kg/m2 (range, 15.3-30.0 kg/m2). Digital clubbing was found J Bras Pneumol. 2013;39(2):181-189

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in 21.6% of the patients. Only 3 patients (8.1%) met diagnostic criteria for diabetes mellitus, and 13 (35.1%) met diagnostic criteria for chronic sinus disease. Regarding sputum microbiology, the most commonly isolated bacterium was P. aeruginosa (43.2%), followed by S. aureus (35.1%). H. influenzae was identified in 7 patients (18.9%), and B. cepacia was isolated in 5.4% of the patients. The mean FEV1 was 68.31 ± 25.40% of predicted, the mean FVC was 80.0 ± 19.4% of predicted, and the mean FEV1/FVC ratio was 71.68 ± 17.34%. Sweat electrolytes were evaluated in two samples, the mean weight of the first sample being 242.00 ± 85.99 mg and the mean weight of the second sample being 228.50 ± 95.00 mg. Chloride concentrations in the first and second samples were, respectively, 54 ± 26.14 mEq/L and 51.76 ± 23.37 mEq/L. Table 2 compares the three groups of patients (those in whom two or more mutations were identified, those in whom only one mutation was identified, and those in whom no mutations were identified) in terms of their characteristics. There were no significant differences among the groups regarding gender, age, race, or family history of CF. There were no significant differences among the three groups regarding exocrine pancreatic insufficiency, which was found in 2, zero, and 3 patients, respectively. There were also no significant differences among the groups regarding presence of digital clubbing, BMI, presence of diabetes mellitus, or presence of chronic sinus disease.

Regarding sputum microbiology, we found no significant differences among the groups in terms of the identification of P. aeruginosa, S. aureus, H. influenzae, and B. cepacia. There were no significant differences among the groups regarding the Shwachman-Kulczycki score, the Williams liver score, or the presence of bronchiectasis. There were also no statistically significant differences among the three groups regarding the mean FVC and FEV1, in % of predicted, or the mean FEV1/ FVC ratio. There were no differences among the groups in terms of sweat sodium and chloride concentrations. There were no differences among the three groups regarding normal, borderline, or abnormal sweat test results. Those results were observed, respectively, in 1, 2, and 1 of the patients in whom at least two mutations were identified; in 1, 3, and 3 of the patients in whom one mutation was identified; and in 12, 4, and 10 of the patients in whom no mutations were identified.

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The mutations identified by molecular analysis are presented in Table 3. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. In 1 patient, we identified three mutations (p.T351S and p.F508del in the first allele, and p.P1290P in the second allele). Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, and p.R1066H.

Discussion This was a cross-sectional study evaluating patients who presented with phenotypic findings consistent with CF and who were referred to a referral outpatient clinic for the diagnosis and treatment of CF in adolescents and adults. The molecular analysis of the CFTR gene contributed to the definitive diagnosis of CF in 4 (10.8%) of the 37 patients evaluated. In 7 patients (18.9%), only one CF-causing mutation was identified, whereas, in 26 patients (70.3%), no mutations were identified. None of the clinical characteristics evaluated were found to be associated with the genetic diagnosis. The presence of exocrine pancreatic insufficiency tended to be more common in patients with a confirmed genetic diagnosis of CF, although the difference was not statistically significant. Of the patients with a genetic diagnosis of CF, only 1 had abnormal sweat test results. However, of the 7 patients in whom one mutation was identified, 3 had abnormal sweat test results, as did 10 of the 26 patients in whom no mutations were identified.

Clinical characteristics and reasons for referral included the presence of chronic lung disease and chronic sinus disease, bronchopulmonary colonization with germs suggestive of CF, digital clubbing, family history of CF, gastrointestinal abnormalities, and nutritional abnormalities.(2) All of the patients had previously undergone sweat tests at least twice.

In the present study, of the 4 patients with a genetic diagnosis of CF, 1 can be characterized as having mild, classic CF because that patient had late manifestations of the disease and abnormal sweat test results, whereas the remaining 3 can be characterized as having atypical CF because they presented with borderline or normal sweat electrolyte values.

The development of molecular analysis techniques allowed the identification of more than

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Table 1 - General characteristics of the patients suspected of having mild or atypical cystic fibrosis.a Patients Variables (n = 37) Gender Male 9 (24.3) Female 28 (75.7) 32.5 ± 13.6 Age, yearsb Race White 36 (97.3) Non-White 1 (2.7) 22.4 ± 3.85 BMI,b kg/m2 Family history of CF 16 (43.2) Exocrine pancreatic insufficiency 5 (13.5) Digital clubbing 8 (21.6) Diabetes mellitus 3 (8.1) Chronic sinus disease 13 (35.1) Sputum bacteriology Pseudomonas aeruginosa 16 (43.2) 7 (18.9) Mucoid P. aeruginosa 10 (27.0) Nonmucoid P. aeruginosa Staphylococcus aureus 13 (35.1) 12 (32.4) Methicillin-sensitive S. aureus 2 (5.4) Methicillin-resistant S. aureus Burkholderia cepacia 2 (5.4) Haemophilus influenzae 7 (18.9) 2.20 ± 0.95 FEV1, Lb 68.31 ± 25.4 FEV1, % of predictedb 2.99 ± 0.90 FVC, Lb 80.0 ± 19.4 FVC, % of predictedb 71.68 ± 17.34 FEV1/FVCb Sweat testb Sample 1 Sodium, mEq/L 57.57 ± 27.34 Chloride, mEq/L 54.00 ± 26.14 Sample weight, mg 242.34 ± 85.99 Sample 2 Sodium, mEq/L 57.19 ± 22.12 Chloride, mEq/L 51.76 ± 23.37 Sample weight, mg 228.50 ± 95.00 CF: cystic fibrosis; and BMI: body mass index. aValues expressed as n (%), except where otherwise indicated. bValues expressed as mean ± SD.

1,900 mutations in the CFTR gene, as can be seen in the Cystic Fibrosis Mutation Database (http:// www.genet.sickkids.on.ca/cftr). Genetic mutations have been classified as severe (class I-III mutations) or mild (class IV-VI mutations) on the basis of the molecular defect of the CFTR protein.(16,17) In individuals with class I mutations, the CFTR protein is not synthesized; in those with class II mutations, the CFTR protein is improperly processed in the endoplasmic reticulum; in those

with class III mutations, the CFTR protein is improperly regulated; in those with class IV mutations, the CFTR protein shows defective conductance; in those with class V mutations, CFTR protein production is defective; and in those with class VI mutations, there is rapid degradation of the CFTR protein.(18,19) Nonclassic forms of CF have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. (20) In general, individuals

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Table 2 - Comparison of three groups of patients (those in whom two or more mutations were identified, those in whom one mutation was identified, and those in whom no mutations were identified) in terms of their characteristics.a No. of mutations Variables ≥2 1 0 p* (n = 4) (n = 7) (n = 26) Gender Male 1 (25.0) 0 (0.0) 8 (30.8) 0.242 Female 3 (75.0) 7 (100.0) 18 (69.2) 30.80 ± 10.90 30.00 ± 9.95 33.00 ± 14.43 0.851 Age, yearsb Race White 4 (100.0) 7 (100.0) 25 (96.2) 0.805 Non-White 0 (0.0) 0 (0.0) 1 (3.8) BMI,b kg/m2 22.9 ± 3.7 23.3 ± 2.3 22.2 ± 4.3 0.801 Family history of CF 3 (75.0) 2 (28.6) 11 (42.3) 0.322 Exocrine pancreatic insufficiency 2 (50.0) 0 (0.0) 3 (11.5) 0.570 Digital clubbing 0 (0.0) 0 (0.0) 8 (30.8) 0.115 OGTT Glucose intolerance 0 (0.0) 2 (28.6) 4 (15.4) 0.624 Diabetes 0 (0.0) 1 (14.3) 2 (7.7) Chronic sinus disease 2 (50.0) 4 (57.1) 7 (26.9) 0.266 Sputum bacteriology Pseudomonas aeruginosa 1 (25.0) 5 (71.4) 10 (38.5) 0.218 1 (25.0) 3 (42.9) 3 (11.5) 0.162 Mucoid P. aeruginosa 0 (0.0) 3 (42.9) 7 (26.9) 0.306 Nonmucoid P. aeruginosa Staphylococcus aureus 3 (75.0) 3 (42.9) 7 (26.9) 0.154 2 (50.0) 3 (42.9) 7 (26.9) 0.530 Methicillin-sensitive S. aureus 1 (25.0) 1 (14.3) 0 (0.0) 0.062 Methicillin-resistant S. aureus Burkholderia cepacia 0 (0.0) 0 (0.0) 2 (7.7) 0.639 Haemophilus influenzae 0 (0.0) 1 (14.3) 6 (23.1) 80 (32.5) 75 (20.0) 70 (31.3) 0.748 Shwachman-Kulczycki scorec 3 (0) 3 (0) 3 (0) 0.399 Liver scorec Presence of bronchiectasis 2 (50.0) 6 (85.7) 19 (73.1) 0.439 3.01 ± 0.71 2.44 ± 0.70 2.20 ± 1.13 0.317 FEV1, Lb 89.7 ± 26.0 72.2 ± 14.7 68.2 ± 29.0 0.338 FEV1, % of predictedb 3.7 ± 0.4 3.2 ± 0.5 2.9 ± 1.2 0.359 FVC, Lb 95.5 ± 16.1 81.7 ± 6.2 78.5 ± 23.2 0.320 FVC, % of predictedb 80.3 ± 12.5 74.8 ± 14.1 73.7 ± 19.0 0.785 FEV1/FVCb Sweat testb Sample 1 Sodium, mEq/L 56.8 ± 20.3 59.14 ± 27.3 56.5 ± 28.0 0.973 Chloride, mEq/L 53.8 ± 15.7 61.3 ± 23.10 51.34 ± 27.7 0.674 Sample 2 Sodium, mEq/L 53.3± 10.3 56.4 ± 27.8 58.1 ± 22.2 0.941 Chloride, mEq/L 49.7 ± 10.50 52.2 ± 26.0 52.2 ± 24.4 0.985 Sweat test result Normal 1 (25.0) 1 (14.3) 12 (46.2) 0.306 Borderline 2 (50.0) 3 (42.9) 4 (15.4) 1 (25.0) 3 (42.9) 10 (38.5) Abnormal CF: cystic fibrosis; BMI: body mass index; and OGTT: oral glucose tolerance test. aValues expressed as n (%), except where otherwise indicated. bValues expressed as mean ± SD. cValues expressed as median (interquartile range). *Oneway ANOVA for continuous variables with normal distribution or Kruskal-Wallis test (ordinal variables or continuous variables without normal distribution); chi-square test (categorical variables), Yates’ correction or Fisher’s exact test being used when necessary.

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Table 3 - Mutations in the groups of patients in whom at least one mutation was identified.

Groups Mutations Patients Allele 1 Allele 2 â&#x2030;Ľ 2 mutations 1 p.T351S/p.F508del p.P1290P 2 p.A559T p.D1152H 3 p.V232D p.F508del 4 p.V232D p.F508del 1 mutation 5 p.T1057A 6 p.I148T 7 p.V754M 8 p.P1290P 9 p.F508del 10 p.F508del 11 p.R1066H

who are homozygous for class I-III mutations present with pancreatic insufficiency, diabetes, high rates of meconium ileus, early mortality, more rapid decline in lung function, more severe malnutrition, and liver disease.(16) Patients with class IV and V mutations present with milder disease, pancreatic sufficiency, and better survival.(20,21) No mutations in the CFTR gene are identified in 1.0-1.5% of all patients with classic CF. In cases of nonclassic CF, various factors are important in order to establish the correct diagnosis. Our molecular analysis of the CFTR gene included analysis of the coding region and of the flanking regions. Mutations located in promoter regions and in distant regulatory sequences are not evaluated. (16) However, mutations in these regions are less common and would probably not have explained all of the cases in our sample.

The most common mutation is p.F508del (deletion of the amino acid phenylalanine at position 508); however, the frequency of this mutation varies across populations, being approximately 47% in Brazil.(22,23) In an analysis of Brazilian patients with CF, one group of authors showed that p.F508del and four other mutations (p.G542X, p.N1303K, p.G551D, and p.R553X) accounted for 56% of CF alleles.(24) The spectrum of CF mutations in Brazil indicates a strong European influence, being particularly similar to that in the Italian population.(25,26) In a previous study conducted at the HCPA, the p.F508del mutation was found in 48.7% of the alleles.(28) The sensitivity of CF genotyping depends entirely on the number of mutations tested and on the ethnicity of the individuals being tested.

The low sensitivity of the method is generally due to the large number of known mutations and to the fact that commercially available panels include only a minority of those mutations.(2) It should be taken into consideration that our study sample consisted of patients selected from among those referred to our facility (a referral center for CF) because of the difficulty in establishing a diagnosis.

One group of authors(27) reported 6 cases of CF diagnosed in adulthood, with suppurative lung disease, preserved pancreatic function, and only one mutation identified. The authors concluded that the diagnostic spectrum of patients investigated in adulthood is different from that of those diagnosed in childhood.

One study sought to determine whether changes in the function of the CFTR protein were responsible for the full spectrum of variant CF phenotypes.(28) The authors analyzed the CFTR gene in 74 patients with nonclassic CF. Of those patients, 29 had two mutations in the CFTR gene, 15 had one mutation, and 30 had no mutations. As occurred in our study, there were no differences among patients with two, one, or no mutations in terms of their clinical characteristics and sweat chloride concentrations. The authors concluded that factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic CF caused by CFTR protein dysfunction.

In 2004, one group of authors(29) published a study evaluating the clinical characteristics and diagnostic parameters of patients diagnosed with CF in adulthood. Of 1,051 individuals with (24)

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CF, 73 (7%) were diagnosed with the disease in adulthood. Of the 46 patients diagnosed with CF after 1990, 30 (65%) were diagnosed by sweat testing, 15 (33%) were diagnosed by mutation analysis, and 31 (67%) were diagnosed by a combination of both methods. Nasal potential difference measurements alone confirmed the diagnosis in the remaining 15 patients (33%).

The authors concluded that patients with CF presenting in adulthood generally present with pancreatic sufficiency, inconclusive sweat test results, and a high prevalence of mutations that are not seen in childhood.

The present study has some limitations. The major limitation of the present study is the small sample size (in particular, the small number of cases with a confirmed diagnosis), which precludes the generalization of the results of the comparison among the three groups in terms of their clinical characteristics and limits the external validity of the study. Another limitation is that we did not perform nasal potential difference measurements, because the method was not available for use at our hospital during the study period.

The clinical implication of the present study is that it demonstrates the difficulty that specialists face in diagnosing CF in adolescents and adults clinically suspected of having the disease.

Diagnostic investigation requires diagnostic tests other than the sweat test. The sweat test is not specific enough to rule out CF in such patients.

In conclusion, in this population of patients who had findings consistent with CF and who were referred to a referral program for adolescents and adults with CF for evaluation, the molecular analysis of the CFTR gene coding region contributed to the definitive diagnosis of CF in 3 patients (8.1%) and allowed the identification of mutations in 1 patient with mild CF, previously confirmed by sweat testing.

Patients with abnormal sweat electrolytes and with no identified mutations probably have alterations that are currently unknown. None of the clinical characteristics evaluated were found to be associated with the genetic diagnosis.

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Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis

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About the authors Vinícius Buaes Dal’Maso

Assistant Professor. University of Passo Fundo, Passo Fundo, Brazil.

Lucas Mallmann

Resident in Internal Medicine. Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Marina Siebert

Graduate Student. Graduate Program in Cellular and Molecular Biology, Genetic Identification Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Laura Simon

Graduate Student. Graduate Program in Cellular and Molecular Biology, Genetic Identification Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre – HCPA, Porto Alegre Hospital de Clínicas – Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Maria Luiza Saraiva-Pereira

Associate Professor. Department of Biochemistry, Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – Porto Alegre, Brazil.

Paulo de Tarso Roth Dalcin

Associate Professor. Universidade Federal do Rio Grande do Sul – UFRGS, Federal University of Rio Grande do Sul – School of Medicine, Porto Alegre, Brazil.

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Original Article Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses*,** Valores de referência para o teste de caminhada com carga progressiva em indivíduos saudáveis: da distância percorrida às respostas fisiológicas

Victor Zuniga Dourado, Ricardo Luís Fernandes Guerra, Suzana Erico Tanni, Letícia Cláudia de Oliveira Antunes, Irma Godoy

Abstract Objective: To determine reference values for incremental shuttle walk distance (ISWD) and peak physiological responses during the incremental shuttle walk test (ISWT), as well as to develop a series of predictive equations for those variables in healthy adults. Methods: We evaluated 103 healthy participants ≥ 40 years of age (54 women and 49 men). We fitted each participant with a gas analysis system for use during the ISWT. Oxygen consumption (VO2), carbon dioxide production, minute ventilation, heart rate (HR), ISWD, and maximal walking velocity (MWV) were obtained as primary outcomes. We also assessed hand grip strength (HGS) and lean body mass (LBM). Results: The regression analysis models, including physiological variables, ISWD, and MWV (adjusted for age, body mass, height, and sex), produced R2 values ranging from 0.40 to 0.65 (for HR and peak VO2, respectively). Using the models including LBM or HGS, we obtained no significant increase in the R2 values for predicting peak VO2, although the use of those models did result in slight increases in the R2 values for ISWD and MWV (of 8% and 12%, respectively). The variables ISWD, MWV, and ISWD × body mass, respectively, explained 76.7%, 73.3%, and 81.2% of peak VO2 variability. Conclusions: Our results provide reference values for ISWD and physiological responses to the ISWT, which can be properly estimated by determining simple demographic and anthropometric characteristics in healthy adults ≥ 40 years of age. The ISWT could be used in assessing physical fitness in the general adult population and in designing individualized walking programs.

Keywords: Reference values; Pulmonary gas exchange; Walking; Exercise test.

Resumo Objetivo: Determinar valores de referência para a distância caminhada (DC) e para respostas fisiológicas durante o teste de caminhada com carga progressiva (TCCP) e desenvolver equações preditivas para essas variáveis em adultos saudáveis. Métodos: Foram avaliados 103 participantes saudáveis com idade ≥ 40 anos (54 mulheres e 49 homens). Os participantes usaram um sistema de análise de gases durante o TCCP. Consumo de oxigênio (VO2), liberação de gás carbônico, ventilação minuto, frequência cardíaca (FC), DC e velocidade máxima da caminhada (VMC) foram obtidos como desfechos primários. Avaliamos também a força de preensão manual (FPM) e a massa magra corporal (MMC). Resultados: Os modelos de regressão utilizando variáveis fisiológicas, DC e VMC ajustados por idade, massa corporal, estatura e sexo apresentaram valores de R2 entre 0,40 e 0,65 (para FC e pico de VO2, respectivamente). Os modelos incluindo MMC e FPM não aumentaram consideravelmente os valores de R2 na previsão do pico de VO2, embora esses modelos tenham aumentado discretamente os valores do R2 para DC e VMC (8% e 12%, respectivamente). As variáveis DC, VMC e DC × massa corporal, respectivamente, explicaram 76,7%, 73,3% e 81,2% da variabilidade do pico de VO2. Conclusões: Nossos resultados originaram valores de referência para a DC e respostas fisiológicas ao TCCP, que podem ser estimados adequadamente por características demográficas e antropométricas simples em adultos saudáveis com idade ≥ 40 anos. O TCCP poderia ser utilizado na avaliação da capacidade física na população geral de adultos e no desenvolvimento de programas de caminhada individualizados.

Descritores: Valores de referência; Troca gasosa pulmonar; Caminhada; Teste de esforço.

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

Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation).

Correspondence to: Victor Z. Dourado. Avenida Ana Costa, 95, CEP 11060-001, Santos, SP, Brasil.

Tel./Fax: 55 13 3261-3324. E-mail: vzdourado@yahoo.com.br or victor.dourado@unifesp.br Submitted: 13 September 2012. Accepted, after review: 15 January 2013. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2013;39(2):190-197

Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses

Introduction The incremental shuttle walk test (ISWT) was developed in order to assess the functional exercise capacity of patients with COPD.(1) The test subject walks back and forth along a 10-m flat course, with progressive increases in pace imposed by audio signals, until no longer able to maintain the pace. The incremental character of the ISWT yields physiological responses closer to those observed in cardiopulmonary exercise testing (CPET).(2) Some authors argue that, as an externally paced walk test, the ISWT is more reproducible and yields greater physiological responses in comparison with self-paced walk tests.(3) One of the greatest advantages of the ISWT is its simplicity. The incremental shuttle walk distance (ISWD) is generally used as an index of cardiorespiratory fitness and has been suggested as a prognostic indicator in patients with chronic disease.(4) Because of its simplicity and low cost, walking is the most popular exercise for middle-aged and older adults. In healthy subjects, the heart rate variability threshold was reported to be a valid tool for estimating the ventilatory threshold during the ISWT.(5) The ISWT has also proven useful for quantifying the benefits of a walking program designed for healthy individuals.(6) Studies evaluating the ISWT in healthy subjects have shown that the ISWT is valid and responsive.

Despite the widespread use of the ISWT in clinical settings, few studies have assessed reference values and physiological responses to the test.

Recently, the ISWD has been investigated in healthy subjects, and regression equations have been developed, allowing a better interpretation of walking performance.(7-9) Two such studies enrolled participants with comorbidities,(7,9) whereas another included only healthy individuals.

(8) However, to our knowledge, there have been no studies evaluating physiological responses to the ISWT in healthy subjects in other than a superficial manner.

Although the operational simplicity of walk tests is recognized as their most important quality, the ISWT has been evaluated with the aid of sophisticated telemetric gas analysis systems in order to evaluate physiological responses, especially in patients with cardiorespiratory diseases.(2,10) In such patients, the peak oxygen consumption (VO2) achieved on the ISWT exhibits a strong correlation with that achieved

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in CPET performed on a treadmill or on a cycle ergometer. (10,11) Therefore, the ISWT appears to induce a maximum exercise response that is appropriate for assessing functional capacity.(12) Elucidation of such physiological responses might be useful for assessing exercise capacity and for designing walking programs for middle-aged and older adults. In addition, reference values, especially for VO2 and ISWD, might provide an easy way to assess the functional exercise capacity in patients with chronic diseases.

In this study, our primary objective was to determine reference values for ISWD and peak physiological responses during the ISWT, developing a series of simple predictive equations for those variables in healthy middle-aged adults and in healthy older adults. We also assessed the influence that body composition and muscle strength have on the main physiological variables obtained during the ISWT.

Methods We conducted a cross-sectional study to evaluate the physiological responses to the ISWT in 103 healthy adults aged 40 years and older.

The Research Ethics Committee of the Federal University of SĂŁo Paulo, located in the city of SĂŁo Paulo, Brazil, approved the study, and all participants provided written informed consent.

We recruited a convenience sample from among employees of the institution and residents of the surrounding community. The following individuals were ineligible for inclusion in the study: those with a body mass index > 35 kg/m2; those who used a walking aid; those who exhibited abnormal post-bronchodilator spirometric results(13); those who reported having cardiorespiratory, metabolic, neuromuscular, or musculoskeletal disease; and those who were current smokers.

Eligible participants underwent a series of evaluations over the course of two mornings, with a 7-day interval between the two. On day 1, the participants completed a physical activity readiness questionnaire, a face-to-face interview based on the main cardiovascular risk factors, and a physical activity questionnaire in accordance with the American College of Sports Medicine recommendations(14) so that we could exclude those involved in high-intensity exercise and sports. They also underwent spirometry, hand grip strength (HGS) assessment, and anthropometric and body composition measurements. Those J Bras Pneumol. 2013;39(2):190-197

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who met the eligibility criteria returned on day 2 and underwent three ISWTs, 20 min apart.

Body mass (in kg) and height (in m) were measured, and the body mass index (in kg/m2) was calculated. Body composition was assessed using a portable scale with a tetrapolar bioelectrical impedance system (TBF-310GS; Tanita, Arlington Heights, IL, USA).(15) Total body fat (TBF), total body water, and lean body mass (LBM) were assessed using regression equations.(16) The LBM was also expressed as a percentage of the predicted value.(17) Spirometry was performed using a handheld spirometer (Spiropalm; Cosmed, Pavona di Albano, Italy) in accordance with the criteria established by the Brazilian Thoracic Association.

(13) We measured FEV1, FVC, and FEV1/FVC ratio.

The HGS of the dominant side was assessed using a hydraulic dynamometer (HS5001; Carci, São Paulo, Brazil).(18) Three measurements were performed at least 30 s apart. The highest value was selected for further analysis.

We conducted the ISWTs in a 10-m corridor, increasing the pace by 0.17 m/s every minute.(1) Dyspnea and leg fatigue were quantified before and after each test with the Borg scale. Three ISWTs were performed 20 min apart. The ISWD (in m) and maximum walking velocity (MWV, in m/s) obtained on the third test were selected for further analysis. Because the ISWT was developed to assess the functional exercise capacity of patients with lung disease, the original protocol consisted of 12 levels (total distance, 1,020 m).(1) However, because we applied the test to healthy subjects, we extended it to 15 levels (1,500 m) in order to minimize the ceiling effect.

During the third ISWT, expired gases were collected and assessed by a portable telemetric gas analysis system (K4b2; Cosmed; Pavona di Albano, Italy). The physiological responses were analyzed breath-by-breath, and the data were filtered every 15 s. The following variables were focused at the peak of the ISWT: VO2, carbon dioxide production, HR, and minute ventilation.

The data were evaluated descriptively and are presented as mean ± standard deviation.

Sex-related differences in the main physiological variables and the rate of perceived exertion were evaluated using Student’s t-test or the MannWhitney test. Pearson’s or Spearman’s coefficients were used in order to assess bivariate correlations.

To ensure that the ISWD obtained in the third test, carried out using the gas analysis system, J Bras Pneumol. 2013;39(2):190-197

was not inferior to that obtained in the second test, conducted without the equipment, we evaluated the intraclass correlation coefficient (ICC) with its 95% CI between those measures and compared their mean values using paired Student’s t-test.

We calculated the sample size considering a minimum acceptable coefficient of correlation of 0.70 or a coefficient of determination (R2) of 0.49. Assuming an alpha error of 0.05 and a beta error of 0.20, a minimum of 12 observations for each variable included in the model would be sufficient. Therefore, 80 participants were necessary, and we were able to include up to 8 variables in each model. A series of multiple linear regression equations was developed using the main physiological responses as dependent variables. The models were first adjusted for age, body mass, height, and sex. This procedure was applied because these variables are easily obtained. For VO2, MWV, and ISWD (the most important variables related to aerobic exercise capacity), the models were also adjusted for body composition variables and HGS. Regarding body composition, we chose LBM and TBF, which presented the strongest correlations in the previous bivariate analysis. In addition, we used linear regressions in alternative prediction models to determine whether peak VO2 correlated with ISWD, with ISWD × body mass, and with MWV. Multicollinearity was assessed before starting the regression procedures. The probability of an alpha error was set at 0.05 for all analyses.

We performed the statistical analysis with the Statistical Package for the Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA) and SigmaStat, version 3.1 (Systat Software Inc., San Jose, CA, USA).

Results The sample comprised 103 participants (54 women and 49 men), and the mean age was 60 ± 10 years (Table 1). The participants were distributed within the following age brackets: 40-49 years (13 women and 12 men); 50-59 years (12 women and 11 men); 60-69 years (14 women and 14 men); and ≥ 70 years (15 women and 12 men). There were no significant differences among the four age groups studied in terms of the proportions of women and men. Between the second and third ISWT, the ISWD reliability was excellent (ICC = 0.973; 95% CI: 0.960-0.982)

Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses

and there was no significant difference between the mean values (510 ± 148 m vs. 519 ± 161 m).

The regression analysis models, using physiological variables, ISWD, and MWV as dependent variables and adjusted for age, body mass, height, and sex, showed R2 values ranging from 0.40 to 0.65 (for HR and peak VO2, respectively; Table 2). Applying the model Table 1 - General characteristics of the study sample.

Sex Female Male Variable (n = 54) (n = 49) Mean SD Mean SD Age, year 59 11 59 9 BM, kg* 68 14 80 12 Height, m* 1.57 0.07 1.71 0.07 27 5 27 3 BMI, kg/m2 TBF, kg* 31 10 20 7 TBF, % of total BM* 35 6 25 5 LBM, kg* 39 5 58 7 LBM, % of total BM* 64 6 74 5 LBM, % of predicted 102 7 103 5 17 1 20 1 LBMI, kg/m2* HGS, kgf* 26 5 43 8 BM: body mass; BMI: body mass index; TBF: total body fat; LBM: lean body mass; LBMI: lean body mass index; and HGS: handgrip strength. *p < 0.05 (females vs. males).

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including LBM and that including HGS did not result in a significant increase in the R2 values for predicting peak VO2 (Table 2), although the use of those models did result in slight increases in the R2 values for ISWD and MWV (of 8% and 12%, respectively). We selected ISWD, MWV, and ISWD × body mass as the sole determinants of peak VO2. In three different models, those variables determined 76.7%, 73.3%, and 81.2% of the peak VO2, respectively (Figure 1).

Discussion This study investigated the major physiological responses to ISWT in healthy subjects. We derived a series of equations that can predict ISWD, as well as cardiovascular, ventilatory, and metabolic responses during the ISWT. Age and sex had significant influences on those variables. However, after adjusting for sex and age, we found that MWV and ISWD were the main determinants of peak VO2, regardless of body composition and peripheral muscle strength.

The main finding of this study was the considerable influence that MWV and ISWD had on the peak VO2 obtained on the ISWT. The correlations between peak VO2 and ISWD, between peak VO2 and MWV, and between peak VO2 and

Table 2 - Linear prediction equations, adjusted for age, body mass, height, sex, body composition, and muscle function, for peak physiological responses, total distance walked, and maximum walking velocity related to the incremental shuttle-walk test.

Constant Body Age, Height, HGS, LBM, TBF, Variable Modela mass, Sexc R2 Sy.x years m kgf kg % Mean LLNb kg VE, L/min A −43.7 −67.2 −0.5* 0.1 69.2* 13.0* - 0.54 14.3 HR, bpm A 146.2 117.9 −1.1* −0.4* 55.5* −2.1 - 0.40 17.2 A 137.6 −493.2 −22.5* 5.4* 1,317.9* 554.5* - 0.63 383.5 VCO2, mL/min A 268.6 −337.9 −21.1* 9.2* 1,101.1* 535.6* - 0.65 368.1 Peak VO2, mL/ min B −134.1 −750.6 −16.2* 8.8 938.7* 297.5 14.8* - 0.65 374.9 C −1,206.3 −1,731.7 −12.6* −21.0 883.3 207.8 56.0* 27.8 0.65 319.2 ISWD, m A 347.7 186.8 −7.2* −3.0* 472.3* 137.2* - 0.65 97.8 B 223.7 86.1 −5.8* −3.2* 421.3 67.1 4.8* - 0.73 83.6 −54.6 −198.4 −5.8* −4.3 666.0* 75.3 2.1 0.64 0.68 87.4 C MWV, m/s A 1.59 1.32 −0.01* −0.004* 0.70* 0.22* - 0.60 0.17 B 0.89 0.66 −0.008* −0.005* 0.92* 0.06 0.008* - 0.72 0.14 C 0.55 0.32 −0.009* −0.007 1.23* 0.11 0.003 0.002 0.67 0.14 LLN: lower limit of normal (calculated as 1.646 × Sy.x); HGS: handgrip strength; LBM: lean body mass; TBF: total body fat; Sy.x: standard error about linear regression; VE: minute ventilation; VCO2: carbon dioxide production; VO2: oxygen uptake; ISWD: incremental shuttle walk distance; and MWV: maximum walking velocity. aModel A included age, body mass, height and sex; model B included age, body mass, height, sex, and HGS; and model C included age, body mass, height, sex, LBM, and TBF. bUse “mean” column for prediction of the expected values and “LLN” column for lower limit of normal. cSex: males = 1; females = 0. *Significant predictors (p < 0.05).

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5000

60

r = 0.78; R2=0.61; p < 0.0001 Peak Vo2 (mL/mim/Kg)

Peak Vo2 (mL/mim)

4000 3000 2000 1000 0

5000

0

200

600 800 1000 1200 ISWD (m) Equation: Peak VO2 = 238.3 - (2.9 x ISWD)

40 30 20 10 0

200

400

600 800 1000 1200 ISWD (m) Equation: Peak VO2 = 3.1 + (0.038 x ISWD)

60 r = 0.85; R2=0.73; p < 0.0001

r = 0.74; R2=0.56; p < 0.0001 Peak Vo2 (mL/mim/Kg)

4000 Peak Vo2 (mL/mim)

50

0

400

r = 0.86; R2=0.76; p < 0.0001

3000 2000 1000

50 40 30 20 10

0 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 MWV ((m/s)

0 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 MWV ((m/s)

Equation: Peak VO2 = -1142 + (1644 x MWV) 5000

Equation: Peak VO2 = -16.1 - (22.4 x MWV)

r = 0.90; R2=0.81; p < 0.0001

Peak Vo2 (mL/mim)

4000 3000 2000 1000 0

0

2000

4000

6000

8000

10000

ISWD x body massa (m x kg) Equation: Peak VO2 = 257 + (0.038 x ISWD x body mass)

Figure 1 - Significant correlations between peak VO2 and incremental shuttle walk distance (ISWD), as well as between peak VO2 and maximal walking velocity (MWV), during the incremental shuttle walk test.

ISWD Ă&#x2014; body mass ranged from 0.75 to 0.90.

These values are similar to those described in the literature for the correlation between ISWD and peak VO2 obtained under laboratory conditions in patients with cardiopulmonary disease. Consistent correlations between peak VO2 and ISWD or J Bras Pneumol. 2013;39(2):190-197

between peak VO2 and ISWD Ă&#x2014; body mass obtained in CPET have been described in COPD patients (range, 0.73-0.88).(2,10,19,20) Correlations of this magnitude have also been described during CPET in patients with idiopathic pulmonary fibrosis(21) and in patients with heart disease.(22-24) These

Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses

results support the assertion that the ISWT is a suitable tool to assess the functional capacity of such patients. Our results indicate that the peak VO2 obtained during the ISWT might be adequately estimated by using ISWD, MWV, or body mass. In fact, Léger & Lambert(25) reported similar results in the study in which they developed the precursor to the ISWT (the incremental shuttle run test). In that study, the peak VO2 of young adults was adequately predicted by the running speed, with a correlation of r = 0.84. In a study conducted by Cooper, who used the 12-min run test,(26) the 12-min run distance was also the most important determinant of cardiorespiratory fitness in healthy young adults, a finding similar to those of the present study. Even in CPET, the work rate, or power, has been identified as the main determinant of peak VO2.(27) Because the ISWT is performed on a flat surface, the MWV ultimately represents the workload of the test.

Sex and age influenced the main variables obtained on the ISWT (peak VO2, ISWD, and MWV). Several studies have reported that peak VO2 suffers a decline with advancing age and is lower in women,(28,29) even when allometric correction is used.(30) In the present study, R2 values for ISWD, adjusted for age, body mass, height, and sex, ranged from 15% to 22%, which are higher than those reported in the study conducted by Jürgensen et al.,(7) in which those attributes explained 50% of the ISWD variability. This difference might be attributable to the characteristics of the sample evaluated in that study, which included individuals with mild hypertension and smokers, whereas only healthy participants were included in the present study. We found that body composition and HGS, although presenting consistent correlations with peak VO2, did not sufficiently increase the predictive power of the equations adjusted only for demographic and anthropometric attributes.

Neder et al.(29) reported similar results in a study involving CPET on a cycle ergometer. In that study, the residuals of the equations involving muscle strength and body composition were narrowed, although the R2 was not sufficiently increased.(29) Our results suggest that equations including age, sex, body mass, and height are useful because those variables are very simple to obtain and provide R2 values similar to those of models with variables that are more difficult to

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obtain, such as body composition and muscle function (Table 2).

Various cardiovascular and ventilatory variables were determined in the present study by a combination of age, sex, height, and body mass (R2 ranging from 0.54 to 0.65). Our results are similar to those described by Neder et al.,(29) who reported that several cardiovascular and ventilatory variables might be determined by the combination of age, sex, height, and body mass, with an R2 ranging from 0.102 to 0.691.

The use of a gas analysis system did not result in worse performance during the third ISWT in the present study, given that the results of the second and third ISWTs were not significantly different and exhibited excellent reliability. Our results differ from those described by Singh et al.,(10) who reported a shorter ISWD with the use of a telemetric gas analysis system. This discrepancy might be explained primarily by the total weight of the equipment we used, which was lower than the 4.1 kg of that used by Singh et al.(10) In addition, those authors(10) evaluated COPD patients, whereas our study involved only healthy participants. Our results show that, despite some minor discomfort related to the use of a face mask, the use of the equipment had no impact on the ISWD. Our study has limitations that should be considered. The main limitation was that we did not perform CPET. However, comparing our results with those expected for CPET on a cycle ergometer derived from a randomized study,(29) the measured peak VO2 during the ISWT was significantly higher than the expected values for CPET on a cycle ergometer (1,760 ± 608 mL/min vs. 1,568 ± 438 mL/min, p = 0.017).

Regarding CPET on a treadmill, when we compare our results with those found in another study conducted in Brazil,(28) albeit qualitatively, the peak VO2 achieved during the ISWT corresponded to 80.6-108.2% of the peak VO2 expected in that study. Another limitation was the convenience sampling technique that we used, which might have resulted in overestimation of the normal physiological responses. However, we took care to include only healthy individuals who were not involved in sports or vigorous physical activity.

We believe that this minimized the bias of the sampling technique used.

Our results provide reference values for ISWD and physiological responses to the ISWT, which can be properly estimated by determining simple J Bras Pneumol. 2013;39(2):190-197

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demographic and anthropometric characteristics in healthy adults ≥ 40 years of age. The inclusion of body composition and muscle function data improved the power of those estimations only slightly.

Therefore, the ISWT could be used in assessing physical fitness in the general adult population and in designing individualized walking programs.

Because the pace set in the initial levels of the ISWT is too slow for healthy individuals, future studies should investigate ways in which the original protocol can be adapted for use in this population.

Acknowledgments The authors would like to thank the Faculty of the American Thoracic Society and the Methods in Epidemiologic, Clinical and Operations Research (MECOR) program, especially Dr. William M. Vollmer, for their support in the statistical analysis during the First MECOR Global Course, held in Nairobi, Kenya, in 2011.

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29. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs A, et al. Prediction of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomised study. Eur Respir J. 1999;14(6):1304-13.

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30. Neder JA, Nery LE, Silva AC, Andreoni S, Whipp BJ. Maximal aerobic power and leg muscle mass and strength related to age in non-athletic males and females. Eur J Appl Physiol Occup Physiol. 1999;79(6):522-30.

Sobre os autores Victor Zuniga Dourado

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.

Suzana Erico Tanni

Pulmonologist. Universidade Estadual Paulista – UNESP, São Paulo State University – Botucatu School of Medicine, Botucatu, Brazil.

Letícia Cláudia de Oliveira Antunes

Professor. Marechal Rondon College, São Manuel, Brazil. Physical Therapist. Universidade Estadual Paulista – UNESP, São Paulo State University – Botucatu School of Medicine Hospital das Clínicas, Botucatu, Brazil.

Irma Godoy

Full Professor. Universidade Estadual Paulista – UNESP, São Paulo State University – Botucatu School of Medicine, Botucatu, Brazil.

J Bras Pneumol. 2013;39(2):190-197

Original Article Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009* Mortalidade por doenças respiratórias em idosos após campanhas vacinais contra influenza no Distrito Federal, Brasil, 1996-2009

Francisca Magalhães Scoralick, Luciana Paganini Piazzolla, Liana Laura Pires, Cleudsom Neri, Wladimir Kummer de Paula

Abstract Objective: To compare mortality rates due to respiratory diseases among elderly individuals residing in the Federal District of Brasília, Brazil, prior to and after the implementation of a national influenza vaccination campaign. Methods: This was an ecological time series analysis. Data regarding the population of individuals who were over 60 years of age between 1996 and 2009 were obtained from official databases. The variables of interest were the crude mortality rate (CMR), the mortality rate due to the respiratory disease (MRRD), and the proportional mortality ratio (PMR) for respiratory diseases. We performed a qualitative analysis of the data for the period prior to and after the implementation of the vaccination campaign (1996-1999 and 2000-2009, respectively). Results: The CMR increased with advancing age. Over the course of the study period, we observed reductions in the CMR in all of the age brackets studied, particularly among those aged 80 years or older.

Reductions in the MRRD were also found in all of the age groups, especially in those aged 80 years or older.

In addition, there was a decrease in the PMR for respiratory diseases in all age groups throughout the study period. The most pronounced decrease in the PMR for respiratory diseases in the ≥ 70 year age bracket occurred in 2000 (immediately following the implementation of the national vaccination campaign); in 2001, that rate increased in all age groups, despite the greater adherence to the vaccination campaign in comparison with that recorded for 2000. Conclusions: Influenza vaccination appears to have a positive impact on the prevention of mortality due to respiratory diseases, particularly in the population aged 70 or over.

Keywords: Influenza, human/mortality; Influenza, human/epidemiology; Influenza vaccines.

Resumo Objetivo: Comparar os índices de mortalidade por doenças respiratórias em idosos residentes no Distrito Federal (DF) antes e após a implantação da campanha nacional de vacinação contra influenza. Métodos: Estudo ecológico de séries temporais. Os dados referentes à população do DF acima de 60 anos entre 1996 e 2009 foram obtidos de bancos de dados oficiais. As variáveis estudadas foram o coeficiente de mortalidade geral (CMG), coeficiente de mortalidade por doenças respiratórias (CMDR) e índice de mortalidade por causas respiratórias (IMR). Foi realizada uma análise qualitativa dos dados referentes ao período antes e após a implantação da campanha de vacinação (1996-1999 e 2000-2009, respectivamente). Resultados: O CMG aumentou com o incremento da faixa etária. No decorrer do período do estudo, houve uma redução no CMG em todas as faixas etárias, especialmente naquela com 80 anos ou mais. Houve redução do CMDR em todos os grupos etários, especialmente naqueles com mais de 80 anos. O IMR mostrou uma redução em todas as faixas etárias por todo o período estudado. Em 2000, ano imediatamente subsequente à primeira campanha vacinal, a redução do IMR foi mais pronunciada na faixa etária ≥ 70 anos; em 2001, houve um aumento do IMR em todas as faixas etárias, apesar da maior adesão à campanha de vacinação em relação a 2000. Conclusões: A vacinação contra a influenza parece influir positivamente na prevenção da mortalidade por doenças respiratórias, particularmente nos idosos com 70 anos ou mais Descritores: Influenza humana/mortalidade; Influenza humana/epidemiologia; Vacinas contra influenza.

* Study carried out carried out under the auspices of the Graduate Program in Health Sciences, University of Brasília, Brasília, Brazil.

Correspondence to: Francisca Magalhães Scoralick. Hospital Regional da Asa Norte, Ambulatório de Geriatria e Gerontologia, SMHN Qd. 101, Asa Norte, CEP 70710-910, Brasília, DF, Brasil.

Tel. 55 61 3327-8471. E-mail: franciscascoralick@gmail.com Financial support: None.

Submitted: 15 December 2012. Accepted, after review: 15 January 2013.

J Bras Pneumol. 2013;39(2):198-204

Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009

Introduction Influenza is an acute respiratory infection caused by Myxovirus influenzae. Worldwide, influenza causes greater morbidity than does any other infectious processes. Typically self-limiting, influenza is seen as having little relevance in its uncomplicated form and resolves spontaneously in approximately one week.(1-3) The typical clinical manifestations of the uncomplicated form include fever, odynophagia, cough, myalgia, rhinitis, headache, and asthenia. In the elderly population, influenza can lead to complications, primarily viral or bacterial pneumonia.(4) During influenza epidemics, the disease spreads rapidly and is responsible for high morbidity and mortality, especially in the elderly. The complications of influenza are responsible for a significant number of hospitalizations in Brazil.

In 2009, 851,044 hospitalizations for influenza and pneumonia were recorded by the Hospital Information Service of the Brazilian Unified Health Care System, a figure that is 10% higher than was the average for the five years preceding that.

Of all hospitalizations, 24% were for individuals 60 years of age or older.(3) The elderly are the most vulnerable group to influenza, because advanced age is associated with a higher prevalence of chronic degenerative diseases and with immunological impairment. (5) The primary prevention measure is influenza vaccination, as has been recommended by the World Health Organization since 1963. In Brazil, influenza vaccination has been made available for free to the elderly throughout the country by the Brazilian National Ministry of Health since 1999.

The vaccination campaign for seniors in Brazil represents a large public investment, involving an expenditure of about R$130 million per year in the purchase and application of the vaccine, as well as in dissemination campaigns.(6) Various studies, especially those conducted in the northern hemisphere, have demonstrated that the influenza vaccine is effective in the elderly, reducing morbidity and mortality.(7,8) In Brazil, one group of authors observed a reduction in mortality rates one year after the vaccine intervention in the state of São Paulo.(9) However, another study observed that the rates of hospitalization and death for respiratory or circulatory diseases were not reduced by vaccination in the elderly population of the city of Fortaleza, Brazil.(10) The objective of the present study was

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to compare mortality rates for respiratory diseases among elderly individuals residing in the Federal District of Brasília, Brazil, prior to and after the implementation of a national influenza vaccination campaign in 1999.

Methods This was an ecological time series analysis involving data from the mortality records for all-cause mortality and mortality from respiratory disease in residents of Brasília who were over 60 years of age between 1996 and 2009; those data were obtained from the Mortality Database of the Brazilian National Ministry of Health Unified Health Care System.(11) Estimates regarding the elderly population residing in Brasília, by age, were obtained from the Brazilian Institute of Geography and Statistics. (12) In developing countries, the United Nations considers individuals 60 years of age or older as elderly. In Brazil, Law no. 8.842/9 also classifies a person 60 years of age or older as elderly. In the present study, the elderly were divided into three age groups: 60-69 years; 70-79 years; and ≥ 80 years.

In order to determine the impact that influenza has on the community, we used the diagnoses of the following respiratory complications of viral infection: pneumonia; influenza; bronchitis; and chronic airway obstruction. For data collected up to 1997, we used the ninth revision of the International Classification of Diseases (ICD9), and, for data collected from 1998 onward, we used the ICD-10. In the ICD-9, the codes assigned to the aforementioned diagnoses are 480-486, 487, 490-491, and 495-496, whereas those same diagnoses are coded as J10-J15, J18, J22, J40-J42, and J44, respectively, in the ICD-10.

Because COPD is prevalent in patients 60 years of age or older and is frequently complicated by viral infection, leading to hospitalization and eventually to death,(5) it was included in the diagnoses.

We calculated the crude (all-cause) mortality rate (CMR) for each age group (60-69 years, 70-79 years, and ≥ 80 years). In addition, we calculated the respiratory disease mortality rate (RDMR), on the basis of the classification described above, also for each of the three age groups. Subsequently, we calculated the proportional mortality ratio (PMR) for respiratory diseases, which is the ratio between the RDMR and the CMR. J Bras Pneumol. 2013;39(2):198-204

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Data regarding vaccination coverage in the study population were obtained from the website of the Department of Information Technology of the Brazilian National Ministry of Health Unified Health Care System and tabulated according to the area of interest (i.e., Brasília) in the specified period (1996-2009).

Results Considering 1996 as the beginning of the analysis period, we found that the CMR increased with advancing age, from 20/1,000 population in the 60- to 69-year age group to 200/1,000 in the ≥ 80-year age group (Figure 1). Over the study period (1996-2009), the CMR remained mostly stable in the 60- to 69-year age group and showed a slight reduction in the 70- to 79-year age group after the implementation of the national vaccination campaign in 1999.

However, in the ≥ 80-year age group, there were significant fluctuations in the CMR over that period. For that age group, despite the decrease in the CMR that occurred in 2000, the year following the implementation of the national vaccination campaign, the CMR increased gradually, reaching 200/1,000 population in 2006. It is of note that, in 2007, the CMR again showed a considerable

reduction, greater than that observed in 2000, reaching approximately 150/1,000 population, and, in 2009 (end of the analysis period), it reached 130/1,000 population. Therefore, as compared with the year immediately following the implementation of the national vaccination campaign, i.e., 2000, the CMR decreased in all three age groups, and the decrease was most pronounced in the ≥ 80-year age group.

The analysis of the RDMR, as shown in Figure 2, indicates that this rate clearly decreased in all three age groups over the analysis period. We found that the RDMR did not fluctuate significantly in the 60- to 69-year age group but that, in 2000, one year after the implementation of the national vaccination campaign, it decreased in the 70- to 79-year age group, a decrease followed by transient rises and then by a steady and mild decline until 2009. In the ≥ 80-year age group, the RDMR fluctuated after 2000, with moderate increases in 2001 and 2002, followed by a decrease in 2003 and marked increases in 2004 and 2005. From 2007 to 2009, there was a progressive reduction in the RDMR, which, in 2009, reached a value similar to that recorded for 2000.

The analysis of the PMR curves revealed that there was a reduction in the PMR for respiratory

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Figure 1 - Crude (all-cause) mortality rate (per 1,000 population) between 1996 and 2009 in the Federal District of Brasília, Brazil, by age group.

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Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009

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Figure 2 - Respiratory disease mortality rate per 1,000 population between 1996 and 2009 in the Federal District of Brasília, Brazil, by age group.

diseases between 1996 and 2009 for all of the age groups evaluated. However, in the 60- to 69-year age group, the PMR for respiratory diseases remained stable after 2000, whereas it continued to oscillate in the other two age groups, with occasional decreases and tendencies toward an increase throughout the period, although never again reaching the high values observed in 1996 (Figure 3).

Table 1 shows that influenza vaccination coverage decreased significantly in 2000 as compared with 1999, when the national vaccination campaign was implemented. After that, between 2001 and 2009, the level of coverage fluctuated, adherence increasing between 2001 and 2003, after which there were additional fluctuations.

Discussion In Brasília, the elderly population increases every year. In the last decade, the Brazilian population over 60 years of age has grown by 41.6%, and this growth was most significant in the ≥ 80-year age group, which increased by 60.2%.(10) Individuals 80 years of age or older, designated as the very elderly, exhibit a higher prevalence

of comorbidities and are at a greater risk of decompensation of their comorbidities in response to a stressor, such as influenza.(5) This could explain the progressive increase in mortality from influenza in this age group. Although there were fluctuations in the CMR and the RDMR, the results of the present study indicate that there was a reduction in mortality after the implementation of the national vaccination campaign. There was a greater reduction in the PMR for respiratory diseases in those 70 years of age or older, and this can be attributed to greater vaccination coverage in this population, as has also been observed by a group of authors in the state of Paraná, Brazil.(13) The greatest decline in the PMR for respiratory diseases, in all three age groups, occurred in 2000, the first year after the implementation of the national vaccination campaign. In 2001, however, the data suggest an increase in mortality from respiratory diseases in all groups. This behavior can be explained by the pattern of adherence to the influenza vaccination campaign, which was lower in 2000. The non-participation of elderly individuals in immunization campaigns reflects their attitudes and beliefs about the risks and benefits of vaccination.(4,6,13) J Bras Pneumol. 2013;39(2):198-204

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45% 40% 35% 30%

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Figure 3 - Proportional mortality ratio for respiratory diseases between 1996 and 2009 in the Federal District of Brasília, Brazil, by age group.

Table 1 - Influenza vaccination coverage (Brazilian National Immunization Campaign for Seniors) among individuals who were 60 years of age or older between 1999 and 2009. Federal District of Brasília, Brazil.

Immunization against Year influenza 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Vaccination coveragea 110,68 77,74 80,47 86,77 97,66 91,93 89,85 99,29 78,22 86,55 87,59 a

Values expressed as %. Source: Brazilian National Immunization Program.

The Brazilian National Immunization Campaign for Seniors began in 1999. The target population was individuals 65 years of age or older, and 87.3% of the estimated population in this age group was vaccinated. In the subsequent year, vaccination was made available to all Brazilians 60 years of age or older. However, vaccination coverage decreased to 71.8%. In 2001, a redoubling of efforts in the campaign resulted in nationwide vaccination coverage of 82.1%.(5) These data are similar to those observed in Brasília.

Studies have shown that adherence to influenza vaccination campaigns is lowest among elderly individuals between 60 and 69 years of age, especially among those with a higher level of education.(6) In that age group, the PMR for respiratory diseases showed no change after the vaccine intervention. It is possible that the

J Bras Pneumol. 2013;39(2):198-204

side effects of the vaccine, such as myalgia, low-grade fever, and malaise, can be mistaken for influenza, leading those individuals to believe that the vaccine does not protect them against influenza or even reinforcing the myth that the influenza vaccine can cause influenza.(5) A number of factors are involved in the behavior of influenza and affect the complexity of the data obtained. The influenza virus exhibits antigenic variations that result in partial changes in its genetic structure. This phenomenon enables the cyclical occurrence of the disease in the population; this is possible because of the high genetic variability and adaptability of the virus. (3,14) Therefore, annual influenza vaccination is necessary.(2) In Brazil, the seasonality of influenza varies from region to region, seasonal differences in

Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009

frequency being more marked in regions with well-defined seasons—higher frequencies being observed in the colder months in areas with a temperate climate and in the wetter months in areas with a tropical climate. Seasonal influenza can manifest in annual outbreaks of varying size, severity, and extent that complicate the accurate diagnosis of the condition and the accurate determination of the efficacy of prophylaxis.(14) In addition to the factors implicated in the difficulty in controlling influenza, another aspect that deserves attention is the increase in the circulation of other viruses with respiratory tropism. In addition to the influenza virus, the viruses most commonly associated with pulmonary infections and their complications include Respiratory syncytial virus, parainfluenza, adenovirus, rhinovirus, and metapneumovirus, the last having been identified most recently.(15,16) This could explain the fluctuations observed in the present study, particularly in the ≥ 80-year age group, because that group is more susceptible to infectious diseases.

The immune system also plays an important role in disease onset and maintenance. The aging of the immune system, known as immunosenescence, is associated with the gradual deterioration of immune function, thereby increasing susceptibility to infections, autoimmune diseases, and cancer.

This deterioration of immune function is associated with changes that can occur in each phase of the development of the immune response.(4) The effectiveness of influenza vaccination in preventing disease is lower in elderly individuals than in younger adults, the effectiveness of vaccination ranging from 30% to 40% in the former group, compared with 70% to 90% in the latter.(5,17,18) An ecological analysis has limited ability to generate causal hypotheses. In the present study, it is relevant to consider the complexity of establishing respiratory infection as the cause of death in elderly individuals, who frequently have multiple comorbidities. Underreporting or erroneous reporting of the cause of death occurs more often in the elderly population.

In Brasília, the CMR can be used reliably, since the death records in Brasília cover almost all occurrences (95%).(19) The present study draws attention to the potential efficacy of the influenza vaccination campaign in reducing mortality from respiratory diseases among elderly individuals residing in

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Brasília. The investments made in health care, with regard to the vaccination campaign, appear to have had a positive impact on the health of this population segment.

References 1. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Oct 1]. Available from: http://www.saude.gov.br/svs 2. Forleo-Neto E, Halker E, Santos VJ, Paiva TM, TonioloNeto J. Influenza [Article in Portuguese]. Rev Soc Bras Med Trop. 2003;36(2):267-74.

3. Brasil. Ministério da Saúde. Coordenação Geral do Programa Nacional de Imunizações. Campanha nacional de vacinação do idoso. Informe Técnico. Brasília: Ministério da Saúde; 2009.

4. Santos ZM: Oliveira ML. Avaliação dos conhecimentos, atitudes e práticas dos idosos sobre vacina contra a Influenza, na UBS, Taguatinga, DF,2009. Epidemiol Serv Saúde. 2010;19(3):205-16.

5. Toniolo-Neto, J; Halker, E; Gagliardi ANZ, Kairala M. Vacinas. In: Freitas EV, Py L, Cançado FA, Gorzone ML, editors. Tratado de Geriatria e Gerontologia. Rio de Janeiro: Guanabara Koogan; 2006. p. 856-63.

6. Donalisio MR. Brazilian policy for influenza vaccination and its impact on the health of the elderly. Cad Saude Publica. 2007;23(3):494-5.

7. Beyer WE, de Bruijn IA, Palache AM, Westendorp RG, Osterhaus AD. Protection against influenza after annually repeated vaccination: a meta-analysis of serologic and field studies. Arch Intern Med. 1999;159(2):182-8.

8. Nichol KL, Wuorenma J, von Sternberg T. Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med. 1998;158(16):1769-76.

9. Francisco PM, Donalisio MR, Lattorre Mdo R. Impact of influenza vaccination on mortality by respiratory diseases among Brazilian elderly persons [Article in Portuguese].

Rev Saude Publica. 2005;39(1):75-81.

10. Façanha MC. Influenza vaccination of individuals over the age of 60: impact on hospital admissions and deaths from respiratory and circulatory diseases in Fortaleza, Brazil. J Bras Pneumol. 2005; 31(5):415-20.

11. DATASUS [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2010 Sep 1]. Informações demográficas e socioeconômicas. Available from: http://www2.datasus. gov.br/DATASUS/index.php?area=0206 12. Instituto Brasileiro de Geografia e Estatística. Pesquisa Nacional por Amostra de Domicílios (PNAD). Rio de Janeiro: IBGE; 2004.

13. Campos EC, Sudan LC, Mattos ED, Fidelis R. Factors associated with influenza vaccination among the elderly: a cross-sectional study in Cambé, Paraná State, Brazil [Article in Portuguese]. Cad Saude Publica. 2012;28(5):878-88.

14. Secretaria de Vigilância em Saúde. O desafio da influenza: epidemiologia e organização da vigilância no Brasil.

Boletim Eletrônico Epidemiológico. 2004;4(1):1-7.

15. Stockton J, Stephenson I, Fleming D, Zambon M. Human metapneumovirus as a cause of community-acquired respiratory illness. Emerg Infect Dis. 2002;8(9):897-901.

16. Boivin G, Abed Y, Pelletier G, Ruel L, Moisan D, Côté S, et al.

Virological features and clinical manifestations associated with human metapneumovirus: a new paramyxovirus responsible for acute respiratory-tract infections in all age groups. J Infect Dis. 2002;186(9):1330-4.

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17. Tatum PE, Mehr DR. Prevention and Health Promotion.

In: Landefeld CS, Palmer RM, Johnson MA, Johnston CB, Lyons WL, editors. In: Current geriatric diagnosis and treatment. New York: MacGraw-Hill; 2004. p.7-15.

18. Francisco PM, Donalisio MR, Barros MB, César CL, Carandina L, Goldbaum M. Factors associated with

vaccination against influenza in the elderly [Article in Portuguese]. Rev Panam Salud Publica. 2006;19(4):259-64.

19. Paes NA, Albuquerque ME. Evaluation of population data quality and coverage of registration of deaths for the Brazilian regions [Article in Portuguese]. Rev Saude Publica. 1999;33(1):33-43.

About the authors Francisca Magalhães Scoralick

Geriatrician. Hospital Regional da Asa Norte – HRAN, North Wing Regional Hospital – Escola Superior de Ciências da Saúde/ Secretaria de Estado da Saúde – ESCS/SES, Graduate School of Health Sciences/State Department of Health – and Master’s Student in the Graduate Program in Health Sciences, Federal University of Brasília, Brasília, Brazil.

Luciana Paganini Piazzolla

Professor. Catholic University of Brasília, Brasília, Brazil.

Liana Laura Pires

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

Cleudsom Neri

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

Wladimir Kummer de Paula

Neurologist. Department of Neurology, Dona Helena Hospital, Joinville, Brazil.

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Original Article Experimental study on the efficiency and safety of the manual hyperinflation maneuver as a secretion clearance technique*,** Estudo experimental sobre a eficiência e segurança da manobra de hiperinsuflação manual como técnica de remoção de secreção

Tatiana de Arruda Ortiz, Germano Forti, Márcia Souza Volpe, Carlos Roberto Ribeiro Carvalho, Marcelo Brito Passos Amato, Mauro Roberto Tucci

Abstract Objective: To evaluate, in a lung model simulating a mechanically ventilated patient, the efficiency and safety of the manual hyperinflation (MH) maneuver as a means of removing pulmonary secretions. Methods: Eight respiratory therapists (RTs) were asked to use a self-inflating manual resuscitator on a lung model to perform MH as if to remove secretions, under two conditions: as routinely applied during their clinical practice; and after receiving verbal instructions based on expert recommendations. In both conditions, three clinical scenarios were simulated: normal lung function, restrictive lung disease, and obstructive lung disease. Results: Before instruction, it was common for an RT to compress the resuscitator bag two times, in rapid succession. Proximal pressure (Pprox) was higher before instruction than after. However, alveolar pressure (Palv) never exceeded 42.5 cmH2O (median, 16.1; interquartile range [IQR], 11.7-24.5), despite Pprox values as high as 96.6 cmH2O (median, 36.7; IQR, 22.9-49.4). The tidal volume (VT) generated was relatively low (median, 640 mL; IQR, 505-735), and peak inspiratory flow (PIF) often exceeded peak expiratory flow (PEF), the median values being 1.37 L/s (IQR, 0.99-1.90) and 1.01 L/s (IQR, 0.55-1.28), respectively. A PIF/PEF ratio < 0.9 (which theoretically favors mucus migration toward the central airways) was achieved in only 16.7% of the maneuvers. Conclusions: Under the conditions tested, MH produced safe Palv levels despite high Pprox. However, the MH maneuver was often performed in a way that did not favor secretion removal (PIF exceeding PEF), even after instruction. The unfavorable PIF/ PEF ratio was attributable to overly rapid inflations and low VT. Keywords: Physical therapy modalities; Respiratory therapy; Respiratory mechanics; Positive-pressure respiration.

Resumo Objetivo: Avaliar, em um modelo pulmonar simulando um paciente sob ventilação mecânica, a eficiência e a segurança da manobra de hiperinsuflação manual (HM) com o intuito de remover secreção pulmonar. Métodos: Oito fisioterapeutas utilizaram um ressuscitador manual autoinflável para realizar HM com o objetivo de remover secreções, em duas condições: conforme rotineiramente aplicada durante sua prática clínica, e após receberem instruções verbais baseadas em recomendações de especialistas. Três cenários clínicos foram simulados: função pulmonar normal, doença pulmonar restritiva e doença pulmonar obstrutiva. Resultados: Antes da instrução, o uso de duas compressões sequenciais do ressuscitador era comum, e a pressão proximal (Pprox) foi mais alta em relação à obtida após a instrução. Entretanto, a pressão alveolar (Palv) nunca excedeu 42,5 cmH2O (mediana, 16,1; intervalo interquartil [IQ], 11,7-24,5), mesmo com valores de Pprox de até 96,6 cmH2O (mediana, 36,7; IQ, 22,9-49,4). O volume corrente (VC) gerado foi relativamente pequeno (mediana, 640 mL; IQ, 505-735) e o pico de fluxo inspiratório (PFI) geralmente excedeu o pico de fluxo expiratório (PFE): 1,37 L/s (IQ, 0,99-1,90) e 1,01 L/s (IQ, 0,55-1,28), respectivamente. Uma relação PFI/PFE < 0,9 (que teoricamente favorece a migração do muco em direção às vias aéreas centrais) foi obtida em somente 16,7% das manobras. Conclusões: Nas condições testadas, a HM gerou valores seguros de Palv mesmo com altas Pprox. Entretanto, a HM foi comumente realizada de um modo que não favorecia a remoção de secreção (PFI excedendo PFE) mesmo após a instrução.

A relação PFI/PFE desfavorável foi explicada pelas insuflações rápidas e o baixo VC. Descritores: Modalidades de fisioterapia; Terapia respiratória; Mecânica respiratória; Respiração com pressão positiva. * Study conducted in the Laboratório de Investigação Médica 09 (LIM-09, Laboratory for Medical Research 09), specializing in Pulmonology, University of São Paulo School of Medicine, São Paulo, Brazil.

Correspondence to: Mauro R. Tucci. Laboratório de Pneumologia LIM-09, Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo, 455, 2º andar, sala 2144, CEP 01246-903, São Paulo, SP, Brasil.

Tel. 55 11 3061-7361. Fax: 55 11 3061-2492. E-mail: mrotucci@gmail.com Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation) and the Brazilian Financiadora de Estudos e Projetos (Finep, Financing Agency for Studies and Projects).

Submitted: 2 July 2012. Accepted, after review: 14 January 2013. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

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Ortiz TA, Forti G, Volpe MS, Carvalho CRR, Amato MBP, Tucci MR

Introduction Manual hyperinflation (MH) is a proposed technique that is purported to promote secretion clearance and to re-expand areas of atelectasis, thereby improving lung compliance and oxygenation in patients on mechanical ventilation.(1,2) Despite a lack of scientific evidence confirming its benefits on clinical outcomes,(2-5) MH is often used in the ICU as a chest physiotherapy technique. The maneuver is widely accepted as effective(6,7) and, in Brazil, is largely embraced as a means of removing retained secretions.(8-10) The rationale for the use of the technique as an aid for secretion removal is that it simulates a cough.(11) When applied before suctioning, it theoretically moves secretions toward the central airways,(12) thus increasing the efficacy of the suctioning procedure.

There has been considerable debate regarding the safety and efficiency of MH.(1,3) It has been shown that the efficiency of the MH maneuver is affected by the operator and the type of manual resuscitator used,(13,14) as well as by the resistance and compliance of the respiratory system,(15,16) largely affecting the pressures and flows generated in the respiratory system. Under certain conditions, the use of this technique can generate high peak airway pressures, increasing the risk of barotrauma.(17) According to expert recommendations,(1,11,18) in order to promote secretion clearance, MH should consist of a slow, deep inspiration, an inspiratory pause, and a quick release of the resuscitation bag to promote passive exhalation with high expiratory flow rates. However, the way in which the MH maneuver is performed can vary from country to country, impeding the understanding of its effects.(1,3,5) Since the 1980s, there has been increasing evidence that the peak expiratory flow to peak inspiratory flow (PEF/PIF) ratio is a critical factor for the removal of lung secretions, especially in heavily sedated or paralyzed patients.(19-21) In fact, more than their ratio, the difference between the two, in terms of their absolute values, seems to be the major determinant: above a given threshold, whenever the PIF exceeds the PEF, secretions migrate deeper into the lung.(21) Intuitively, respiratory therapists (RTs) have been promoting maneuvers to increase expiratory flows, analogous to those observed during coughing. However, relatively little attention J Bras Pneumol. 2013;39(2):205-213

has been given to their inspiratory counterpart, despite expert recommendations to apply a slow, deep inspiration during MH. The inspiratory phase of MH can be performed in many different ways, depending on the personal experience of the operator, and there is little evidence that the MH maneuver generates an adequate flow bias (i.e., with PEF exceeding PIF) or that the ultimate goal of the maneuver (i.e., improved secretion clearance) is achieved.

The aim of this study was to evaluate the efficiency and safety of MH (as performed by RTs in a lung model simulating a mechanically ventilated patient) as a means of increasing secretion clearance under two different conditions: MH performed in accordance with the routine clinical practice of RTs; and MH performed in accordance with expert recommendations.(1,15,18) The efficiency of MH was determined through analysis of the volume and flow patterns generated in relation to the anticipated effects on secretion removal. The safety of MH was evaluated on the basis of the inspiratory pressures achieved (i.e., whether those pressures remained within safe limits during the maneuver). Our ultimate objective was to obtain a qualitative analysis of how MH is performed by experienced professionals and not to address how it is performed in Brazil.

Methods This was an experimental study conducted in the Laboratory for Medical Research 09, specializing in Pulmonology, at the University of São Paulo School of Medicine, in the city of São Paulo, Brazil. The study was approved by the Research Ethics Committee of the University of São Paulo School of Medicine Hospital das Clínicas. All participants gave written informed consent.

The study comprised two phases, evaluating the effects of MH, as performed by RTs, in promoting the clearance of pulmonary secretions. In the first phase (the pre-instruction phase), the RTs were given no explicit verbal instructions on how to apply the maneuver. In the second phase, the RTs were given instructions based on expert recommendations, as detailed below. The two phases are hereafter referred to as the pre- and post-instruction phases.

All maneuvers were performed with selfinflating manual resuscitator (SPUR®; Ambu, Ballerup, Denmark), with a capacity of 1,500 mL.

Experimental study on the efficiency and safety of the manual hyperinflation maneuver as a secretion clearance technique

The maneuver was applied by eight experienced RTs (four males and four females), with an average of 2.6 years in practice (range, 2-4 years) in ICUs in the city of São Paulo. Five of the eight had graduated from universities located within the state of São Paulo, and all had completed one of the one-year postgraduate training programs in respiratory therapy offered by university hospitals.

The maneuver was applied to a mechanical model of the respiratory system known as a training and test lung (TTL 2600; Michigan Instruments, Grand Rapids, MI), connected to a tracheal tube (8.5 mm). The airway flow was measured proximally (between the manual resuscitator and proximal pressure sensor) by a pneumotach. Two pressure transducers were connected to the model: one to measure proximal pressure (Pprox—at the airway, between the flow sensor and tracheal tube); and another to record alveolar pressure (Palv). Figure 1 illustrates the experimental setup.

In both study phases, we altered the resistance and compliance of the lung model in order to simulate three different clinical scenarios: a patient with obstructive lung disease (resistance at 20 cmH2O/L per second and compliance at 0.08 L/cmH2O); a normal patient (resistance at 5 cmH2O/L per second and compliance at 0.05 L/cmH2O); and a patient with restrictive lung

Flow sensor

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disease (resistance at 5 cmH2O/L per second and compliance at 0.025 L/cmH2O).

In the pre-instruction phase (as previously mentioned), the RTs were instructed to perform MH to promote pulmonary secretion clearance in accordance with their routine clinical practice.

The lung model was set according to those three clinical scenarios explained above and covered with a bed sheet, allowing RTs to sense the movement of the bellows while remaining blinded to the clinical scenario selected. After approximately eight cycles of MH, the settings were changed to simulate the next scenario (in the sequence described above) until all three scenarios had been run. In the post-instruction phase, each RT received brief verbal instructions on how to perform MH according to expert recommendations,(1,11,18) and all of the steps performed in the pre-instruction phase were repeated. The verbal instructions were given within the space of approximately 2 min, and the RTs were not trained to follow a given pattern of insufflation. The instructions were always given by the same researcher, who instructed each RT as follows: “Now you should perform MH with a slow inflation and a 2-s inspiratory pause, followed by rapid release of the bag”. While giving the instructions, the researcher demonstrated the maneuver with the manual resuscitator used in the study. The instructions were given twice.

Alveolar pressure sensor

Pressure sensor

Tracheal tube

Resistor

Lung Simulator

Manual resuscitator

Computer

Figure 1 - Experimental setup.

J Bras Pneumol. 2013;39(2):205-213

Ortiz TA, Forti G, Volpe MS, Carvalho CRR, Amato MBP, Tucci MR

Results For each of the six experimental conditions (three clinical scenarios in each study phase), we analyzed three respiratory cycles, corresponding to eighteen respiratory cycles for each of the eight RTs. Therefore, we analyzed a total of 144 respiratory cycles.

Among all of the respiratory cycles analyzed, the maximum Palv observed was 42.5 cmH2O (median, 16.1 cmH2O; IQR, 11.7-24.5), despite the much higher Pprox values (maximum, 96.6 cmH2O—median, 36.7; IQR, 22.9-49.4). The VT values were relatively low (maximum, 955 mL—

J Bras Pneumol. 2013;39(2):205-213

median, 640; IQR, 505-735), and the TI was short (median, 1.29 s; IQR, 0.95-1.72).

Overall, PIF was significantly higher than PEF (p < 0.02). A PIF/PEF ratio < 0.9, which theoretically favors mucus migration toward the central airways,(19) was achieved in only 24 (16.7%) of the 144 maneuvers evaluated. This favorable ratio occurred primarily in the postinstruction phase (in 18 of the 24 maneuvers) and was strongly associated with just one of the RTs tested (who was responsible for 12 of the 24 maneuvers). During the pre-instruction phase, six of the eight RTs performed MH using two compressions of the resuscitator bag and produced a PIF higher than that produced in the post-instruction phase (Figure 2).

Table 1 shows a comparison between the pre- and post-instruction phases, in terms of the mechanical variables evaluated. After instruction, MH was performed in a slower manner, with a 50

A Pre-instruction Post-instruction

40 Proximal pressure (cmH2O)

The analog signals from the flow and pressure transducers were amplified, digitized, and recorded at 200 Hz, using a data acquisition and off-line analysis system developed within the software Laboratory Virtual Instrumentation and Engineering Workbench (LabVIEW; National Instruments, Austin, TX, USA). For each experimental condition, three of the (approximately) eight respiratory cycles were randomly selected for analysis. The beginning of the inspiratory phase was defined as zero flow immediately before bagging, and the end of the respiratory cycle was defined as zero flow at the end of exhalation. The Pprox was defined as the peak pressure value during the inspiratory phase, measured by the proximal pressure transducer. The PIF was defined as the peak flow value during the inspiratory phase, measured by the flow transducer, and the PEF was defined as the peak flow during expiratory phase. Tidal volume (VT) was calculated by integration of the inspiratory flow signal. The Palv was defined as the peak pressure value during the inspiratory phase, measured by the alveolar pressure transducer. Inspiratory time (TI) was defined as the duration of the inflation plus the inspiratory pause.

Data are shown as median and 25-75% interquartile range (IQR). Repeated measures ANOVA was used to evaluate, for each variable, the following within-subject factors: the three clinical scenarios; and the two phases (before and after instructions). All two-way interactions between those factors were also tested. Inspiratory versus expiratory flow and alveolar versus proximal pressures were also tested as within-subject factors to compare peak flow and peak pressure variables, respectively. Values of p < 0.05 were considered statistically significant.

30 20 10 0 0

1

50

2 Seconds

3

4

5 B

Pre-instruction Post-instruction

40 Proximal pressure (cmH2O)

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30 20 10 0 0

1

2 Seconds

3

4

5

Figure 2 - Differences in proximal pressures achieved by two different respiratory therapists (A and B) before and after explicit verbal instruction (routine clinical practice vs. expert recommendations—dashed lines and solid lines, respectively).

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Table 1 - Mechanical variables before and after verbal instruction (routine clinical practice vs. expert recommendations).

Variable Pre-instruction Post-instruction p Proximal pressure (cmH2O) 44.5 (33.4-63.4) 26.8 (18.6-37.5) 0.004 16.3 (11.6-25.8) 14.8 (11.7-23.8) 0.93 Alveolar pressure (cmH2O) Peak inspiratory flow (L/s) 1.84 (1.28-2.19) 1.14 (0.87-1.44) 0.001 Peak expiratory flow (L/s) 1.04 (0.57-1.33) 0.99 (0.55-1.27) 0.28 Tidal volume (mL) 628 (497-699) 647 (518-746) 0.63 Inspiratory time (s) 0.95 (0.78-1.19) 1.71 (1.44-2.13) <0.001 PIF/PEF ratio 1.80 (1.29-2.34) 1.15 (0.87-1.80) 0.004 Values are expressed as median (25-75% interquartile range). PIF: peak inspiratory flow; PEF: peak expiratory flow.

longer TI and a lower PIF, producing a lower Pprox.

There were no statistically significant differences between the two phases in terms of the Palv, VT and PEF. Figure 2 illustrates the difference between the two study phases and between two different RTs. Comparing all three clinical scenarios tested and the two phases of the study, we found that Pprox was markedly higher than was Palv in all instances, with the exception of the restrictive lung disease scenario in the post-instruction phase (Figure 3). In the pre-instruction phase, PIF values were consistently higher than were PEF values. In the post-instruction phase, the PIF/ PEF ratio was closer to 1:1. The only situation in which that ratio was consistently unfavorable (PIF still far exceeding PEF) was the obstructive lung disease scenario (Figure 4).

Discussion The major finding of the present study was that, even after receiving explicit instructions, the RTs evaluated here performed MH in a way that probably would not aid secretion removal, with PIF commonly exceeding PEF. Compressing the resuscitator bag multiple times, in rapid succession, resulted in high values of PIF and Pprox. However, this finding was typically associated with a relatively low VT, probably because of short bag-compression times. Therefore, the Palv was often low at the start of exhalation, resulting in a low PEF. Both factors (rapid, multiple compressions and low Palv) appear to be responsible for the unfavorable relationship between PIF and PEF. Finally, although the MH maneuver might not promote secretion clearance, our results suggest that this maneuver, as performed in our study, is unlikely to cause barotrauma, a concern expressed by other authors because of the high

Pprox it generates.(17) In the present study, we also observed high Pprox values. However, the Palv values—roughly represented by plateau pressures, which correlate better with barotrauma than do Pprox values—were within the safe range.

The MH maneuver was originally described as consisting of a slow, deep inspiration, with an inspiratory pause and rapid release of the resuscitator bag.(22) Since then, many different MH techniques have been described, including one providing a VT that is greater than the baseline VT for the patient in question(15); one providing a VT that is 50% greater than that delivered by the ventilator(23); and one consisting of a slow (3-s) inspiration to achieve a peak airway pressure of 40 cmH2O.(24) In contrast, we found that RTs working in the city of São Paulo have customized the maneuver according to personal practice and bias, frequently applying two compressions of the resuscitator bag, without an inspiratory pause, resulting in PIF being higher than PEF. One possible explanation is that the maneuver applied in that way stimulates coughing and, consequently, improves secretion clearance, or at least gives the RT that impression. As observed in this study, however, applying the maneuver in that way might make it ineffective, with unfavorable relationships between inspiratory and expiratory flows, especially if the patient has a depressed cough reflex or is unable to cough efficiently.

According to previous studies,(19,20) above a given flow threshold, the direction of mucus transport (in or out of the respiratory system) is governed by the highest peak flow: a PEF 10% higher than the PIF (i.e., a PIF/PEF ratio < 0.9) will favor secretion movement from the distal to the central airways. A recent study evaluating the transport of artificial mucus in a test lung system(21) reported that mucus transport is better explained by the absolute difference between PIF J Bras Pneumol. 2013;39(2):205-213

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Ortiz TA, Forti G, Volpe MS, Carvalho CRR, Amato MBP, Tucci MR

Pre-instruction

Post-instruction Normal #

Restrictive #

100

Obstructive #

Pressure (cmH2O)

80

*

60

*

*

40 20 0 Proximal Pressure

Alveolar Pressure

Proximal Pressure

Alveolar Pressure

Proximal Pressure

Alveolar Pressure

Figure 3 - Median values of proximal and alveolar pressures (interquartile ranges as error bars) obtained in the pre-instruction (routine clinical practice) and post-instruction (in accordance with expert recommendations) phases of the study. The major effect of instruction was the generation of lower proximal pressures. The dashed line indicates 30 cmH2O. *p< 0.01 (difference between pre-instruction and post-instruction). #p < 0.05 (difference between proximal and alveolar pressure).

Pre-instruction

3.0

Post-instruction

Normal #

Restrictive #

Obstructive #

Flow (L/sec)

2.5 2.0 1.5

*

*

*

1.0 0.5 0.0

Inspiratory Flow

Expiratory Flow

Inspiratory Flow

Expiratory Flow

Inspiratory Flow

Expiratory Flow

Figure 4 - Median values for peak inspiratory and expiratory flows (interquartile ranges as error bars) obtained in the pre-instruction (routine clinical practice) and post-instruction (in accordance with expert recommendations) phases of the study. The major effect of instruction was the generation of lower peak inspiratory flow. The dashed line indicates 1 L/sec. *p< 0.01 (difference between pre-instruction and postinstruction). #p < 0.05 (difference between peak inspiratory and expiratory flows).

and PEF than by the PIF/PEF ratio. When PEF is higher than PIF, a greater difference between the two translates to better mucus transport. In the present study, the PIF/PEF ratio was below 0.9 in only 24 (16.7%) of the 144 maneuvers evaluated, most of those 24 being performed in the post-instruction phase. Consequently, the median PIF was much higher than was the median PEF, which is a cause for great concern.

This disappointing result is in agreement with

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the findings of some other studies in which self-inflating resuscitators were also used.(5,25) The manual resuscitator tested in the present study had a self-inflating bag (the type of manual resuscitator most widely used in ICUs in Brazil).

Such resuscitators usually generate a lower VT than that achieved with resuscitators that have flow-inflating bags.(12,14,15) Even after receiving explicit instructions, the RTs produced VT values that were lower than those reported in other

Experimental study on the efficiency and safety of the manual hyperinflation maneuver as a secretion clearance technique

studies.(12,13,15,17) That difference might be related solely to the size of the bag employed: 1.5 L in the present study, compared with 1.6-2.0 liters in the other studies cited. Much more favorable PIF/PEF ratios have been reported when flowinflating devices were used.(13) The verbal instruction on how to perform the MH improved the performance of the RTs in that the post-instruction maneuvers generated lower PIFs and longer TIs. However, those differences did little to improve the efficiency of the technique, because the PEFs were still quite low. That is likely attributable to the fact that the Palv was also quite low at the start of exhalation, which resulted in a low driving pressure for expiratory flow. Other authors have reported great variability in the practical implementation of the MH maneuver,(4,5,13-15,26) the execution of which rarely follows its original description. This makes it practically impossible to compare the effectiveness of MH across clinical studies.(27) If we accept the concept that the relationship between PIF and PEF is responsible for the direction in which secretions move,(19-21) we should question the use of an inspiratory pause on physiological grounds. Because of stress relaxation, the effective driving pressure for flow after a pause will be always lower than immediately after end-inspiration.(28) Therefore the use of an inspiratory pause could decrease the PEF and, consequently, impair the efficiency of the MH maneuver.

The small number of RTs participating in this study prevents us from generalizing our data for application in clinical practice. However, we believe that this qualitative analysis, performed with representative operators (of both genders, recruited from different hospitals from within the same city), illustrated scenarios that commonly occur in some ICUs. Another limitation of this study was the use of a lung model, which cannot be extrapolated to the complexity of human lungs.

Nevertheless, we believe that similar resultsâ&#x20AC;&#x201D;high PIF/PEF ratios, low VT, and high Pproxâ&#x20AC;&#x201D;would also be obtained in human patients on mechanical ventilation, especially in those that are heavily sedated, and this should draw the attention of the RTs to the way in which they perform the MH maneuver. Whether applying high PIF during MH will enhance secretion clearance in patients with preserved cough is a question that merits further investigation. That notwithstanding, the

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key message here is that performing MH with high PIF/PEF ratios in patients who are unable to cough will not aid secretion removal and might even contribute to mucus retention.

Another point that should be mentioned is that the MH maneuver can be performed in combination with expiratory chest compression in order to maximize the increase in the PEF(10,29); however we were not able to investigate the use of that combination, because of the experimental system used. In addition, as previously mentioned, we cannot discard the possibility that the use of a different resuscitator device (a self-inflating resuscitator with larger internal volume bags or a flow-inflating resuscitator) might produce better results.

Given that, in Brazil, MH is typically performed without Pprox monitoring, the option of performing the maneuver with a mechanical ventilator, so that inspiratory flow, VT and pressure can be easily monitored and adjusted,(27,30) should be considered. In studies comparing MH with a manual resuscitator and MH with a mechanical ventilator,(7,27,30) no differences were found between the two modalities in terms of the amount of secretion removed, although the advantages of better monitoring with the mechanical ventilator were acknowledged.

It is important to note that, although the MH maneuver was originally designed to reduce lung collapse and to improve oxygenation or lung compliance, those potential benefits were not tested here. In fact, we believe that MH should be used only as a secretion clearance technique. If the technique is applied to recruit collapsed lungs, its beneficial effects are going to be offset, at least in part, by the fact that the patient must be disconnected from the ventilator, thus exposing the lung to the lower pressure of the ambient air at the end of each compression.

Finally, we found no evidence that the MH maneuver, as performed here, increases the risk of barotrauma. The Palv value is a result of the insufflating volume and lung compliance, Pprox values that are higher than the Palv are caused by resistance in the orotracheal tube and airways.

Although there have been anecdotal reports of high Pprox during MH in adults, with volumes < 1 L,(17) there is no hard evidence that the maneuver is dangerous.

In conclusion, when asked to apply MH in accordance with their routine clinical practice,

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Ortiz TA, Forti G, Volpe MS, Carvalho CRR, Amato MBP, Tucci MR

this small sample of RTs performed the maneuver quite differently from what is recommended by experts, producing a concerning pattern of ventilation in terms of secretion clearance.

The repetition of the maneuver after explicit instructions reduced the Pprox but did not help much. Alveolar pressures were usually low (because of the small generated VT) despite high proximal pressures and high inspiratory peak flows. As a result, PEF was also low, far lower than the preceding PIF, a condition theoretically impacting the secretions deeper into the lung. Further studies are necessary in this area, especially focusing on the use of flow-inflating devices delivering higher tidal volumes.

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manual lung hyperinflation in critically ill patients.

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About the authors Tatiana de Arruda Ortiz,

Adjunct Professor. Department of Physiotherapy. University of Cuiabá, Tangará da Serra, Brazil.

Germano Forti

Researcher. Laboratório de Investigação Médica 09 (LIM-09, Laboratory for Medical Research 09), specializing in Pulmonology, University of São Paulo School of Medicine, São Paulo, Brazil.

Márcia Souza Volpe

Adjunct Professor. Department of Physiotherapy. Federal University of Triângulo Mineiro, Uberaba, Brazil.

Carlos Roberto Ribeiro Carvalho

Full Professor of Pulmonology. University of São Paulo School of Medicine, São Paulo, Brazil.

Marcelo Brito Passos Amato

Coordinating Physician. Respiratory Intensive Care Unit, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Mauro Roberto Tucci

Physician. Respiratory Intensive Care Unit, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil

J Bras Pneumol. 2013;39(2):205-213

Original Article Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil* Prevalência de infecção latente por Mycobacterium tuberculosis e risco de infecção em pacientes com insuficiência renal crônica em hemodiálise em um centro de referência no Brasil

Jane Corrêa Fonseca, Waleska Teixeira Caiaffa, Mery Natali Silva Abreu, Katia de Paula Farah, Wânia da Silva Carvalho, Silvana Spindola de Miranda

Abstract Objective: To determine the prevalence of latent tuberculosis infection (LTBI) and the risk of infection in patients with chronic kidney disease treated at a hemodialysis center. Methods: We included 307 patients with chronic kidney disease undergoing hemodialysis at the Mineiro Institute of Nephrology, located in the city of Belo Horizonte, Brazil. All of the patients were submitted to tuberculin skin tests (TSTs). We investigated the booster effect and TST conversion. If the initial TST (TST1) was negative, a second TST (TST2) was performed 1-3 weeks later in order to investigate the booster effect. If TST2 was also negative, a third TST (TST3) was performed one year after TST2 in order to determine whether there was TST conversion. Results: When we adopted a cut-off induration of 5 mm, the prevalence of LTBI was 22.2% on TST1, increasing by 11.2% on TST2. When we adopted a cut-off induration of 10 mm, the prevalence of LTBI was 28.5% on TST1, increasing by 9.4% on TST2. The prevalence of LTBI increased significantly from TST1 to TST2 (booster effect), as well as from TST2 to TST3 (p < 0.01 for both). In our sample, the mean annual risk of infection was 1.19%. Conclusions: In the population studied, the prevalence of LTBI was high, and the mean annual risk of infection was similar to that reported for the general population of Brazil, which suggests recent infection.

Keywords: Tuberculosis; Renal insufficiency, chronic; Tuberculin test.

Resumo Objetivo: Determinar a prevalência da infecção latente por Mycobacterium tuberculosis (ILMT) e o risco de infecção em pacientes com insuficiência renal crônica em um centro de hemodiálise. Métodos: Foram incluídos no estudo 307 pacientes com insuficiência renal crônica em tratamento hemodialítico no Instituto Mineiro de Nefrologia, na cidade de Belo Horizonte (MG). Todos os pacientes foram submetidos a testes tuberculínicos (TTs).

O efeito booster e a viragem tuberculínica foram avaliados. Se o primeiro TT (TT1) era negativo, um segundo (TT2) era realizado 1-3 semanas após o TT1 para investigar o efeito booster. Se o TT2 também era negativo, um terceiro (TT3) era realizado um ano após o TT2 para identificar a viragem tuberculínica. Resultados: A prevalência da ILMT, quando considerado o ponto de corte de 5 mm de enduração, foi de 22,2% no TT1, com incremento de 11,2% no TT2. A prevalência da ILMT, quando considerado o ponto de corte de enduração de 10 mm, foi de 28,5% no TT1, com incremento de 9,4% no TT2. Um aumento significativo da prevalência da ILMT foi observado entre TT1 e TT2 (efeito booster) e entre TT2 e TT3 (p < 0,01 para ambos). Na nossa amostra, o risco médio anual de infecção foi de 1,19%. Conclusões: Na população estudada, a prevalência da ILMT foi alta, e o risco de infecção foi semelhante ao da população geral no Brasil, o que sugere infecção recente.

Descritores: Tuberculose; Insuficiência renal crônica; Teste tuberculínico.

* Study carried out at the Mineiro Institute of Nephrology and at the Federal University of Minas Gerais, Belo Horizonte, Brazil.

Correspondence to: Silvana Spindola de Miranda. Avenida Alfredo Balena, 190, Faculdade de Medicina/Departamento de Clínica Médica, 2º andar, Santa Efigênia, CEP 30130-100, Belo Horizonte, MG, Brasil.

Tel. 55 31 3248-9599. E-mail: spindola@medicina.ufmg.br Financial support: This study received financial support from the Federal University of Minas Gerais School of Medicine Graduate Program, the Secretaria Municipal da Saúde de Belo Horizonte (SMSA, Belo Horizonte Municipal Department of Health), the Mineiro Institute of Nephrology, and the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG, Foundation for the Support of Research in the state of Minas Gerais).

Submitted: 14 September 2012. Accepted, after review: 22 January 2013.

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Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil

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Introduction

Methods

Tuberculosis remains a serious public health problem worldwide. The World Health Organization estimates that there were 50 million people infected with Mycobacterium tuberculosis, 92,000 new cases (incidence, 48/100,000 population), and 49,000 new smear-positive cases (incidence, 26/100,000 population) in Brazil in 2007. In addition, the number of deaths from tuberculosis has been estimated at 8,400, i.e., 4.4 deaths per 100,000 population.(1) In 2008, the incidence of tuberculosis was 50/100,000 population in Brazil, 23/100,000 population in the state of Minas Gerais, and 31/100,000 population in the city of Belo Horizonte. In southeastern Brazil, the prevalence of tuberculosis is high, which is probably due to worsening of living conditions in urban areas, incorrect diagnosis and treatment, and inappropriate use of available resources.(2,3) Patients with chronic kidney disease (CKD) are immunosuppressed, given that uremia reduces the expression of B7-2 costimulatory molecule on antigen-presenting cells; this alters the function of polymorphonuclear cells and interferes with phagocytic efficiency, migration efficiency, and chemotactic efficiency, reducing the ability of cells to kill intracellular microorganisms.

(4) Nevertheless, the tuberculin skin test (TST) remains the standard method for diagnosing latent tuberculosis infection (LTBI) in patients with CKD undergoing hemodialysis and in kidney transplant candidates, although anergy rates vary widely.(5-9) In developed countries, the most common causes of entry into renal replacement therapy programs are diabetes mellitus (DM) and systemic arterial hypertension (SAH), which account for approximately 70% of all admissions to dialysis centers. In developing countries, there is a higher prevalence of nephropathy related to infectious diseases, although the available data are inaccurate.(10) In patients with CKD undergoing hemodialysis, the risk of developing tuberculosis is 6.9-52.5 times as high as it is in the general population, which is why all patients presenting with positive TST results should receive treatment for LTBI.(11) The objective of the present study was to determine the prevalence of LTBI and the risk of infection in patients with CKD treated at a hemodialysis center.

This was a prospective longitudinal study conducted at the Mineiro Institute of Nephrology, located in the city of Belo Horizonte, Brazil. All patients over 18 years of age and undergoing hemodialysis between December of 2008 and December of 2009 were invited to participate in the study.

The study participants completed a standardized, previously validated questionnaire on the following: date of hemodialysis initiation; sociodemographic data (including gender, age, race, and marital status); smoking; alcohol consumption; body mass index; presence of DM; HIV, HBV, and HCV serology; and use of immunosuppressants. In addition, the participants were evaluated in terms of the following: presence of a BCG vaccination scar; history of tuberculosis; and history of contact with a tuberculosis patient.

The etiology of kidney disease and the use of medications (antihypertensives, recombinant human erythropoietin, iron, insulin, diuretics, antidepressants, immunosuppressants, vasodilators, bronchodilators, B vitamins, vitamin C, folic acid, and vitamin D analogs) were reported and evaluated in terms of their association with TST results.

Patients who failed to return for the reading of the TST results, those who had previously undergone a TST, those who had previously been treated for LTBI, and those who presented with a history of tuberculosis were excluded from the present study.

All of the study participants underwent chest X-ray.

The present study was approved by the Research Ethics Committee of the Federal University of Minas Gerais (ETIC Ruling no. 25/08), located in the city of Belo Horizonte, Brazil.

The TST was performed by the Mantoux method, which consists of intradermal administration of 0.1 mL (2 tuberculin units) of PPD RT23 (State Serum Institute, Copenhagen, Denmark) on the volar aspect of the forearm. The results of the test were read within 72-96 h after PPD RT23 administration. The maximum transverse diameter of the area of palpable induration was measured with a millimeter ruler, and the results were expressed in mm. If the initial TST (TST1) was negative, a second TST (TST2) was performed 1-3 weeks later in order to investigate the booster effect. If TST2 was also negative, a J Bras Pneumol. 2013;39(2):214-220

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third TST (TST3) was performed one year after TST2 in order to determine whether there was TST conversion.(12) We used two cut-off points for TST induration.

In general, for patients with CKD, a positive TST result was defined as an induration ≥ 10 mm.

For kidney transplant candidates, HIV-positive patients, immunosuppressed patients, patients using prednisone or equivalent at a dose ≥ 15 mg/day for more than one month, and candidates for the use of TNF-α inhibitors, a positive TST result was defined as an induration ≥ 5 mm.

The latter cut-off point was chosen on the basis of recommendations made by the American Thoracic Society and other authors,(13,14) given that patients receiving immunosuppressants after transplantation have a high risk of developing active tuberculosis.

The booster effect was defined as a TST2 induration ≥ 10 mm, the TST2 induration having increased by more than 6 mm in comparison with the TST1 induration.(3) We defined TST conversion as a TST3 induration ≥ 10 mm in comparison with the TST2 induration.(3) For all of the individuals with LTBI, we recommended treatment with isoniazid at a dose of 10 mg/kg per day (maximum dose, 300 mg/ day) after hemodialysis.

In order to calculate the mean annual risk of infection (MARI), we used the formula proposed

by Ruffino-Netto.(15) Descriptive statistics were calculated for all study variables. For categorical variables (such as race and gender), we employed frequency distribution tables. For continuous variables (such as age and weight), we adopted measures of central tendency (mean and median) and variability (minimum/maximum values and standard deviation).

In order to determine the differences between the two groups regarding continuous variables, we used the nonparametric Mann-Whitney test, which was chosen because the study variables showed non-normal distribution. The OR was calculated with a confidence interval of 95%.

Adjustment for gender and age was made by ordinal logistic regression. For all analyses, we set the level of significance at 5% and used the Statistical Package for Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA).

J Bras Pneumol. 2013;39(2):214-220

Results A total of 335 patients were invited to participate in the present study. Of those, 28 were excluded because they declined to undergo or failed to return for the reading of the results of any of the TSTs and 21 were excluded because they reported a history of tuberculosis. Therefore, the study sample consisted of 307 patients. The mean age was 53 years (range, 19-85 years), with a predominance of males (56.4%), non-White individuals (65.4%), married individuals (59.4%), alcoholics (6.6%), and smokers (88%). Only 46 patients (13.8%) were underweight (body mass index < 18.5 kg/m2). Regarding comorbidities, 86 patients (28%) had DM, 12 (4%) were HCV-positive (although none were HBV-positive), and 2 (0.6%) were HIV-positive. Only 9 patients (3%) were using immunosuppressants. A total of 225 patients (73.4%) had a BCG vaccination scar, and 63 (20.6%) reported having had contact with a tuberculosis patients. Of the sample as a whole, 57.3% had no radiographic changes, whereas 42.7% (131 patients) did. Of those, none were diagnosed with active tuberculosis.

The main causes of CKD were hypertensive nephrosclerosis (in 22.1%), chronic glomerulonephritis (in 18.8%), diabetic nephropathy (in 17.9%), and other diseases (in 41.2%). The etiology of CKD had little or no impact on the results of the TSTs, the chi-square test having revealed no significant differences among the results of TST1, TST2, and TST3 (p > 0.05).

When we adopted a cut-off induration ≥ 5 mm (for kidney transplant candidates, HIV-positive patients, immunosuppressed patients, and candidates for the use of TNF-α inhibitors), the prevalence of LTBI was 22.2% on TST1, increasing by 11.2% on TST2 (booster effect) and 2.8% on TST3 (TST conversion).

When we adopted a cut-off induration ≥ 10 mm (for CKD patients who were not kidney transplant candidates), the prevalence of LTBI was 28.5% on TST1, increasing by 9.4% on TST2 (booster effect) and 2.5% on TST3 (TST conversion).

For the two cut-off indurations (of 5 mm and 10 mm), the prevalence of LTBI increased significantly from TST1 to TST2, as well as from TST2 to TST3 (p < 0.01 for both). The cumulative frequency (TST1 and TST2) was 33.4% (cut-off induration, 5 mm) and 37.9% (cut-off induration, 10 mm), respectively (Table 1).

Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil

In our sample of patients with CKD, the MARI was 1.19%.

There were no significant associations of age, etiology of CKD, hemodialysis efficiency, iron stores, use of vitamin D analogs, anemia, DM, malnutrition, date of hemodialysis initiation, duration of hemodialysis, HCV serology results, or presence of a BCG vaccination scar with the results of any of the TSTs (p > 0.05).

Risk factors such as smoking, alcoholism, DM, use of immunosuppressants, hypoalbuminemia, HIV infection, and absence of a BCG scar were evaluated in the study population, and we found no statistically significant associations between the tests and their respective cut-off points (TST1 induration ≥ 5 mm or ≥ 10 mm, booster effect, and TST conversion) when evaluated in isolation.

The TST result was more likely to be positive with a cut-off point of 10 mm in association with alcoholism and the male gender.

We found that TST1 induration was more likely to be ≥ 10 mm in males (28%) than in females (15%).

We found no statistically significant associations between the TST response and any of the following: maximum ferritin levels, as measured annually; mean ferritin levels, as calculated on the basis of four quarterly measurements (typically performed at the center for renal replacement therapy); transferrin saturation; albumin levels; and hemoglobin levels.

In comparison with nonsmokers, former smokers (31.1%) showed a trend toward TST1 positivity (cut-off indurations of 5 mm and 10 mm).

Having DM was not a significant risk factor for LTBI. All of the CKD patients who were not vitamin D users showed a trend toward TST3 positivity (p = 0.033).

The LTBI treatment abandonment rate was 44.4%. There were no adverse reactions that constituted an obstacle to the use of isoniazid.

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Discussion Between 2005 and 2006, 6 cases of tuberculosis occurred at our hemodialysis center, suggesting patient-to-patient transmission occurring in the cafeterias, in the procedure rooms, in the waiting rooms, or in the reception area. Therefore, it was important to determine the prevalence of LTBI and the risk of infection in patients with CKD treated at our center.

Our sample of patients with CKD consisted mostly of non-White males, as has been reported elsewhere.(16) We found that a positive TST result (i.e., a TST1 induration ≥ 10 mm) was more likely to occur in males (28%), a finding that is consistent with those of other studies.(5,6) We found no association between race and the TST response.

Nutritional data (including body mass index) and the etiology of CKD had no significant influence on the TST response, a finding that is consistent with those reported in previous studies.(5,6,8) In the present study, having a history of contact with tuberculosis (20.6%) did not coincide with the prevalence of tuberculosis infection, which was 33.4% for a cut-off induration of 5 mm and 37.9% for a cut-off induration of 10 mm (cumulative frequency of TST1 and TST2).

This can be explained by a lack of awareness of contact.

Our findings are consistent with those of a prevalence study involving elderly patients on hemodialysis.(5) In that study, some of the patients had negative TST results (anergy), which were attributed to advanced age or immunological changes caused by uremia.(5) Some of the negative TST results in our study might be related to uremia, given that the mean age of the participants was 53 years. Despite the limitations of the TST, the high prevalence of tuberculosis infection warrants the recommendation that the test be performed

Table 1 - Prevalence of latent tuberculosis infection in 307 patients with chronic kidney disease, Mineiro Institute of Nephrology, 2008-2009.a Patients in relation to the selected cut-off point for TST induration Results 5 mm 10 mm Negative 46 (63.8) 140 (59.6) Positive 16 (22.2) 67 (28.5) Booster effect 8 (11.2)* 22 (9.4)* TST conversion 2 (2.8)* 6 (2.5)* TOTAL 72 (100.0) 235 (100.0) TST: tuberculin skin test. aValues expressed as n (%). *Chi-square test (p < 0.05).

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more carefully in CKD patients, who are at a high risk of active tuberculosis.(5,8) The 12.7% increase in the prevalence of LTBI from TST1 to TST2 and the 5% increase in the prevalence of LTBI from TST2 to TST3 were statistically significant (p < 0.01), suggesting the importance of a second test for early detection of LTBI and a third test for those who show no booster effect. The TST conversion was probably due to contact in the community, given that the incidence of tuberculosis in the city of Belo Horizonte is high (> 30/100,000 population), according to the World Health Organization,(16) as well as to the fact that there were no cases of active (transmissible) tuberculosis at our center during the study period.

Some of the relevant findings of the present study include the fact that the prevalence of LTBI in patients with CKD was high and the fact that TST2 and TST3 significantly increased the detection of LTBI in individuals who had initially tested negative.

Various studies have found that patients with CKD are at a high risk of developing tuberculosis, a finding that is inconsistent with those of the present study and that is probably due to the use of isoniazid in those patients who completed the preventive treatment or to the short follow-up period.(10,11,17,18) The LTBI treatment abandonment rate found in the present study (i.e., 44.4%) is consistent with the rate reported by other authors,(19) reinforcing the need for health policies aimed at improving treatment adherence in such patients.

In the present study, we found no association between cases of active tuberculosis and any of the following: hemoglobin and hematocrit levels; iron stores; and positive TST results (LTBI).

Genetic disorders in humans, such as mutations in ferroportin 1, can increase the risk of tuberculosis or negatively interfere with the response to treatment if there is an increase in the supply of iron to the macrophage. Therefore, iron status can play an important role in tuberculosis prevention and treatment, as well as in the development of tuberculosis vaccines.(20) In the present study, we found no significant association of the study variables (age, being married, etiology of CKD, dialysis efficiency, iron stores, anemia, DM, malnutrition, date of hemodialysis initiation, HCV serology results, and presence of a BCG vaccination scar) with the results of the TSTs (TST1, TST2, and TST3) J Bras Pneumol. 2013;39(2):214-220

when analyzed in isolation, a finding that is consistent with those of other studies.(5,18) False-positive reactions can occur in individuals vaccinated with BCG, especially after the first year of vaccination, when the vaccine produces reactions that are stronger and last longer. However, the reaction tends to decrease over time, and, if the TST is performed within 10 years or more after the last vaccination, the effect of BCG vaccination might be minimal. This probably did not affect the results of the present study, given that, in Brazil, individuals usually receive BCG vaccination in the first days of life.(2) Vitamin D deficiency probably had no role in reducing the cellular response (negative TST),(19) given that patients with vitamin D deficiency tended to show positive TST3 results (p = 0.033).

Although studies have shown an association of tuberculosis with alcoholism and smoking,(21,22) our study showed no association of those variables with tuberculosis or LTBI, the exception being an association of tuberculosis and LTBI with the male gender and alcohol consumption when a cut-off induration of 10 mm was adopted.

In the CKD patients investigated in the present study, the MARI was similar to that reported for the general population of Brazil, which suggests recent infection. The highest MARI in the world is found in sub-Saharan Africa (1.5-2.5%). In developed countries, the MARI is 0.1%. In South America, the MARI has been estimated at 0.5-1.5%.

In Brazil, the MARI is currently 1%, being lower in the southern region of the country and larger in the southeastern, northern, and northeastern regions.(19) Although gamma interferon release assays and TSTs are similar in terms of their ability to detect LTBI, the relatively high cost and the need for laboratory infrastructure are some of the limitations of the former.(23) There is a lack of data on the use of gamma interferon release assays for detecting LTBI in patients with CKD undergoing hemodialysis.(9,24) In Brazil, interferon gamma release assays have yet to be more widely employed as a method for diagnosing LTBI.(3,12) In the present study, the TST proved to be a useful tool for the detection of LTBI in patients with CKD undergoing hemodialysis. We can conclude that the prevalence of LTBI in the study population was high and the MARI was similar to that reported for the general population of Brazil, which suggests recent infection.

Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil

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4. Girndt M, Sester M, Sester U, Kaul H, Köhler H. Defective expression of B7-2 (CD86) on monocytes of dialysis patients correlates to the uremia-associated immune defect. Kidney Int. 2001;59(4):1382-9.

5. Wauters A, Peetermans WE, Van den Brande P, De Moor B, Evenepoel P, Keuleers H, et al. The value of tuberculin skin testing in haemodialysis patients. Nephrol Dial Transplant. 2004;19(2):433-8.

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8. Shankar MS, Aravindan AN, Sohal PM, Kohli HS, Sud K, Gupta KL, et al. The prevalence of tuberculin sensitivity and anergy in chronic renal failure in an endemic area: tuberculin test and the risk of post-transplant tuberculosis.

Nephrol Dial Transplant. 2005;20(12):2720-4.

9. Maden E, Bekci TT, Kesli R, Atalay H, Teke T, Solak Y, et al. Evaluation of performance of quantiferon assay and tuberculin skin test in end stage renal disease patients receiving hemodialysis. New Microbiol. 2011;34(4):351-6.

10. Hussein MM, Mooij JM, Roujouleh H. Tuberculosis and chronic renal disease. Semin Dial. 2003;16(1):38-44.

11. Lundin AP, Adler AJ, Berlyne GM, Friedman EA. Tuberculosis in patients undergoing maintenance hemodialysis. Am J Med. 1979;67(4):597-602.

12. Ministério da Saúde. Secretaria de Vigilância em Saúde.

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

13. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med. 2000;161(4 Pt 2):S221-47.

14. Manuel O, Humar A, Preiksaitis J, Doucette K, Shokoples S, Peleg AY, et al. Comparison of quantiferon-TB gold with tuberculin skin test for detecting latent tuberculosis infection prior to liver transplantation. Am J Transplant.

2007;7(12):2797-801.

15. Ruffino-Netto A. Epidemiometric models in tuberculosis.

Definition of “states” and risk of infection [Article in Portuguese]. Rev Saude Publica. 1977;11(2):188-98.

16. Guilbert JJ. The world health report 2002 - reducing risks, promoting healthy life. Educ Health (Abingdon).

2003;16(2):230.

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17. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K, et al. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.

18. Klote MM, Agodoa LY, Abbott KC. Risk factors for Mycobacterium tuberculosis in US chronic dialysis patients. Nephrol Dial Transplant. 2006;21(11):3287-92.

19. Kritski AL, Conde MB, Souza MG, editors. Tuberculose: do ambulatório à enfermaria. 3rd ed. São Paulo: Atheneu; 2005.

20. Boelaert JR, Vandecasteele SJ, Appelberg R, Gordeuk VR. The effect of the host’s iron status on tuberculosis.

J Infect Dis. 2007;195(12):1745-53.

21. Caron-Ruffino M, Ruffino-Netto A. Association of alcoholism and pulmonary tuberculosis [Article in Portuguese]. Rev Saude Publica. 1979;13(3):183-94.

22. Sopori ML, Kozak W. Immunomodulatory effects of cigarette smoke. J Neuroimmunol. 1998;83(1-2):148-56.

23. Dagnew AF, Hussein J, Abebe M, Zewdie M, Mihret A, Bedru A, et al. Diagnosis of latent tuberculosis infection in healthy young adults in a country with high tuberculosis burden and BCG vaccination at birth. BMC Res Notes.

2012;5:415.

24. Herrera V, Perry S, Parsonnet J, Banaei N. Clinical application and limitations of interferon-gamma release assays for the diagnosis of latent tuberculosis infection.

Clin Infect Dis. 2011;52(8):1031-7.

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About the authors Jane CorrĂŞa Fonseca

Nephrologist. Mineiro Institute of Nephrology, Belo Horizonte, Brazil.

Waleska Teixeira Caiaffa

Full Professor. Department of Public Health, Federal University of Minas Gerais School of Medicine, Belo Horizonte, Brazil.

Mery Natali Silva Abreu

Adjunct Professor. Department of Statistics. Federal University of Minas Gerais School of Nursing, Belo Horizonte, Brazil.

Katia de Paula Farah

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

Wânia da Silva Carvalho,

Associate Professor I. Department of Social Pharmacy, Federal University of Minas Gerais School of Pharmacy, Belo Horizonte, Brazil.

Silvana Spindola de Miranda

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

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Brief Communication Completeness of tuberculosis reporting forms in five Brazilian capitals with a high incidence of the disease* Completude das fichas de notificações de tuberculose em cinco capitais do Brasil com elevada incidência da doença

Normeide Pedreira dos Santos, Monique Lírio, Louran Andrade Reis Passos, Juarez Pereira Dias, Afrânio Lineu Kritski, Bernardo Galvão-Castro, Maria Fernanda Rios Grassi

Abstract The aim of this study was to evaluate the completeness of tuberculosis reporting forms in the greater metropolitan areas of five Brazilian capitals where the incidence of tuberculosis was high in 2010—Salvador, Rio de Janeiro, Cuiabá, Porto Alegre, and Belém—using tabulations obtained from the Sistema Nacional de Informação de Agravos de Notificação (National Case Registry Database). The degree of completeness was highest in Porto Alegre and Cuiabá, whereas it was lowest in Rio de Janeiro, where there are more reported cases of tuberculosis than in any other Brazilian capital. A low degree of completeness of these forms can affect the quality of the Brazilian National Tuberculosis Control Program, which will have negative consequences for health care and decision-making processes.

Keywords: Tuberculosis; Public health surveillance; Disease notification.

Resumo O objetivo deste estudo foi avaliar a completude das fichas de notificações de tuberculose de cinco capitais brasileiras com alta incidência regional de tuberculose em 2010 — Salvador, Rio de Janeiro, Cuiabá, Porto Alegre e Belém — através dos relatórios de tabulação do Sistema Nacional de Informação de Agravos e Notificações.

Porto Alegre e Cuiabá apresentaram os melhores resultados, enquanto o Rio de Janeiro, capital com o maior número de notificações de tuberculose no país, apresentou o pior. A baixa completude desses formulários pode comprometer a qualidade do Programa Nacional de Controle da Tuberculose e repercutir na assistência e nos processos decisórios.

Descritores: Tuberculose; Vigilância da população; Notificação de doenças.

It is estimated that, on an annual basis, there are eight million new cases of tuberculosis and two million related deaths. More than 95% of all cases occur in developing countries.(1) Brazil ranks 17th among the 22 countries with the highest annual incidence of tuberculosis,(2) at 32 cases/100,000 population. The incidence of tuberculosis in the country varies by geographic region, the lowest rates occurring in the central-west, southern, and northeastern regions (21.90, 33.18, and

38.77 cases/100,000 population, respectively). In southeastern Brazil, the incidence is 40.98/100,000 population, whereas, in northern Brazil, it is 47.77/100,000 population. The highest proportions of treatment dropout, HIV co-infection, incidence, and tuberculosis-related mortality occur in the capital cities. Among the Brazilian capitals, in their respective regions, the incidence rates are highest in Belém (northern Brazil; 94.09/100,000 population), Rio de Janeiro (southeastern Brazil;

* Study carried out under the auspices of the Graduate Program in Medicine and Health, Bahia School of Medicine and Public Health, and in the Advanced Laboratory of Public Health, Gonçalo Moniz Research Center, Oswaldo Cruz Foundation-Bahia, Salvador, Brazil.

Correspondence to: Maria Fernanda Rios-Grassi. Laboratório Avançado de Saúde Pública, Fundação Oswaldo Cruz-Bahia (FIOCRUZ-BA), Rua Waldemar Falcão, 121, Candeal, CEP 40296-710, Salvador, BA, Brasil.

Tel. 55 71 9971-7961. E-mail: grassi@bahia.fiocruz.br Financial support: Louran Andrade Reis Passos is the recipient of a Young Investigator Grant from the Programa Institucional de Bolsas de Iniciação Científica (PIBIC, Institutional Program for Scientific Initiation Scholarships) of the Fundação Oswaldo CruzBahia (FIOCRUZ-BA, Oswaldo Cruz Foundation-Bahia). Afrânio Lineu Kritski is the recipient of 1A Research Productivity Grant and Bernardo Galvão-Castro Filho is the recipient of a 1B Research Productivity Grant from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development).

Submitted: 3 September 2012. Accepted, after review: 28 January 2013.

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89.42/100,000 population), Cuiabá (centralwest Brazil; 85.65/100,000 population), Salvador (northeastern Brazil; 72.62/100,000 population), and Porto Alegre (southern Brazil; 44.39/100,000 population).(3) Tuberculosis is a disease for which reporting has been mandatory in Brazil since 1998. Reporting and follow-up forms are completed by the staff at the health care clinics in the cities and delivered to the Sistema de Informação de Agravos de Notificação (SINAN, Brazilian Case Registry Database) for processing.(4,5) The completeness of the fields on the reporting forms can be considered a marker of quality, complete data sets making it possible to understand the dynamics of the disease, set intervention priorities, and assess the impact of the interventions implemented.

(5) In order to reduce morbidity and mortality, as well as to improve tuberculosis control, the

Programa Nacional de Controle da Tuberculose (PNCT, Brazilian National Tuberculosis Control Program) has classified certain cities as priority cities for tuberculosis control. Priority cities include all capital cities and any city with more than 100,000 inhabitants, as well as cities where the tuberculosis incidence is ≥ 80% above the national average or the annual tuberculosisrelated mortality rate is higher than 2.5/100,000 population.(6) Tuberculosis surveillance studies have demonstrated that, paradoxically, the degree of completeness of reporting forms is low in priority cities.(7,8) The aim of the present study was to evaluate the completeness of tuberculosis reporting and follow-up forms in five Brazilian capitals.

To that end, we conducted a descriptive study in which we evaluated the SINAN database information for the Brazilian capitals of Belém, Rio de Janeiro, Cuiabá, Salvador, and Porto Alegre for the 2001-2010 period; applying the selection criterion of investigating the greater metropolitan areas of the capitals where the incidence of tuberculosis was highest in 2010.(3) The information on the completeness of reporting forms was obtained from the SINAN tabulations, with automatic table generation, by two previously trained undergraduate investigators, under the supervision of the researchers. We excluded fields that read “omitted”, “left blank”, or “in progress”.

The variables of interest were grouped as follows: sociodemographic variables—gender, age group, and institutionalization; clinical variables—type J Bras Pneumol. 2013;39(2):221-225

of admission, clinical presentation of tuberculosis (pulmonary or extrapulmonary, and, in cases of extrapulmonary tuberculosis, whether it presented as a single-system or multisystem disease [classified in the present study as extrapulmonary tuberculosis 1 and 2, respectively]), and HIV co-infection; and diagnostic and follow-up variables—first and second smears, smears at 2 and 6 months of treatment, sputum culture, HIV serology, and treatment outcome. To analyze the completeness of the reporting forms, we used the SINAN qualitative evaluation system, with categories ranging from 1 to 4, corresponding to completeness of 0.0-25.0%, 25.1-50.0%, 50.1-75.0%, and 75.1-100.0%, respectively.(9) In the 2001-2010 period, 160,719 cases of tuberculosis were reported in the capitals evaluated—82,604 in Rio de Janeiro, 34,118 in Salvador, 22,836 in Porto Alegre, 17,132 in Belém, and 4,029 in Cuiabá—accounting for 18% of all cases in Brazil. The variables “age group” and “gender” were classified as category 4 in all capitals, with a degree of completeness of nearly 100%, whereas the field “institutionalization” was classified as category 2 in the five capitals, with a degree of completeness ranging from 31.6% to 48.4%. Tables 1 and 2 show the rates of completeness for the different variables for the five capitals of interest.

The results of the present study show that, although more than 40% of the variables of interest were classified as category 4 (degree of completeness of 75.1-100.0%), the proportion of variables for which the degree of completeness was low (categories 1 and 2) was high. In none of the capitals of interest were more than 70% of the variables classified as category 4, despite the recommendation of the National Pulmonology Health Care Council of the Brazilian National Ministry of Health for completeness of reporting forms. The degree of completeness was lowest in the cities of Rio de Janeiro and Belém, with almost 50% of the variables being classified as categories 1 and 2, followed by Salvador, with 40%, whereas it was highest in Porto Alegre and Cuiabá. These results confirm those of previous studies, which showed that surveillance quality was poor in one third of the Brazilian cities in the 2001-2003 period(7) and that the degree of completeness of reporting forms was lower in cities where there are more cases of tuberculosis.(7,8)

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Table 1 - Completeness of tuberculosis reporting forms in the Brazilian capitals of Salvador, Rio de Janeiro, Cuiabá, Porto Alegre, and Belém, 2001-2010: clinical variables.a Reporting forms completed Clinical variable Salvador Rio de Janeiro Cuiabá Porto Alegre Belém (n = 34,118) (n = 82,604) (n = 4,029) (n = 22,836) (n = 17,132) Type of admission 34,006 (99.7) 82,604 (100.0) 4,025 (99.9) 22,831 (99.9) 16,986 (99.1) Clinical presentation 34,06 (99.7) 82,604 (100.0) 4,025 (99.9) 22,831 (99.9) 16,986 (99.1) AIDS 8,101 (23.7) 22,122 (26.8) 1,506 (37.4) 14,130 (61.9) 1,242 (7.2) Extrapulmonary 1 5,043 (14.8) 15,078 (18.3) 591 (14.7) 6,592 (28.9) 3,114 (18.2) Extrapulmonary 2 320 (0.9) 1,139 (1.4) 41 (1.0) 829 (3.6) 301 (1.6) a Values expressed as n (%). Source: Brazilian National Ministry of Health/Department of Health Surveillance/Brazilian Case Registry Database; data collated by the authors.

Table 2 - Completeness of tuberculosis reporting forms in the Brazilian capitals of Salvador, Rio de Janeiro, Cuiabá, Porto Alegre, and Belém, 2001-2010: diagnostic and follow-up variables.a Variable Reporting forms completed Salvador Rio de Janeiro Cuiabá Porto Alegre Belém (n = 34,118) (n = 82,604) (n = 4,029) (n = 22,836) (n = 17,132) First smear 34,006 (99.7) 82,604 (100.0) 4,025 (99.9) 22,831 (99.9) 16,986 (99.1) Second smear 12,194 (35.7) 35,515 (43.0) 1,780 (44.2) 11,148 (48.8) 6,948 (40.5) Smear at 2 months 18,701 (54.8) 20,044 (24.3) 3,551 (88.1) 22,175 (97.1) 7,458 (43.5) Smear at 6 months 16,071 (47.1) 19,435 (23.5) 3,111 (77.2) 22,063 (96.6) 5,418 (31.6) Culture 27,609 (80.9) 67,899 (82.2) 3,415 (84.8) 22,493 (98.5) 15,892 (92.8) HIV serology 27,224 (79.8) 58,482 (70.8) 3,401 (84.4) 22,673 (99.3) 15,487 (90.4) Treatment outcome 27,524 (80.7) 51,052 (61.8) 3,673 (91.2) 22,354 (97.9) 16,130 (94.1) a Values expressed as n (%). Source: Brazilian National Ministry of Health/Department of Health Surveillance/Brazilian Case Registry Database; data collated by the authors.

Although the degree of completeness was high for the variable “HIV serology” (classified as category 3 in one capital and as category 4 in the other ones), it was low for the variable “HIV co-infection”. For the variable “HIV serology”, the proportion of fields that read “not performed” ranged from 22.9% to 65.3%, which is in disregard of the recommendation of the Brazilian National Ministry of Health that all tuberculosis patients should undergo HIV testing.(10) In Brazil, the number of cases of tuberculosis has increased by 12% since the beginning of the AIDS epidemic, and the risk of an unfavorable outcome (treatment failure, multidrug resistance, and mortality) is approximately three times higher in tuberculosis patients who are co-infected with HIV than in those who are not(11) and can be as high as 55.0%.

(12) Incomplete data on treatment outcomes and HIV infection can be reconstructed using the linkage (relationship between records) technique,(13) comparing records among the Brazilian National Mortality Database, the Brazilian National CD4+/ CD8+ T Lymphocyte Count and Viral Load Network Laboratory Test Control System, the Logistic

Medication Monitoring System, and the SINAN/ AIDS. However, this and other techniques for retrieval of epidemiological data have not been incorporated into the routine of the technicians at the state or regional health departments, and it is more feasible to invest in improving the degree of data completeness on the SINAN forms.

One of the five pillars upon which directly observed treatment stands is the implementation of a network database for collating information on case detection, treatment outcomes, and the performance of the control program.(14) Low degrees of completeness reflect operational inadequacies of the PNCT and limit the analysis of information from health databases, which can negatively affect interventions aimed at tuberculosis control.

In the 2004-2007 period, the Brazilian government invested in training, allocated more resources for PNCT database operation, and instituted a system of rewards for priority cities where the degree of completeness for treatment outcome was higher than 90% in 2004 and for those where 75% of that goal was met in 2006. (15) Nevertheless, possible explanations J Bras Pneumol. 2013;39(2):221-225

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for the low degree of completeness observed in these cities are related to inadequacies in the number of health care staff and in the information technology infrastructure, hindering the flow and updating of information. In addition, the health care teams might view the filling out of forms as a bureaucratic chor, dissociating it from the quality of care. Therefore, it is recommended that the information technology infrastructure be improved and that the health care staff be trained and sensitized.

The present study has limitations, such as the use of secondary data and the limited number of variables of interest. However, the results obtained are relevant because we evaluated 18% of approximately 900,000 cases of tuberculosis reported in Brazil in the last ten years.

In conclusion, our evaluation of these five capitals over a ten-year period shows that the degree of completeness of reporting forms is lower than that recommended by the Brazilian National Ministry of Health. This situation can affect the quality of the PNCT, given that it has negative consequences for health care and decisionmaking processes, which suggests an urgent need for the implementation of innovative strategies that can increase the degree of completeness of tuberculosis reporting forms at all levels (national, state, and municipal).

References 1. World Health Organization. Global tuberculosis control: WHO report 2011. Geneva: World Health Organization; 2011.

2. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Jan 24]. Notícias. Available from: http://portal.saude.gov.br/portal/aplicacoes/noticias/ default.cfm?pg=dspDetalheNoticia&id_area=124&CO_ NOTICIA=1165 3. DATASUS [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Jan 24]. Taxa de Incidência de

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Tuberculose. Available from: http://tabnet.datasus.gov. br/cgi/tabcgi.exe?idb2011/d0202.def 4. Brasil. Portaria GM/MS nº 2325 de 08 de dezembro de 2003. Define a relação de doenças de notificação compulsória para todo território nacional. Diário Oficial da União. Brasília, n° 240, p. 81, 10 de dezembro de 2003. Seção 1.

5. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Jan 24]. O que é o Sinan. Available from: http://dtr2004.saude.gov.br/ sinanweb/index.php?name=Tnet 6. Portal da Saúde [homepage on the Internet]. Brasília: Ministério da Saúde. [cited 2012 Jan 24]. Nota técnica n° 15 CGPNCT/DEVEP/SVS/MS. [Adobe Acrobat document, 4p.]. Available from: http://portal.saude.gov.br/portal/ arquivos/pdf/nota_tecnica_prioritarios.pdf 7. Braga JU. Tuberculosis surveillance and health information system in Brazil, 2001-2003 [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:77-88.

8. Moreira CM, Maciel EL. Completeness of tuberculosis control program records in the case registry database of the state of Espírito Santo, Brazil: analysis of the 2001-2005 period. J Bras Pneumol. 2008;34(4):225-9.

9. Ministério da Saúde. SINAN - Relatórios - Manual de operação. Brasília: Ministério da Saúde; 2012.

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

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

11. Sanchez M, Bartholomay P, Arakaki-Sanchez D, Enarson D, Bissell K, Barreira D, et al. Outcomes of TB treatment

by HIV status in national recording systems in Brazil, 2003-2008. PLoS One. 2012;7(3):e33129.

12. Oliveira HB, Marín-León L, Cardoso JC. Perfil de mortalidade de pacientes com tuberculose relacionada à comorbidade tuberculose-aids. Rev Saude Publica.

2004;38(4):503-10.

13. Almeida MA, Alencar GP. Informações em Saúde: Necessidade de Introdução de Mecanismos de Gerenciamento dos Sistemas. Informe Epidemiológico do SUS. 2000;9(4):241-48.

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

Guia de vigilância epidemiológica. Brasília: Ministério da Saúde; 2009.

15. Santos J. Brazilian response to tuberculosis control [Article in Portuguese]. Rev Saude Publica. 2007;41 Suppl 1:89-94.

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About the authors Normeide Pedreira dos Santos

Doctoral Student. Graduate Program in Medicine and Health, Bahia School of Medicine and Public Health, Salvador, Brazil.

Monique Lírio

Resident in Infectious Diseases. Federal University of Bahia, Salvador, Brazil.

Louran Andrade Reis Passos

Medical Student. Bahia School of Medicine and Public Health, Salvador, Brazil.

Juarez Pereira Dias

Physician. Epidemiological Surveillance, Bahia State Health Department, Salvador, Brazil.

Afrânio Lineu Kritski

Full Professor. Tuberculosis Academic Program. Federal University of Rio de Janeiro School of Medicine, Rio de Janeiro, Brazil.

Bernardo Galvão-Castro

Physician-Researcher. Graduate Program in Medicine and Health, Bahia School of Medicine and Public Health, and Advanced Laboratory of Public Health, Gonçalo Moniz Research Center, Oswaldo Cruz Foundation-Bahia, Salvador, Brazil.

Maria Fernanda Rios Grassi

Physician-Researcher and Advisor. Graduate Program in Medicine and Health, Bahia School of Medicine and Public Health, and Advanced Laboratory of Public Health, Gonçalo Moniz Research Center, Oswaldo Cruz Foundation-Bahia, Salvador, Brazil.

J Bras Pneumol. 2013;39(2):221-225

Review Article Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration* Estado atual e aplicabilidade clínica da punção aspirativa por agulha guiada por ultrassom endobrônquico

Viviane Rossi Figueiredo, Márcia Jacomelli, Ascédio José Rodrigues, Mauro Canzian, Paulo Francisco Guerreiro Cardoso, Fábio Biscegli Jatene

Abstract Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has played a key role in the diagnosis of mediastinal, paratracheal, and peribronchial lesions, as well as in lymph node staging for lung cancer. Despite its minimally invasive character, EBUS-TBNA has demonstrated a diagnostic yield comparable with that of established surgical methods. It has therefore gained credibility and has become a routine procedure at various referral centers. A successful EBUS-TBNA procedure requires careful planning, which includes a thorough review of the radiological imaging and special care during specimen collection and preparation, as well as technical expertise, experience with the procedure itself, and knowledge of the potential complications inherent to the procedure. The most common indications for EBUS-TBNA include lymph node staging for lung cancer and the diagnostic investigation of mediastinal/hilar masses and lymph node enlargement. Recently, tumor biomarkers in malignant samples collected during the EBUS-TBNA procedure have begun to be identified, and this molecular analysis has proven to be absolutely feasible. The EBUS-TBNA procedure has yet to be included on the Brazilian Medical Association list of medical procedures approved for reimbursement. The EBUS-TBNA procedure has shown to be a safe and accurate tool for lung cancer staging/restaging, as well as for the diagnosis of mediastinal, paratracheal, and peribronchial lesions/lymph node enlargement.

Keywords: Endoscopic ultrasound-guided fine needle aspiration; Lung neoplasms; Neoplasm staging.

Resumo Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA, punção aspirativa por agulha guiada por ultrassom endobrônquico) tem desempenhado um papel fundamental no diagnóstico de lesões mediastinais, paratraqueais e peribrônquicas, assim como no estadiamento linfonodal da neoplasia pulmonar.

Por se tratar de exame endoscópico minimamente invasivo cujo rendimento diagnóstico tem se mostrado comparável aos métodos cirúrgicos estabelecidos, o procedimento de EBUS-TBNA ganhou espaço rapidamente e já se encontra integrado à rotina de investigação em serviços de referência. Para a realização de EBUSTBNA, é importante o planejamento prévio ao procedimento, que deve incluir uma análise minuciosa dos exames radiológicos e cuidado especial com a coleta e preparo do material, além do domínio da técnica e conhecimento de eventuais complicações inerentes ao procedimento. As principais indicações para a realização de EBUS-TBNA são o estadiamento linfonodal da neoplasia pulmonar e a investigação diagnóstica de massas e linfonodomegalias mediastinais ou hilares. Recentemente, iniciou-se a identificação de biomarcadores tumorais em amostras neoplásicas; essa análise molecular no material coletado durante o procedimento de EBUS-TBNA provou ser totalmente possível. Até o momento, o procedimento de EBUS-TBNA não consta nas tabelas de procedimentos médicos da Associação Médica Brasileira. O procedimento de EBUS-TBNA tem se mostrado seguro e eficaz no estadiamento e reestadiamento de neoplasia de pulmão e no esclarecimento diagnóstico de lesões ou linfonodomegalias mediastinais, paratraqueais e peribrônquicas.

Descritores: Biópsia por agulha fina; Neoplasias pulmonares; Estadiamento de neoplasias.

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

Correspondence to: Viviane Rossi Figueiredo. Serviço de Endoscopia Respiratória, Instituto do Coração, Avenida Dr. Enéas de Carvalho Aguiar, 44, Bloco I, 7º Andar, Cerqueira César, CEP 05403-900, São Paulo, SP, Brasil.

Tel. 55 11 2661-5612. E-mail: vivianerossifigueiredo@gmail.com Financial support: None.

Submitted: 7 December 2012. Accepted, after review: 10 January 2013.

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Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration

Introduction Flexible fiberoptic bronchoscopy plays a welldefined role in the diagnostic approach to lung masses and nodules, as well as in aspiration of mediastinal lesions and enlarged mediastinal lymph nodes. Although imaging tests such as chest CT and positron emission tomography combined with CT (PET/CT) can demonstrate the presence of lesions in the lungs or mediastinum, in most cases, cell or tissue sample collection is required to define the therapeutic approach.

During flexible fiberoptic bronchoscopy, endobronchial biopsy (EBB) and cytology brush of endoscopically visible lesions can be performed, as can (fluoroscopically or non-fluoroscopically guided) transbronchial biopsy (TBB) of parenchymal lesions and fine needle aspiration of mediastinal lesions and enlarged subcarinal lymph nodes.(1) In a review of studies between 1971 and 2004, the American College of Chest Physicians observed that the overall diagnostic sensitivity of conventional bronchoscopy in lung cancer was, respectively, 88% (range, 67-97%) and 78% (range, 36-88%) for central and peripheral carcinoma.(2) Each sample collection procedure has specific efficacy. The diagnostic yield of TBB alone in lung cancer ranges from 25% to 58% for nodules smaller than 2 cm, increasing to 60-83% for nodules greater than 2 cm.(3) Likewise, the diagnostic yield of fine needle aspiration of mediastinal masses or lymph nodes will vary according to lesion size. The yield will be higher if there is bulging of the tracheobronchial tree or thickening of the carina and interlobular septa.(4) New equipment and advanced technologies have been developed with the aim of improving the efficacy of bronchoscopic methods in the diagnosis of diseases of the lung and mediastinum.

In this context, electromagnetic navigation and endobronchial ultrasound-guide sheath—or radial endobronchial ultrasound—have been developed to guide biopsies of peripheral nodules, whereas endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is used in the diagnostic approach to the mediastinum and in lung cancer staging. Among these new methods, EBUS-TBNA has played a key role in the diagnosis of mediastinal, paratracheal, and peribronchial lesions, as well as in lymph node staging for lung cancer. Despite its minimally invasive character, EBUS-TBNA has demonstrated a diagnostic yield comparable with that of established surgical

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methods.(5) It has therefore gained credibility and has become a routine procedure at various referral centers. The experience of implementing EBUS-TBNA in Brazil has brought to light some difficulties and peculiarities that merit discussion.

The objective of this review article was to describe EBUS-TBNA, the equipment used, the indications for the procedure, the technique for performing the procedure, and recent results.

The EBUS-TBNA system In the last decade, EBUS systems, which allow needle aspiration, were developed, the differences from one to another being small.

The following are currently available in Brazil: • BF-UC180F (Olympus Medical Systems, Tokyo, Japan), used with an Olympus EU-ME1 ultrasound processor or a ProSound Alpha 5 ultrasound processor (Aloka, Tokyo, Japan).

• EB-530US (Fujifilm Corporation, Tokyo, Japan), used with a Fujinon SU-8000 processor (Fujifilm Corporation).

As of 2013, the EB-1970UK (Pentax Medical Company, Montvale, NJ, USA), used with a Hitachi EUB-5500 ultrasound processor (Hitachi Medical Corporation, Kashiwa, Japan), will also be available in Brazil.

The system is dedicated for EBUS-TBNA, having a distal diameter of 6.3-6.9 mm (depending on the brand) and a 2-mm working channel capable of accommodating a 19G or 22G needle.

The bronchoscopic view is oblique (35°-45°) rather than frontal. Imaging can be achieved by videobronchoscopy or can be hybrid, with optical fiber transmission to the imaging sensor, which is located at the proximal end of the device.

The device has a convex ultrasound transducer (probe) integrated into the distal end, with a 60° scanning angle. The systems provide different frequencies (5-12 MHz), there being variation among the brands available. Because lower frequencies translate to greater tissue scanning depth, the use of higher frequencies results in better image quality at more superficial layers. The Doppler function of the system allows identification of vascular structures, providing greater safety during aspiration of mediastinal lesions or enlarged mediastinal lymph nodes. The picture-in-picture feature of the bronchoscope processor allows the bronchoscopic and ultrasound images to be displayed side by side on the same screen.(6) J Bras Pneumol. 2013;39(2):226-237

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The probe located at the distal end of the system should be inserted into a latex balloon, and, during the procedure, this balloon should be inflated with distilled water at the time of ultrasound visualization of the structure that will be aspirated (Figures 1 and 2).

An EBUS-TBNA needle available in Brazil is dedicated (22G), disposable, and compatible with the system used, as well as having grooves in the distal end, which allows its visualization on ultrasound. Together with the needle, there is a vacuum syringe and a dedicated valve that connects the needle to the working channel of the EBUS system.(6)

Procedure for performing EBUS-TBNA

Figure 1 - Olympus echo-bronchoscope. Courtesy of Olympus Medical Systems.

Planning Regardless of the purpose of the procedure, it is essential that radiological (CT and/or PET/ CT) findings be analyzed in detail. The aspiration sites and their sequence should be defined before the beginning of the procedure.

In lymph node staging (N-staging) for lung cancer, systematizing the sequence is extremely important, since, in most centers where EBUSTBNA is part of routine care, a single needle is used for the entire procedure.(6) The sequence of aspiration sites should begin with the lymph node stations located furthest from the tumor (N3 stations), followed by those located closest to the tumor (N1). When the primary tumor has not yet been histologically diagnosed and is accessible to aspiration, this tumor should be aspirated last in the sequence. Therefore, the sequence of aspiration sites should be maintained to prevent the neoplastic cells present in the needle from producing false-positive results at stations located furthest from the tumor.(6,7)

Technique for performing EBUS-TBNA The procedure should be performed in the operating room or in the outpatient bronchoscopy room. In all cases, it is necessary that there be a suitable environment for performing bronchoscopic examinations as well as special furniture, with space for the medical and paramedical staff to move around. The room should be equipped with J Bras Pneumol. 2013;39(2):226-237

Figure 2 - Pentax echo-bronchoscope. Courtesy of Pentax Medical Company.

a mobile anesthesia apparatus and emergency supplies.

If possible, the EBUS-TBNA procedure should be preceded by conventional bronchoscopy in order to evaluate the entire respiratory tree, and aspiration of the site of an intraluminal lesion, which could produce false-positive results because of the presence of neoplastic cells in the aspiration pathway, should be avoided.(8) The preparation of the system includes connecting the ultrasound probe to a latex balloon and testing the balloon by inflating it with distilled water, removing any air bubbles that are detrimental to providing the ultrasound window. The preparation of the examination table includes topical anesthesia supplies, an EBUS-TBNA needle, a vacuum syringe, cytology slides, and vials for embedded cell blocks.

The EBUS-TBNA procedure can be performed under general anesthesia or under sedation, similarly to what is done in conventional

Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration

bronchoscopy.(9-12) Topical anesthesia should be performed with 1% or 2% lidocaine. Regardless of whether the procedure is performed under general anesthesia or under sedation, the EBUS system should be introduced orally, given that its diameter prevents it from being introduced through the nasal cavity.(9,10,12) The device should be passed through the larynx with caution, given that the bronchoscopic view is oblique and the ultrasound probe is located posteriorly to that view. Subsequently, ultrasound imaging of the lesion that will be diagnosed or of the first lymph node station that will be aspirated should be performed. After the tip of the device touches the tracheobronchial wall, the balloon should be inflated with distilled water so that the ultrasound probe is flat against the tracheal or bronchial wall, and the best ultrasound window to the lesion or lymph node should be found before aspiration. A 3- or 4-cm ultrasound depth is sufficient for the purpose of the examination.

At this point, the gain, contrast, and brightness of the ultrasound image can be adjusted to obtain the highest resolution image of the lesion or structure. Doppler is recommended to differentiate between solid structures (lymph node or tumor) and vascular structures (Figure 3).(6) In order to locate the hilar and mediastinal lymph node stations, it is necessary to know the anatomical landmarks between the tracheobronchial tree structures and the mediastinum, as well as the position of these lymph node stations that will be mapped. The lymph node map described

by Yasufuku et al. is a useful tool.(13) For lung cancer staging, it is recommended that there be a systematic approach to mediastinal and hilar lymph nodes. One technique involves ultrasound mapping of all accessible lymph nodes, with aspiration being performed only after mapping is complete. Thus, priority is given to aspiration of lymph nodes with a higher index of suspicion for malignancy, and these lymph nodes consequently have a significant impact on staging and on change of management.

(10) Another technique is performing aspiration simultaneously with mapping, choosing lymph nodes with characteristics suggestive of malignancy.

(14) In addition, any lymph node greater than 5 mm in diameter that is found during the procedure can be aspirated, and the sequence going from N3 stations to N1 stations should be respected.(15)

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Figure 3 - Doppler ultrasound image of a lymph node and a vessel. Courtesy of the Department of Bronchoscopy, Heart Institute, University of SĂŁo Paulo School of Medicine Hospital das ClĂ­nicas.

In order to give priority to aspiration of lymph nodes suspected of harboring malignancy, ultrasound morphology has been studied to identify the predictors for metastasis. Fujiwara et al. investigated the size of lymph nodes (greater or smaller than 10 mm in the shortest axis), their shape (round or oval), their border definition, and their echogenicity (heterogeneous or homogeneous), as well as the presence or absence of the hilar lymph node and the presence or absence of necrosis. The accuracy of each studied parameter in predicting metastasis ranged from 63.8% to 86.0%. A multivariate analysis revealed that a round shape, well-defined borders, heterogeneous echogenicity, and the presence of necrosis were predictors for lymph node metastasis.

At least one of these four characteristics was present in the lymph nodes found to be metastatic, whereas none of them were present in 96% of the lymph nodes found to be benign.(14) Recently, the vascular image patterns of lymph nodes were investigated by Nakajima et al.(16) The image findings were graded as follows: grade 0, no vessels within the lymph nodes; grade I, small vessels running toward the hilum; grade II, punctiform vessels or small vessels found as a long strip of a curve; and grade III, various twisted vessels with different diameters. When the authors defined grades 0 and I as benign and grades II and III as malignant, the sensitivity, specificity, and diagnostic accuracy were 87.7%, 69.6%, and 78.8%, respectively.

Another important aspect concerns the diameter of lymph nodes. Unlike what is observed for

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imaging methods used in radiological staging of lung cancer, EBUS-TBNA findings have demonstrated that lymph nodes measuring less than 10 mm in diameter on CT scans can be metastatic, even if there is no evidence of uptake on PET/CT scans. The EBUS-TBNA procedure can detect metastasis in lymph nodes measuring between 5 and 10 mm with a sensitivity of 89% and a negative predictive value (NPV) of 98.9%.(17)

Sample collection Wang needle (21G) transtracheal/transbronchial aspiration is still often used in conventional bronchoscopy because of its ease of use, safety, and low cost; however, up to 43% of the collected samples are unsatisfactory for diagnosis.(18) Available in Brazil, EBUS needles measure 22G in diameter, are provided with a protective sheath, have an exposure of approximately 4 cm, and have two to three safety locks to reduce the risk of accidents related to aspiration (vessels and other mediastinal structures) and the risk of perforation of the working channel of the device. The needle set includes a dedicated valve that fits into the working channel port of the device, thereby making it possible to connect the needle to the EBUS equipment. Once the needle is introduced into the working channel, it should be pushed until it fully fits into the valve connected to the device and is locked. The sheath should remain exposed until it is seen bronchoscopically, and only then can the safety lock of the needle be released. The needle should be advanced through the tracheobronchial wall in order to aspirate paratracheal or peribronchial lymph nodes or lesions (Figure 4).

Regarding the aspiration technique, the literature suggests at least three aspirations per lymph node or lesion, with various passes (10-15 needle movements) being performed per aspiration in order to obtain sufficient material in the absence of an on-site cytopathologist. Yasufuku et al. recommend that the number of aspirations per lymph node should be limited to five, even when there is an on-site cytopathologist.(6) The same authors believe that, if no adequate material is obtained in any of the aspirations, this material should be considered inconclusive for diagnosis.

In clinical practice, we have observed that the number of passes performed per aspiration can be adapted to suit each individual case.

Aspiration of highly vascularized lymph nodes J Bras Pneumol. 2013;39(2):226-237

often results in samples replete with blood, which makes it difficult for the cytopathologist to analyze the material. In such cases, performing few passes (from 3 to 7) per aspiration is usually sufficient to prevent the needle lumen from being filled with blood. Another particular case is aspiration of hilar and mediastinal lymph nodes after chemotherapy. In such cases of suspected mediastinal recurrence of cancer or in mediastinal restaging after neoadjuvant therapy, samples should be collected from the lymph node periphery, as required in mediastinoscopy/thoracoscopy, thereby avoiding the central region of the lymph node, which usually has the largest area of necrosis.

Another interesting observation concerns how the needle is inserted into the lymph node in order to obtain histological rather than cytological samples. To that end, once the needle is within the lymph node, and after the guide wire is removed, the vacuum syringe is connected and the passes are performed quickly and forcefully (jab), thereby aspirating lymph node fragments.(6) For subsequent cytological and/or histological analysis, the samples should be placed on slides (dry slides or slides fixed in absolute alcohol) and in formalin (cell block). When infection (such as tuberculosis or fungal infection) is suspected, some of the samples should be sent for microbiological analysis (in sterile saline for tests and culture for bacteria, fungi, and AFB).(8,12)

Preparation of the collected samples Proper preparation of specimens for cytology is essential for ensuring that EBUS-TBNA has a

Figure 4 - Ultrasound image from lymph node fine needle aspiration. Courtesy of the Department of Bronchoscopy, Heart Institute, University of SĂŁo Paulo School of Medicine Hospital das ClĂ­nicas.

Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration

good diagnostic yield. Usually, aspiration samples consist of a liquid phase (a fluid or thick drop, with or without blood), a semisolid phase, and a solid phase.

After the fluid or thick drop is placed on the cytology slide, another slide or a coverslip is placed against the first slide at an angle of 45° or is placed horizontally on top of it and is gently slid along the base slide until it reaches the opposite end, causing the liquid sample to spread uniformly (Figure 5). For semisolid samples, the procedure is similar, and clots and small solid fragments remaining at the edge of the drop should be gently compressed or removed from the slide with a needle and placed in fixative for paraffin-embedded cell-block analysis.

Solid samples are placed in a vial containing fixative and are then centrifuged, concentrating the cellular material that was in suspension after the syringe and needle are washed. The fragments as well as the resulting sediment (pellet) are embedded in paraffin as “mini biopsies” (cell block; Figure 6), making it possible to obtain histological sections that will examined using histochemistry (routine staining, H&E, or specific staining) or immunohistochemistry (Figure 7).(8) The presence of an on-site physician or cytotechnologist is important for determining whether or not the material is adequate and for screening the samples in complementary analyses (immunohistochemical analysis, gene mutation determination, culture, etc.).(19) Some studies, however, have found no improvement in the diagnostic yield of EBUS-TBNA resulting from the presence of an on-site cytopathologist, which can be standardized after all staff involved in the procedure have overcome the learning curve.(20) In our initial experience with 50 procedures, we observed that inadequate material was collected in approximately 26% of the aspirations,(21) compared with 13% currently (unpublished data).

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stations include all cases of diagnosed lung cancer without distant metastasis, with the exception of cases classified as stage Ia (clinical/radiological staging) with negative PET/CT findings in the mediastinum.(22) Various methods have been used for lung cancer staging, assisting in therapeutic decision making and in patient prognosis. Both CT and PET/CT are

Figure 5 - Cytology slide preparation. Courtesy of Dr. Cristina Mitteldorf.

Figure 6 - Paraffin block containing lymph node aspirate. Courtesy of Dr. Cristina Mitteldorf.

Indications for EBUS-TBNA The most common indications for EBUS-TBNA include lymph node staging for lung cancer and the diagnostic investigation of mediastinal/hilar masses and lymph node enlargement.

Lung cancer staging The current recommendations for invasive mediastinal staging by sampling five lymph node

Figure 7 - Photomicrograph of a cytology slide from a lymph node aspirate, indicating adenocarcinoma (thionine; magnification, ×400). Courtesy of the Anatomic Pathology Laboratory, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas.

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widely used for this purpose. A prospective study involving 102 patients compared the accuracy of CT, PET/CT, and EBUS-TBNA for the detection of lymph node metastasis in lung cancer. With the exception of the patients with extensive N2 disease (bulky disease or involvement of multiple ipsilateral lymph node stations) and N3 disease diagnosed by EBUS-TBNA, the other patients underwent lobectomy with lymph node dissection, making it possible to confirm the EBUS-TBNA cytohistological findings. The diagnostic accuracy of CT, PET/CT, and EBUS-TBNA was 60.6%, 72.5%, and 98.0%, respectively, the differences between the groups being significant (p < 0.0001).(23) Herth et al. have questioned the CT and PET/CT criteria used for the detection of lymph node metastasis. In their study, 97 patients with confirmed non-small cell lung cancer and with no lymph node changes suggestive of metastasis on CT or PET/CT scans underwent EBUS-TBNA. Lymph nodes measuring 5-10 mm in diameter at stations 2, 4, 7, 10, and 11 were aspirated, and, subsequently, all of the patients underwent surgical staging. Lymph node metastasis was detected at surgical staging in 9 patients. In 8 of those patients, lymph node metastasis had been identified by EBUS-TBNA. The sensitivity of EBUS-TBNA for the detection of mediastinal metastasis was 89%, and its specificity and NPV were 100% and 99%, respectively.(17) Another widely discussed issue is the value of EBUS-TBNA when compared with that of mediastinoscopy in lymph node staging for lung cancer. A prospective study included 59 patients and compared the diagnostic yield of EBUSTBNA with that of cervical mediastinoscopy for the detection of lymph node metastasis in lung cancer. Although, in terms of the overall yield per lymph node, the EBUS-TBNA results were better than were those of mediastinoscopy (98% vs. 78%; p = 0.007), there were no significant differences between the methods when the evaluation was performed by patient (sensitivity, 87%; specificity, 100%; and NPV, 78% for EBUSTBNA vs. sensitivity, 68%; specificity, 100%; and NPV, 59% for mediastinoscopy).(24) More recently, another prospective study comparing EBUS-TBNA and mediastinoscopy demonstrated that the results of both methods were similar in terms of mediastinal staging in 91% of the patients studied. The sensitivity, NPV, and diagnostic accuracy were 81%, 91%, and J Bras Pneumol. 2013;39(2):226-237

93%, respectively, for EBUS-TBNA, compared with 79%, 90%, and 93%, respectively, for mediastinoscopy, and there were no statistically significant differences between the methods.(5)

Lung cancer restaging after neoadjuvant therapy For lung cancer restaging after neoadjuvant therapy, it is necessary to identify the patients who demonstrate reduction in staging and who will therefore potentially benefit from surgical treatment. There are many response criteria, most of which are based on imaging methods.

A multicenter study involving 124 patients with stage IIIa (N2) lung cancer observed that EBUS-TBNA identified persistent nodal metastases (N2) in 72% of the patients. In the remaining patients (without lymph node metastasis) who underwent thoracotomy, the sensitivity, specificity, positive predictive value (PPV), NPV, and diagnostic accuracy of EBUS-TBNA were 76%, 100%, 100%, 20%, and 77%, respectively. Those authors believe that the low NPV was due to sampling error rather than to detection error. Therefore, they recommend that, in cases of restaging by EBUSTBNA, negative findings be confirmed by surgical restaging before thoracotomy.(25) A prospective study included 61 patients with stage IIIa and IIIb lung cancer as determined by EBUS-TBNA after neoadjuvant chemotherapy, presenting with stable lymph nodes or with partial response after chemotherapy as demonstrated by chest CT scans, and whose clinical condition allowed surgical resection. All of them underwent restaging by EBUS-TBNA. The patients with negative EBUS-TBNA results for cancer underwent transcervical extended mediastinal lymphadenectomy for histological confirmation.

Lymph node metastasis was detected by EBUSTBNA in 18 (30%) of the 61 patients and in 22 (26%) of the 85 of the aspirated nodes. Metastatic lymph nodes were identified in 9 (15%) of the 43 patients who underwent transcervical extended mediastinal lymphadenectomyâ&#x20AC;&#x201D;in 7 patients, at lymph node stations accessible by EBUS-TBNA (stations 2R, 4R, and 7), and, in 2 patients, at a station not accessible by EBUS-TBNA (station 5).

The sensitivity, specificity, accuracy, PPV, and NPV of EBUS-TBNA for the detection of lymph node metastasis in restaging were 67%, 86%, 80%, 91% e 78%, respectively. No complications of EBUSTBNA were observed. The authors concluded that

Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration

EBUS-TBNA is an effective and safe method for mediastinal restaging of patients with (non-small cell) lung cancer and that surgical restaging of the mediastinum might not be mandatory in such cases.(26)

Investigation of mediastinal tumors Various studies have demonstrated the good diagnostic yield of EBUS-TBNA in undiagnosed mediastinal or peribronchial lesions, whether they are benign or malignant. Yasufuku et al. studied 140 patients with mediastinal tumors in the absence of lung cancer or extrapulmonary cancer. The EBUS-TBNA was diagnostic in 93.6% of all (benign and malignant) disorders.(27) A study involving 60 patients observed that EBUS-TBNA was able to diagnose mediastinal lesions with a sensitivity, specificity, and accuracy of 95%, 100%, and 98%, respectively.(28) In assessing the potential accuracy of EBUS-TBNA in cases of suspected thymoma, a retrospective analysis of 1,458 EBUS-TBNA procedures found 4 cases of thymic cancer, 3 of which were cases of type B thymoma (one each of B1, B2 and B3 subtypes, all of which were diagnosed by cytology) and 1 of which was a case of thymic carcinoma diagnosed by immunocytochemistry analysis of cell blocks and flow cytometry.(29)

Investigation of lymph node enlargement from other causes The EBUS-TBNA procedure has been used in the investigation of mediastinal and hilar lymph node enlargement in benign and malignant non-pulmonary disease. A retrospective study of the usefulness of EBUS-TBNA for the diagnostic investigation of mediastinal and hilar lymph node enlargement observed that, in 95 of 120 patients, the material collected was diagnostic.

The diagnoses included lymphoid hyperplasia, granulomatous lymphadenitis, Hodgkin lymphoma, non-Hodgkin lymphoma, etc. The study concluded that EBUS-TBNA provides sufficient sample for diagnosis and classification of most disorders in patients with mediastinal lymphadenopathy.

(30) Another similar study concluded that, in 31 of 33 patients investigated for mediastinal and hilar lymph node enlargement who underwent EBUS-TBNA, adequate material was obtained for diagnosis: reactive lymph nodes, in 8; granulomatous inflammation, in 11; lymphoma,

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in 8; suspected non-Hodgkin lymphoma, in 2; and presence of atypical cells, in 2.(31)

Lymphoma Kennedy et al. performed a retrospective review of 25 patients with mediastinal lymph node enlargement referred for EBUS-TBNA in whom lymphoma was suspected. Adequate samples for diagnosis were observed in 24 patients (96%), and there were no complications of the procedure. Lymphoma was identified in 10 patients, benign disease was identified in 14 patients, and there was one false negative for lymphoma (lymphoma prevalence: 11/25, 44%). Follow-up over approximately 10 months confirmed stable or regressive lymph node enlargement in all 14 patients without a lymphoma diagnosis, consistent with a benign diagnosis. The sensitivity, specificity, PPV, and NPV of EBUS-TBNA for the diagnosis of lymphoma was 90.9%, 100.0%, 100.0%, and 92.9%, respectively.(32)

Sarcoidosis Among benign mediastinal and hilar lymphadenopathies, stage I and stage II sarcoidosis can be diagnosed by EBUS-TBNA. A prospective multicenter study evaluated 65 patients with suspected sarcoidosis (stage I and II in 74% and 26%, respectively) and with hilar/ mediastinal adenopathy on CT. Patients with suspected malignancy, those who had been previously diagnosed with sarcoidosis, and those in whom no granulomas were found in the aspirates were excluded. The selected patients underwent diagnostic surgical procedures and were followed up clinically. A definitive diagnosis of sarcoidosis was made in 61 patients (93.8%).

Of the remaining 4 patients, 1 was diagnosed with Wegenerâ&#x20AC;&#x2122;s granulomatosis and 3 had no definitive diagnosis. In 56 (91.8%) of the 61 patients with a final diagnosis of sarcoidosis, noncaseating epithelioid cell granulomas were found in the aspirates. No complications were reported, demonstrating that EBUS-TBNA is safe and has a high diagnostic yield.(8) Navani et al. evaluated 40 patients suspected to have stage I or stage II sarcoidosis on the basis of the clinical details and radiological findings. Of those 40 patients, 39 underwent EBUS-TBNA and conventional bronchoscopy with TBB, EBB, and blind transcarinal aspiration. Lymph node samples J Bras Pneumol. 2013;39(2):226-237

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were obtained by mediastinoscopy in patients in whom the two methods were inconclusive.

In the patients diagnosed with sarcoidosis, the sensitivity of EBUS-TBNA was 85%, compared with a sensitivity of 35% for conventional bronchoscopy with TBB, EBB, and blind transcarinal aspiration.

When the two methods were combined, the sensitivity increased to 93%.(33)

Mediastinal lymph node tuberculosis Tuberculosis should be considered in the differential diagnosis of mediastinal and hilar lymph node enlargement, even in the absence of pulmonary changes. A multicenter study included 156 patients with mediastinal adenopathy as demonstrated by chest CT scans and excluded those with pulmonary or extrathoracic tuberculosis. The EBUS-TBNA was diagnostic in 94% of the cases, and culture was positive in 47%,(12) including the diagnosis of multidrug-resistant tuberculosis in 8 cases. Aspirate histology consistent with lymph node tuberculosis was observed in 86% of the cases.

Analysis of the molecular profile of lung cancer Molecular analysis of neoplastic samples is essential in the identification of tumor biomarkers.

The objective is to identify patients who will respond better to certain types of chemotherapeutic agents (target therapy). Cytological and histological specimens acquired by EBUS-TBNA have been used for the analysis of these tumor markers.

In a study involving 43 patients with lung adenocarcinoma who underwent EBUS-TBNA for staging, the lymph node samples collected were analyzed for epidermal growth factor receptor (EGFR) mutation. The cell blocks were positive for the EGFR mutation in 11 cases, all of which were confirmed by direct sequencing. In conclusion, the EGFR mutation is easily detected in specimens acquired by EBUS-TBNA.(34) Another study, also involving 43 patients with non-small cell lung cancer, analyzed some markers (KRAS, EGFR, BRAF, and PIK3CA mutation) in the specimens acquired

by EBUS-TBNA and by endoscopic ultrasoundguided fine needle aspiration and found that there was complete concordance between the results obtained by the analysis of tumor markers performed on the cytological specimens acquired by the two aspiration methods and those obtained J Bras Pneumol. 2013;39(2):226-237

on surgical histological specimens.(35) Those authors concluded that, if properly prepared, specimens acquired by EBUS-TBNA enable the analysis of genetic markers of lung cancer.

Complications of EBUS-TBNA A recent meta-analysis evaluated the effectiveness of EBUS-TBNA in lung cancer staging.

Among the 11 included studies, involving a total of 1,299 patients, only one major complication was observed (0.07%) in a patient with hypoxemia and severe COPD, this complication being followed by pneumothorax, which required drainage.(36) In a group of 156 patients investigated for mediastinal lymph node enlargement, 1 patient presented with septicemia (group G β-hemolytic streptococcus) two days following EBUS-TBNA. There were no complications during the procedures.

(12) This infection suggests that intratracheal material entered the mediastinum. This mechanism had been described in a study involving 45 patients investigated for bacteremia following EBUS-TBNA (7% of the patients; incidence comparable to that following conventional bronchoscopy).(37) In a recent review of 14 studies involving 1,627 patients who underwent EBUS-TBNA, no major complications during or following the procedure were reported.(38) In our experience, we observed a single case of moderate endobronchial bleeding, controlled with local measures, during EBUS-TBNA in a group of 50 patients.(21)

Costs and reimbursement To date in Brazil, there have been no studies of the costs of using EBUS-TBNA, nor have there been any studies comparing the EBUSTBNA procedure and mediastinoscopy in terms of costs. A recent study conducted in Great Britain observed that the overall cost of the EBUS-TBNA procedure was US$2,998, which was lower than that of mediastinoscopy, which was US$5,115..(39) A review article including U.S. data(40) reported that the price of an EBUS bronchoscope, excluding bronchoscope processors and ultrasound processors, is approximately US$ 44,800. Each EBUS-TBNA needle costs approximately US$90.

These costs are not reproducible in Brazil.

This is due, in part, to the high import taxes on the equipment and the needles. Currently, in Brazil, the direct import price (free on board price,

Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration

i.e., no shipping fees or import taxes) of an EBUS bronchoscope, excluding bronchoscope processors and ultrasound processors, is approximately US$73,000. Each EBUS-TBNA needle costs approximately R$1,200 for purchase on the domestic market.

The EBUS-TBNA procedure has yet to be included on the Brazilian Medical Association list of medical procedures approved for reimbursement.

This restricts the availability of the procedure to patients with private health insurance plans or to those treated at hospitals that subsidize the difference in the amount paid by the Brazilian Unified Health Care System for conventional bronchoscopy.

Final considerations The EBUS-TBNA procedure is efficient in lung cancer staging/restaging, as well as in the diagnosis of mediastinal, paratracheal, and peribronchial lesions/lymph node enlargement.

A single EBUS-TBNA procedure can diagnose paratracheal and peribronchial lung cancer and can provide lymph node staging information at the same time, especially if performed in a planned, sequential, and standardized way.

In addition to enabling cytological diagnosis, proper preparation of aspirates can enable assessment of the material as cell blocks. This allows genetic analysis of tumor markers, as well as storage of material for future evaluation with new techniques.

The implementation of EBUS-TBNA in Brazil requires a restructuring of facilities, the purchase of equipment, and the training of the multidisciplinary medical team and the paramedical team. Successful implementation also requires changes in the approach to patients who will benefit from the procedure. Finally, in order to increase and ensure access to this technology at health care facilities in Brazil, the pricing policy for equipment, as well as for the respective accessories, must be revised.

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About the authors Viviane Rossi Figueiredo

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

Márcia Jacomelli

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

Ascédio José Rodrigues

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

Mauro Canzian

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

Paulo Francisco Guerreiro Cardoso

Professor. Thoracic Surgery Section, Department of Cardiorespiratory Diseases, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (InCor-HCFMUSP, University of São Paulo School of Medicine Hospital das Clínicas Heart Institute), São Paulo, Brazil.

Fábio Biscegli Jatene

Full Professor. Thoracic Surgery Section, Department of Cardiorespiratory Diseases, Faculdade de Medicina da Universidade de São Paulo – FMUSP, University of São Paulo School of Medicine – São Paulo, Brazil.

J Bras Pneumol. 2013;39(2):226-237

Case Report Pulmonary hypertension and pulmonary artery dissection*,** Dissecção da artéria pulmonar e hipertensão pulmonar

Ricardo de Amorim Corrêa, Luciana Cristina dos Santos Silva, Cláudia Juliana Rezende, Rodrigo Castro Bernardes, Tarciane Aline Prata, Henrique Lima Silva

Abstract Pulmonary artery dissection is a fatal complication of long-standing pulmonary hypertension, manifesting as acute, stabbing chest pain, progressive dyspnea, cardiogenic shock, or sudden death. Its incidence has been underestimated, and therapeutic options are still scarce. In patients with pulmonary hypertension, new chest pain, acute chest pain, or cardiogenic shock should raise the suspicion of pulmonary artery dissection, which can result in sudden death.

Keywords: Hypertension, pulmonary; Chest pain; Pulmonary artery.

Resumo A dissecção da artéria pulmonar é uma complicação fatal da hipertensão pulmonar de longa duração que se manifesta como dor torácica aguda e lancinante, dispneia progressiva, choque cardiogênico ou morte súbita.

Sua incidência é subestimada, e as opções terapêuticas são ainda limitadas. O aparecimento de uma dor torácica aguda ou nova, choque cardiogênico ou morte súbita em pacientes portadores de hipertensão pulmonar deve alertar para o diagnóstico de dissecção da artéria pulmonar Descritores: Hipertensão pulmonar; Dor no peito; Artéria pulmonar.

Introduction Pulmonary hypertension is a common syndrome that encompasses a large spectrum of conditions that sometimes have similar pathogenesis, resulting in increased pulmonary vascular resistance, right ventricular overload and dysfunction, and occasionally death. The use of recently approved pulmonary hypertension drugs has led to improved functional capacity and survival of patients with pulmonary hypertension. However, this improved survival creates clinical challenges related to the increased incidence of chronic complications.

Case report A 50-year-old male patient diagnosed four years prior with pulmonary hypertension related to schistosomiasis mansoni was admitted to the emergency room of the Federal University of Minas Gerais School of Medicine Hospital das Clínicas, located in the city of Belo Horizonte, Brazil. He

presented with new onset, progressively worsening retrosternal chest pain and shortness of breath (functional class III pulmonary hypertension according to the World Health Organization).

He had been diagnosed with chronic myeloid leukemia seven months prior and had since been on chemotherapy. At admission, transthoracic echocardiography revealed a large non-obstructive central thrombus in the right main pulmonary artery. The right atrium was dilated, and there was mild tricuspid regurgitation, with an estimated pulmonary artery systolic pressure of 63 mmHg. He was diagnosed as having in situ thrombosis as a complication of the longstanding pulmonary hypertension. After the possibility of acute coronary syndrome had been excluded, he was discharged on warfarin.

He was re-admitted two months later due to progressively worsening, refractory chest pain.

* Study carried out in the Department of Pulmonology and Thoracic Surgery, Federal University of Minas Gerais School of Medicine Hospital das Clínicas, Belo Horizonte, Brazil.

Correspondence to: Ricardo de Amorim Corrêa. Rua Abadessa Gertrudes Prado, 77 apto. 802, Vila Paris, CEP 30380-790, Belo Horizonte, MG, Brasil.

Tel. 55 31 3293-3910. E-mail: racorrea9@gmail.com Financial support: None.

Submitted: 2 July 2012. Accepted, after review: 7 December 2012. **A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

J Bras Pneumol. 2013;39(2):238-241

Pulmonary hypertension and pulmonary artery dissection

At that time, he had an SpO2 of 96%, and a third heart sound was audible at the lower left parasternal space, accompanied by a murmur of tricuspid regurgitation. The lungs were clear, and the peripheral arterial pulses were symmetric.

Laboratory test results were unremarkable, including serum levels of creatine kinase, creatine kinase MB isoenzyme, and troponin.

A resting electrocardiogram showed evidence of acute myocardial ischemia in the anterior leads. Transthoracic Doppler echocardiogram revealed a pulmonary artery systolic pressure of 62 mmHg, a thrombus in the right pulmonary artery, as in the previous examination, and the presence of a flap at that level that was compatible with pulmonary artery dissection (Figure 1).

The diagnosis was confirmed by subsequent CT pulmonary angiography (CTPA; Figure 2).

He was transferred to another cardiovascular treatment facility, where attempts were made to correct the defect with an endovascular procedure (via the femoral vein). During the perioperative period, the patient presented with refractory cardiogenic shock. Multiple efforts to resuscitate the patient were unsuccessful, and he died in the operating room.

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Discussion Aneurysmatic dilatation of the pulmonary artery trunk and its branches is a well-known condition that has been widely reported in the literature. It occurs as a consequence of longstanding pulmonary hypertension, most of the reported cases having been diagnosed at autopsy.(1) The first reports of that condition in patients with schistosomiasis came from Egypt (in patients with schistosomiasis haematobium or mansoni), followed, much later, by reports from Brazil (exclusively in patients with schistosomiasis mansoni).(2,3) Pulmonary artery dissection appears to be related to pulmonary artery dilatation, intimal inflammation, in situ thrombosis, and acute increases in pulmonary pressure.(4,5) Pulmonary artery dilatation and pulmonary aneurysm have been reported to be risk factors that are also associated with other complications.(4) To our knowledge, this is only the second report of a case of pulmonary artery dissection in a patient with schistosomiasis-related pulmonary hypertension, the first such case having been diagnosed at autopsy.

(6) Clinically, these cases present with aggravation of previous symptoms of dyspnea and chest pain. The chest pain is typically sharp and can mimic acute

Figure 1 - Transthoracic echocardiogram depicting a thrombus (TB) in the right pulmonary artery and a flap at that level, which is consistent with pulmonary artery dissection. PAT: pulmonary artery trunk; and Ao: aorta.

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Ricardo de Amorim Corrêa, Luciana Cristina dos Santos Silva, Cláudia Juliana Rezende, Rodrigo Castro Bernardes, Tarciane Aline Prata, Henrique Lima Silva

A

B PAT

FL

ET

FL FL

PA TB RA RV

RV

C

D FL FL

PAT TB

PA

FL

RA RV

Figure 2 - CT pulmonary angiography scans depicting a flap in the area of dissection in the pulmonary artery trunk (PAT; in A); in situ thrombus (TB) and the entry tear (ET, arrow) into the false lumen (FL; in B); the area of dissection (in C); and three-dimensional volume rendering reconstruction (in D). PA: pulmonary artery (lumen); RA: right atrium; and RV: right ventricle.

coronary syndrome or acute aorta dissection. Cyanosis can be present.(7) The diagnosis is often obtained postmortem, because most patients die suddenly due to cardiac tamponade or severe pulmonary bleeding. If the diagnosis is made antemortem, the first finding is the emergence of a flap in the lumen of the dilated pulmonary artery or trunk formed from the intimal layer, denoting the entry tear into the false lumen but rarely an exit, which is the opposite of what is found in cases of aortic dissection.(8) Magnetic resonance imaging or CTPA of the chest can confirm the diagnosis and the associated complications, such as an increase in pulmonary artery dilatation, bloody pleural fluid, and pulmonary opacities.(1) The evolution is usually rupture of the vessel with blood flowing into the mediastinum, pericardium, or lung, because there is no exit from the false lumen. The intimal tear that leads to the dissection occurs at the point

J Bras Pneumol. 2013;39(2):238-241

of greatest dilatation as a consequence of an increased parietal tension. It has been reported that inflammation due to in situ thrombosis can play a synergistic role in the development of the intimal disruption.(4,9,10) Although it is reasonable to think that the early diagnosis and treatment of pulmonary hypertension would postpone pulmonary artery dissection, there is no confirmatory evidence of that in the literature on this topic, which consists exclusively of reviews and case reports. Therapeutic options are scarce. Surgical repair and heart-lung transplantation are the procedures of choice but have yet to be widely employed, the amount of data available therefore being limited.(7) In patients with pulmonary hypertension, new chest pain, acute chest pain, or cardiogenic shock should raise the suspicion of pulmonary artery dissection, which can result in sudden death.

Pulmonary hypertension and pulmonary artery dissection

References 1. Moraes MG, Comparato LFL, Madi K. Aneurisma de artéria pulmonar: relato de um caso. Rev Med HSE. 1974;26(2):109-15 2. Zaky HA. Aneurysm of the pulmonary artery due to schistosomiasis. Dis Chest. 1952;21(2):194-204.

3. Santiago JM, Barros J, Rocha LF, Kalil M, Malleta CA, Chuster M. Aneurisma de artéria pulmonar secundário à hipertensão esquistossomótica. Relato de um caso.

Arq Bras Cardiol. 1974;27(6):733-6.

4. Degano B, Prevot G, Têtu L, Sitbon O, Simonneau G, Humbert M. Fatal dissection of the pulmonary artery in pulmonary arterial hypertension. Eur Respir Rev. 2009;18(113):181-5.

5. Inayama Y, Nakatani Y, Kitamura H. Pulmonary artery dissection in patients without underlying pulmonary hypertension. Histopathology. 2001;38(5):435-42. Erratum in: Histopathology. 2001;39(5):550.

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6. Miziara HL, Filomeno AP, Yunes MA. Dissecting aneurysm of the pulmonary artery, associated with pulmonary schistosomiasis. Report of a case [Article in Portuguese].

Arq Bras Cardiol. 1981;37(2):107-10.

7. Senbaklavaci O, Kaneko Y, Bartunek A, Brunner C, Kurkciyan E, Wunderbaldinger P, et al. Rupture and dissection in pulmonary artery aneurysms: incidence, cause, and treatment--review and case report. J Thorac Cardiovasc Surg. 2001;121(5):1006-8.

8. Song EK, Kolecki P. A case of pulmonary artery dissection diagnosed in the Emergency Department. J Emerg Med. 2002;23(2):155-9.

9. Moser KM, Fedullo PF, Finkbeiner WE, Golden J. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation.

1995;91(3):741-5.

10. Andrews R, Colloby P, Hubner PJ. Pulmonary artery dissection in a patient with idiopathic dilatation of the pulmonary artery: a rare cause of sudden cardiac death.

Br Heart J. 1993;69(3):268-9.

About the authors Ricardo de Amorim Corrêa

Professor. Department of Pulmonology and Thoracic Surgery, Federal University of Minas Gerais School of Medicine Hospital das Clínicas, Belo Horizonte, Brazil.

Luciana Cristina dos Santos Silva

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

Cláudia Juliana Rezende

Head. Diagnostic Imaging Center, Hospital Madre Teresa, Belo Horizonte, Brazil.

Rodrigo Castro Bernardes

Head. Department of Cardiovascular Surgery, Hospital Madre Teresa, Belo Horizonte, Brazil.

Tarciane Aline Prata

Pulmonologist. Department of Pulmonology and Thoracic Surgery, Federal University of Minas Gerais School of Medicine Hospital das Clínicas, Belo Horizonte, Brazil.

Henrique Lima Silva

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

J Bras Pneumol. 2013;39(2):238-241

Letter to the Editor Efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in evaluating lung cancer recurrence Eficácia da tomografia por emissão de pósitrons com 18F fluordesoxiglicose com tomografia computadorizada na avaliação de recidiva de câncer de pulmão

Nobuhiro Asai, Yoshihiro Ohkuni, Kazufusa Shoji, Norihiro Kaneko

To the Editor: For patients with non-small cell lung cancer (NSCLC) classified as stage I using the tumornode-metastasis (TNM) staging system (T1N0M0 or T2N0M0), the standard treatment is complete resection of the affected lobes and associated lymph nodes. However, lung cancer is usually inoperable in elderly patients, mostly because of their poor performance status. In general, resection of these early-stage tumors, typically by lobectomy, has been associated with three-year and fiveyear survival rates ranging from 60% to 80%. (1,2) Unfortunately, significant complications have been associated with lobectomy in elderly patients or in those with medical comorbidities, such as limited pulmonary reserve and cardiovascular disease. (3-6) With the popularization of CT screening, lung cancers have been increasingly detected at an early stage.(7) Stereotactic radiation therapy (SRT) has become one of the standard treatment options for patients with stage I lung cancer, mainly in patients with inoperable NSCLC.(7,8) Following irradiation, radiation pneumonitis frequently occurs. On chest X-rays or chest CT scans, physicians often have difficulty in distinguishing between the recurrence of lung cancer and radiation pneumonitis. Another tool that has been used in the detection of lung cancer recurrence is 18F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT). We have found significantly elevated standardized uptake values (SUVs) in patients with recurrent lung cancer, compared with those who had no disease progression. To our knowledge, this is the first report demonstrating the efficacy of FDG-PET/CT in patients with post-SRT recurrence of lung cancer. Here, we report the cases of two such patients.

We retrospectively reviewed the cases of all patients receiving SRT for the treatment of

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lung cancer at the Kameda Medical Center, in Kamogawa, Japan, between April of 2005 and March of 2011. The characteristics of the patients are shown in Table 1. There were a total of 28 patients (20 males and 8 females). The median age was 77 years (range, 59-88 years). All of the patients were classified as having stage IA lung cancer. Comparing the pre-SRT and post-SRT values, we found that there was a significant decrease in the SUV for the primary lesion (8.0 vs. 2.2; p < 0.001). During the follow-up period, 2 of the patients experienced recurrence, as evidenced by the finding that their SUVs had increased significantly over the values obtained in the immediate post-SRT period (Table 2). In those 2 patients, there was subsequent clinical and pathological confirmation of the recurrence of the lung cancer.

The first patient was a 69-year-old man with stage IA NSCLC who was submitted to SRT. The tumor was inoperable because of the poor heath status of the patient. The total SRT was 50 Gy in five doses. Prior to SRT, FDG-PET/CT revealed an SUV of 12.6 and a tumor with a diameter of 21 mm. After SRT, the SUV decreased to 4.78, although the size of the tumor increased to 29 mm due to radiation pneumonitis. The radiated lesion could not be appropriately evaluated, because of the scar produced by irradiation.

Therefore, we performed FDG-PET/CT every four months. During the follow-up period, the SUV rose to 18.44 and transbronchial lung biopsy was performed. The biopsy confirmed the suspicion of the recurrence of adenocarcinoma.

The second patient was a 76-year-old man who was diagnosed as having stage IA squamous cell lung carcinoma. He suffered from COPD and had a history of heavy smoking. Although he was, at his level of pulmonary function, a candidate

Efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in evaluating lung cancer recurrence

Table 1 - Characteristics of the 28 cases studied.a Variable Results Age, years 77 (59-88) Genderb Male 20 (71.4) Female 8 (28.6) Histologyb Adenocarcinoma 11 (39.3) Squamous cell carcinoma 5 (17.9) Large cell carcinoma 1 (3.6) Unknown 11 (39.3) Size of primary cancer, mm 19.2 (6.0-34.0) Standardized uptake value Before SRT 7.18 (1.58-19.7) After SRT 2.55 (0.00-5.87) SRT: stereotactic radiation therapy. aValues expressed as mean (range), except where otherwise indicated. bValues expressed as n (%).

Table 2 - Mean standardized uptake values before and after stereotactic radiation therapy for the 28 cases studied, as well as for the 2 patients experiencing recurrence of the cancer during the follow-up period.

Variable Standardized uptake value Before SRT 7.18 After SRT 2.55* Follow-up (recurrent 22.30* cancer) SRT: stereotactic radiation therapy. *p < 0.01 (unpaired or paired t-test).

for surgical treatment, he was submitted to SRT. Before and after SRT, the SUV was 8.48 and 3.49, respectively, and the size of the tumor increased from 25 mm before SRT to 59 mm after. During the follow-up period, the SUV increased to 26.06, revealing recurrence of the tumor.

It has been reported that FDG-PET/CT has a therapeutic impact in 60% of lung cancer patients, approximately 30% of the cases being upstaged, 10% being downstaged, and up to 40% requiring a change in the chemotherapy regimen.(9,10) In addition, the effectiveness of chemotherapy can be determined by measuring the SUV.(9,10) Therefore, FDG-PET/CT is a useful tool in the diagnosis and management of lung cancer.

The use of SRT has been shown to be efficacious for the treatment inoperable earlystage NSCLC in elderly patients.(8) A standard follow-up protocol for patients with early-stage NSCLC submitted to SRT has yet to be established.

Third-line chemotherapy can also be efficacious in elderly patients, depending on their condition.

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Here, we have reported two cases of recurrent cancer that were successfully diagnosed by FDG-PET/CT, thereby demonstrating that it can be a useful tool in the follow-up of patients having undergone SRT. Additional cases should be examined in order to corroborate our findings.

Acknowledgments We are grateful for the diligent and thorough critical reading of our manuscript by Mr. John Wocher, Executive Vice President and Director, International Affairs/International Patient Services, Kameda Medical Center, Kamogawa, Japan.

Nobuhiro Asai Resident, Kameda Medical Center, Kamogawa, Japan Yoshihiro Ohkuni Chief, Kameda Medical Center, Kamogawa, Japan Kazufusa Shoji Chief, Kameda Medical Center, Kamogawa, Japan Norihiro Kaneko Chief, Kameda Medical Center, Kamogawa, Japan

References 1. Mountain CF. A new international staging system for lung cancer. Chest. 1986;89(4 Suppl):225S-233S. 2. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg. 1988;96(3):440-7. Erratum in: J Thorac Cardiovasc Surg 1989;97(3):350.

3. Dominguez-Ventura A, Cassivi SD, Allen MS, Wigle DA, Nichols FC, Pairolero PC, et al. Lung cancer in octogenarians: factors affecting long-term survival following resection. Eur J Cardiothorac Surg.

2007;32(2):370-4.

4. Sรกnchez PG, Vendrame GS, Madke GR, Pilla ES, Camargo Jde J, Andrade CF, et al. Lobectomy for treating bronchial carcinoma: analysis of comorbidities and their impact on postoperative morbidity and mortality. J Bras Pneumol.

2006;32(6):495-504.

5. Asmis TR, Ding K, Seymour L, Shepherd FA, Leighl NB, Winton TL, et al. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol. 2008;26(1):54-9.

6. Sekine Y, Behnia M, Fujisawa T. Impact of COPD on pulmonary complications and on long-term survival of patients undergoing surgery for NSCLC. Lung Cancer.

2002;37(1):95-101.

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Asai N, Ohkuni Y, Shoji K, Kaneko N

7. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys. 2011;81(5):1352-8.

8. Stephans KL, Djemil T, Reddy CA, Gajdos SM, Kolar M, Mason D, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol. 2009;4(8):976-82.

Submitted:Â 16 May 2012. Accepted, after review:Â 04 June 2012.

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9. Hicks RJ, Kalff V, MacManus MP, Ware RE, Hogg A, McKenzie AF, et al. (18)F-FDG PET provides highimpact and powerful prognostic stratification in staging newly diagnosed non-small cell lung cancer. J Nucl Med. 2001;42(11):1596-604.

10. Verboom P, van Tinteren H, Hoekstra OS, Smit EF, van den Bergh JH, Schreurs AJ, et al. Cost-effectiveness of FDG-PET in staging non-small cell lung cancer: the PLUS study. Eur J Nucl Med Mol Imaging.

2003;30(11):1444-9.

Letter to the Editor Impending paradoxical embolism across the interatrial septum Embolia paradoxal iminente através do septo interatrial

Nilson Lopez Ruiz

To the Editor: Acute pulmonary embolism (PE) is considered a cardiovascular emergency because it can lead to acute life-threatening right ventricular failure.

It has been reported that approximately 5% of patients with acute PE present with right heart thrombus (RHT),(1-3) which occasionally straddles the interatrial septum, posing a threat to the pulmonary arteries and systemic circulation.

A 63-year-old man presented to the Pablo Tobon Uribe Hospital, in Medellin, Colombia, complaining of dyspnea in the preceding two weeks. Physical examination revealed tachycardia, tachypnea, mild hypertension, jugular venous distention, abdominal distention, and edema in the lower limbs. However, cardiac and pulmonary findings were unremarkable. An electrocardiogram revealed only sinus tachycardia. The cardiac troponin I level was 0.2 ng/mL (normal, < 0.04 ng/mL), and the N-terminal pro-brain natriuretic peptide level was 3,590 pg/mL (normal, < 125 pg/mL).

Subsequent helical CT scans of the chest confirmed PE by showing filling defects involving the main pulmonary artery and its primary branches (Figure 1).

A venous ultrasound revealed left iliofemoral deep vein thrombosis. Intravenous heparin was started.

A bedside echocardiogram revealed a large, highly mobile, “snake-like” mass in the right atrium, attached to the interatrial septum (Figure 2) and penetrating into the left atrium (Video 11).

That image was also evident on a second review of the helical CT scans. The right ventricle (RV) was dilated (basal diameter, 4.5 cm), hypokinetic (decreased global longitudinal strain; Figure 2), and pressure overloaded (systolic RV pressure, 45 mmHg).

Despite the RHT and the findings of impending systemic embolism, the cardiovascular surgeon refused to perform surgical thrombectomy because of the simultaneous, heavy clot burden on the pulmonary arteries. In addition, the size of the thrombus at the left atrium raised concerns

regarding the risk of systemic embolism, which prevented us from performing thrombolysis. Hence, the patient was treated with anticoagulants only, and transesophageal echocardiography was deemed futile. Further diagnostic work-up confirmed malignant ascites, and the final diagnosis was adenocarcinoma of unknown primary origin.

The clinical evolution was satisfactory. Because of heparin-induced thrombocytopenia type I (his platelet count fell down from 590,000 at admission to 102,000 after 8 days of heparin use), he was discharged on fondaparinux. However, the patient was readmitted several times for the palliative treatment of ascites. There was no clinical evidence of cardioembolic events until his death, which occurred four months later.

Currently, only the presence of RV strain on echocardiography and elevated biomarkers are recommended for assessing the need of thrombolysis in the setting of submassive PE.(4) In rare cases, echocardiography can reveal RHT. In the International Cooperative Pulmonary Embolism Registry, 1,135 patients with PE were assessed by echocardiography, and 42 (4%) were found to have RHT.(1) Likewise, two single-center studies, each including more than 300 patients, reported echocardiographic evidence of RHT in approximately 5% of the patients.(2,3) The appearance of RHT might suggest the etiology of the clot.(5) Type A thrombi are tubular-shaped, highly mobile, and believed to represent peripheral venous clots temporarily lodged in the right heart.

Type B thrombi resemble left heart thrombi, are less mobile, and appear to be associated with underlying cardiac abnormalities. Finally, type C thrombi are rare, are similar to myxomas in their appearance, and are highly mobile. The appearance of the thrombi has been associated with short-term prognosis.(5) Not only is early mortality (< 8 days) higher for patients with type A than for those with type C or B (42%,

1 Video available in the online version of the Brazilian Journal of Pulmonology (http://www.jornaldepneumologia.com.br/portugues/artigo_detalhes.asp?id=1994).

J Bras Pneumol. 2013;39(2):245-247

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Ruiz NL

14%, and 4%, respectively), but also the risk of pulmonary embolism is higher for those with type A than for those with type C or B (79%, 62%, and 38%, respectively). However, the final outcome depends on the total clot burden and on RV myocardial performance rather than on the intracardiac thrombus alone. In addition, after hospital discharge, the prognosis appears to depend largely on the underlying disease (sepsis, tumor, heart disease, etc.) and not on the thrombus itself.(5) When associated with cardiac septum defects, RHT poses a risk of paradoxical,

Ao

MPA T

RPA

T LPA

T

Figure 1 - CT scan of the chest showing various intraluminal filling defects—thrombi (T)—involving the main pulmonary artery (MPA), the left pulmonary artery (LPA), and the right branches of the right pulmonary artery (RPA). Ao: aorta.

A

systemic embolism. Mostly, the thrombi pass through an interatrial septum defect or patent foramen ovale (PFO), from the right to the left cardiac chambers. A PFO increases the relative risk (RR) of death (RR = 2.4), ischemic stroke (RR = 5.9), peripheral arterial embolism (RR = 15), and complicated hospital course (RR = 5.2). (4) Recent guidelines recommend screening for PFO in patients with PE,(4) although whether and when surgery is indicated remains unclear.

Finally, in the presence of massive or submassive PE, the treatment of PE in patients with impending systemic embolism remains controversial. According to a statement from the American Heart Association,(4) surgical thrombectomy (particularly in patients with an intracardiac thrombus) might reduce the incidence of stroke, whereas thrombolysis might be associated with higher mortality. A recent systematic review(6) supported that recommendation by showing that the incidence of the composite endpoint of 30-day mortality or systemic embolism during treatment was lower among patients undergoing surgical thrombectomy than among those treated with anticoagulants alone (OR = 0.26; 95% CI, 0.11-0.60; p < 0.001). That incidence was not significantly lower in those undergoing thrombolysis (OR = 0.90; 95% CI, 0.282.86; p = 0.86). However, these recommendations might not be appropriate for cancer patients, in whom the risk of venous thromboembolism is higher and more conservative treatment would be advised, given that anticoagulation might suffice without producing any clinically significant thromboembolic complications.

C

B RV

LV RV RA

T

LV T LA

Figure 2 - In A, echocardiogram showing a large thrombus (T) in the right atrium crossing the interatrial septum into the left atrium (arrowheads). In B, detail of a CT scan of the chest revealing a thrombus (T) in the right atrium (RA). In C, right ventricle (RV) dysfunction, as evidenced by decreased global longitudinal strain. LV: left ventricle; and LA: left atrium.

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Impending paradoxical embolism across the interatrial septum

Nilson Lopez Ruiz Attending Cardiologist, Unidad de Cardiologia, Hospital Pablo Tobon Uribe, Medellin, Colombia

References 1. Torbicki A, Galié N, Covezzoli A, Rossi E, De Rosa M, Goldhaber SZ, et al. Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry. J Am Coll Cardiol.

2003;41(12):2245-51.

2. Pierre-Justin G, Pierard LA. Management of mobile right heart thrombi: a prospective series. Int J Cardiol.

2005;99(3):381-8.

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3. Ferrari E, Benhamou M, Berthier F, Baudouy M. Mobile thrombi of the right heart in pulmonary embolism: delayed disappearance after thrombolytic treatment.

Chest. 2005;127(3):1051-3.

4. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16):1788-830.

Erratum in: Circulation. 2012;125(11):e495. Circulation.

2012;126(7):e104.

5. The European Cooperative Study on the clinical significance of right heart thrombi. European Working Group on Echocardiography. Eur Heart J. 1989;10(12):1046-59.

6. Myers PO, Bounameaux H, Panos A, Lerch R, Kalangos A. Impending paradoxical embolism: systematic review of prognostic factors and treatment. Chest.

2010;137(1):164-70.

Submitted: 08 May 2012. Accepted, after review: 05 August 2012.

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Letter to the Editor Whole-body magnetic resonance imaging for the evaluation of thoracic involvement in disseminated paracoccidioidomycosis Ressonância magnética de corpo inteiro na avaliação do comprometimento torácico na paracoccidioidomicose disseminada

Edson Marchiori, Elisa Carvalho Ferreira, Gláucia Zanetti, Bruno Hochhegger

To the Editor: Whole-body magnetic resonance imaging (MRI) is a diagnostic tool that enables the visualization of the entire body and combines fast acquisition times with high contrast resolution. An important advantage of this technique is the absence of ionizing radiation. Thus, whole-body MRI offers a radiation-free alternative to radionuclide imaging and CT for the diagnosis, staging, and monitoring of young patients who require frequent follow-up examinations. Because MRI is the best method to evaluate bone marrow and soft tissues, it represents an ideal tool for the assessment of numerous systemic diseases, especially those affecting the skeletal system.(1) Paracoccidioidomycosis, a systemic fungal disease caused by the fungus Paracoccidioides brasiliensis, is endemic in Central and South America.(2,3) In Europe and North America, it is considered a rare imported disease, the incidence of which is expected to continue rising due to the increase in migration and international travel.(4) Given that the disease can affect virtually any organ, whole-body MRI seems to be a suitable diagnostic tool for evaluating systemic manifestations of disseminated paracoccidioidomycosis, because it provides a global view. The aim of the present report was to present the whole-body MRI findings of a patient with systemic manifestations of paracoccidioidomycosis, with an emphasis on lymphatic, skeletal, and pleural involvement. To our knowledge, thoracic findings of disseminated paracoccidioidomycosis on whole-body MRI have not been described previously.

A 24-year-old man was referred to our facility for the diagnostic investigation of multiple complaints. The symptoms began approximately 15 months prior to hospitalization and mainly consisted of emaciation, fever, painful lymphadenopathy, and crusted, ulcerated skin lesions. The epidemiologic history of the patient

J Bras Pneumol. 2013;39(2):248-250

revealed that he had worked for the past two years as a farm worker, taking care of animals.

Upon physical examination, the patient presented with fever, multiple honey-colored scabs, and ulcerated lesions on the face, trunk, upper limbs, and perianal region. Pulmonary auscultation findings were normal, as were those of the cardiac examination, and there was no abdominal organomegaly.

A left cervical lymph node was aspirated, and direct examination for fungi revealed refringent blastoconidia with multiple buds suggestive of P. brasiliensis in the specimen. Blood agar culture was also positive for P. brasiliensis. A skin biopsy specimen stained with Grocott and periodic acidSchiff stains revealed yeast cells with multiple buds in the form of a ship’s wheel, which is a typical finding of P. brasiliensis. Serology by double immunodiffusion techniques was positive for paracoccidioidomycosis. A blood test for HIV was negative. A diagnosis of the acute or subacute so-called “juvenile” type of disseminated paracoccidioidomycosis was made, and the patient was hospitalized for treatment.

Before the necessary treatment was started, written informed consent was obtained and the patient was submitted to whole-body MRI in order to further investigate the systemic involvement of the disseminated disease. The examination revealed extensive involvement at multiple locations throughout the body, including the subcutaneous tissue, lymph nodes, skeletal system, pleural cavity, and peritoneal cavity. Lymph node enlargement was seen on whole-body MRI in multiple lymph node chains. On a gadoliniumenhanced volumetric interpolated breath-hold examination (VIBE) sequence, the lymph nodes presented peripheral contrast enhancement (Figure 1A). On a short-tau inversion-recovery (STIR) sequence, the central portions of those

Whole-body magnetic resonance imaging for the evaluation of thoracic involvement in disseminated paracoccidioidomycosis

lymph nodes exhibited hyperintense signals, giving them a necrotic appearance.

On T1-weighted images, the skeletal lesions varied from hypointense to isointense, exhibiting, at some sites, cortical bone destruction and an extensive soft tissue component. In a gadoliniumenhanced VIBE sequence with fat suppression, the lesions exhibited an insufflating pattern, with contrast enhancement predominantly in the peripheral regions (Figures 1B and 2A). On a STIR sequence, the central portions of the lesions presented hyperintense signals, suggestive of necrotic tissue.

Whole-body MRI with STIR sequences also revealed pleural and peritoneal involvement, manifesting as pleural effusion and ascites, as evidenced by a typical hyperintense signal (Figure 2B). There were no other sites of involvement.

Paracoccidioidomycosis is divided into two polar forms, depending on its epidemiological, immunopathological, and clinical aspects.(5) The acute or subacute form most frequently affects children, teenagers, and young adults and is known as the juvenile type. It manifests as extensive involvement of the mononuclear phagocytic system, mainly in the spleen, liver, lymph nodes, and intestinal tract. Lung and mucosal lesions are rare.(5) The chronic form, known as the adult type, is more common, accounting for 90% of all cases, and predominantly affects adults over 30 years of age. The chronic form is more likely to be localized than is the acute form. Initially, the disease is localized in the lungs, and less A

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frequently, in the mucosa or skin.(5) Therefore, our case can be classified as the acute form of paracoccidioidomycosis.(3) In the case presented here, whole-body MRI showed involvement at multiple locations throughout the body, including the subcutaneous tissue, lymph nodes, skeletal system, pleural cavity, and peritoneal cavity. Of the systemic manifestations, we focused on the extensive thoracic skeletal involvement. Bone and joint infections are relatively uncommon in patients with paracoccidioidomycosis. The lesions are described as circumscribed, well-delineated areas of lysis, with or without a rim of sclerosis that can occur in any bone, although such lesions are usually seen in clavicles, ribs, and scapulae.(6) Although the patient had no symptoms of skeletal involvement, we decided to perform whole-body MRI in order to conduct a detailed investigation. Whole-body MRI seemed suitable for the case presented here, because, in addition to its high contrast resolution and excellent ability to visualize bone marrow components, the method has the advantage of not using ionizing radiation, making it an ideal tool for the initial evaluation and follow-up assessment of children and young adults such as our patient.(7) In conclusion, the case presented here illustrates the potential of whole-body MRI as a diagnostic tool for evaluating systemic diseases, such as deep mycosis. This radiation-free evaluative method creates images that can be used as baseline assessments for longitudinal monitoring.

B

Figure 1 - Whole-body magnetic resonance imaging using a gadolinium-enhanced volumetric interpolated breath-hold examination sequence. In A, a scan demonstrating the enlargement of a cervical lymph node and peripheral contrast enhancement (arrows). In B, a scan in the axial plane showing insufflated lesions on the clavicle (long arrow), scapula (arrowhead), and vertebra (short arrow).

J Bras Pneumol. 2013;39(2):248-250

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Marchiori E, Ferreira EC, Zanetti G, Hochhegger B

A

B

Figure 2 - Whole-body magnetic resonance imaging scans in the coronal plane. In A, lesions in the left humerus (arrow) with heterogeneous contrast enhancement, and axillary lymph node enlargement (arrowheads).

In B, bilateral pleural effusion (arrow).

Edson Marchiori Associate Professor of Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Elisa Carvalho Ferreira Radiologist, Hospital de Ipanema, Rio de Janeiro, Brazil Gláucia Zanetti Professor of Clinical Medicine, Petrópolis School of Medicine, Petrópolis, Brazil Bruno Hochhegger Chest Radiologist, Santa Casa Hospital Complex, Porto Alegre, Brazil

Submitted: 10 July 2012. Accepted, after review: 30 July 2012.

J Bras Pneumol. 2013;39(2):248-250

References 1. Ferreira EC, Brito CC, Domingues RC, Bernardes M, Marchiori E, Gasparetto EL. Whole-body MR imaging for the evaluation of McCune-albright syndrome. J Magn Reson Imaging. 2010;31(3):706-10.

2. Martinez R. Paracoccidioidomycosis: the dimension of the problem of a neglected disease. Rev Soc Bras Med Trop. 2010;43(4):480.

3. Nogueira SA, Guedes AL, Wanke B, Capella S, Rodrigues K, Abreu TF, et al. Osteomyelitis caused by Paracoccidioides brasiliensis in a child from the metropolitan area of Rio de Janeiro. J Trop Pediatr. 2001;47(5):311-5.

4. Buitrago MJ, Bernal-Martínez L, Castelli MV, RodríguezTudela JL, Cuenca-Estrella M. Histoplasmosis and paracoccidioidomycosis in a non-endemic area: a review of cases and diagnosis. J Travel Med. 2011;18(1):26-33.

5. Valera ET, Mori BM, Engel EE, Costa IS, Brandão DF, Nogueira-Barbosa MH, et al. Fungal infection by Paracoccidioides brasiliensis mimicking bone tumor.

Pediatr Blood Cancer. 2008;50(6):1284-6.

6. Nogueira MG, Andrade GM, Tonelli E. Clinical evolution of paracoccidioidomycosis in 38 children and teenagers.

Mycopathologia. 2006;161(2):73-81.

7. Ley S, Ley-Zaporozhan J, Schenk JP. Whole-body MRI in the pediatric patient. Eur J Radiol. 2009;70(3):442-51.

Letter to the Editor Successful thoracoscopic thymectomy in an infant Timectomia toracoscópica bem sucedida em um lactente

Damian Palafox, Brenda Tello-López, Miguel Angel Vichido-Luna, Walid Leonardo Dajer-Fadel, José Palafox

To the Editor: Minimally invasive surgery is gaining worldwide acceptance for the treatment of mediastinal tumors in children. It has been shown to have several advantages over conventional open surgical approaches. For instance, Lawal et al. showed that thoracoscopy, in comparison with thoracotomy, was associated with significantly fewer midterm musculoskeletal sequelae and a better cosmetic outcome.(1) The authors also found that chest asymmetry in the horizontal plane was significantly less frequent after videoassisted thoracic surgery (VATS) than after conventional surgery (mean relative difference, 0.996 ± 0.003 vs. 0.964 ± 0.008; p < 0.001), as was scoliosis (9% vs. 54%; p < 0.001).(1) Another group of authors demonstrated that undesirable comorbidities, such as rib fusion, deformities of the thorax, and scoliosis, can be avoided using thoracoscopic procedures.(2) For anterior mediastinal masses in children, less invasive approaches are preferred, because of the wide spectrum of clinical manifestations associated with such masses.(3) Here, we present the case of an eighteen-month-old infant who underwent thoracoscopic thymectomy, which proved to be safe and provided a satisfactory clinical outcome.

We believe that it is of the utmost importance that the thoracoscopic approach be promoted to pediatric pulmonologists and thoracic surgeons.

An eighteen-month-old male infant presented with a six-month history of recurrent respiratory infections. He had previously been diagnosed with bronchiolitis, which had been treated with bronchodilators and symptomatic management.

However, poor results had been obtained. There was no record of any previous hospitalization, and no imaging studies had been performed before he was referred to our facility. He was hospitalized during an acute episode of severe dyspnea. Simple X-rays showed a widened mediastinum and a mass in the anterior mediastinum. Therefore, CT was performed. The presence of an anterior

mediastinal mass was confirmed. The mass was solid, without any cystic or calcified areas.

The results of all laboratory tests were normal, including those for tumor markers. We decided to perform elective surgery based on his history of infections and progressive dyspnea. Other causes of enlarged mediastinum and dyspnea, such as bronchogenic cysts, were ruled out.

We decided to use a thoracoscopic approach.

The tumor was found to be thymus-dependent and the surgery therefore consisted of thoracoscopic thymectomy. The patient was anesthetized, and a double-lumen endotracheal tube was used in order to perform single-lung ventilation, which has been shown to be a safe procedure.(4) We used a left-sided approach. The surgical technique was performed in accordance with one of our previous reports.(5) In brief, the surgical technique involves the use of three ports; one is placed in the fourth intercostal space in the anterior axillary line; another is placed in the fifth intercostal space in the posterior axillary line; and the third is placed in the seventh space in the anterior axillary line. The camera can be moved from one port to another during the surgery. We begin the procedure with the identification of the phrenic nerve, followed by the dissection of the right inferior pole of the thymus and the placement of vascular clips (one to three) on the thymic veins close to the venous brachiocephalic trunk.

We then dissect the left pole in a similar fashion (Figure 1). We continue with gentle cephalicto-caudal traction of the right superior lobe, placing clips deep into the cervical tissue. Then, the left superior lobe is also dissected in order to complete the excision of the gland (Figure 2).

Finally, we resect the mediastinal adipose tissue from the cardiophrenic angle up to the pretracheal and perivascular fat. A chest tube was placed intraoperatively and removed after the first 24 h.

The histopathological examination of the tissue confirmed thymoma. The postoperative course J Bras Pneumol. 2013;39(2):251-253

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Palafox D, Tello-López B, Vichido-Luna MA, Dajer-Fadel WL, Palafox J

Figure 1 - Placement of vascular clips on the thymic veins prior to the dissection of the left inferior pole.

results have been satisfactory.(8-10) Regarding the side of the surgical approach, in general terms, left thoracoscopic thymectomy is associated with a lower risk of vena cava injury during surgical manipulation and while gaining access to the aortopulmonary window. However, it has been reported that right thoracoscopy allows better surgical manipulation because of the larger dimensions of the right pleural cavity and easier identification of the innominate vein.

We particularly prefer the left-sided approach, because it provides adequate visualization of vascular and nervous structures. The decision to perform or not perform the procedure should be made only after careful study of the case in question. An enlarged thymus alone does not constitute an indication for surgery. In our experience with pediatric patients, thoracoscopy and VATS have both ultimately been related to less postoperative pain, less thoracic trauma, shorter hospital stays, better cosmetic results, and less midterm musculoskeletal sequelae, making it possible to perform the resection of the gland safely, with similar clinical results and better acceptance by patients and parents alike.

Figure 2 - Clips placed deep into the cervical tissue, with gentle cephalic-to-caudal traction of the right superior lobe applied for the excision of the thymus.

Damian Palafox Resident in Surgery, General Hospital of Mexico, Mexico City, Mexico

was uneventful, and patient was discharged on the third postoperative day. At this writing (seven months after discharge), the patient remained asymptomatic.

To our knowledge, there have been no randomized controlled trials or controlled clinical trials comparing minimally invasive surgery with open surgery for the treatment of thoracic neoplasms in children.(6) Therefore, we agree with De Lijster et al.,(6) who stated that no definitive conclusions or statements can be made regarding the role of minimally invasive thoracic surgery in infants. However, there have been several reports of cases in which minimally invasive thoracic surgery provided positive outcomes in infants. In fact, Ure et al. conducted a state of the art study on the use of VATS for the treatment of thoracic conditions in children.(7) In general terms, thoracoscopic thymectomy has long been successfully performed in young patients with myasthenia, and the

Brenda Tello-López Resident in Pediatrics, Federico Gómez Children’s Hospital of Mexico, Mexico City, Mexico

J Bras Pneumol. 2013;39(2):251-253

Miguel Angel Vichido-Luna Resident in Pediatrics, National Institute of Pediatrics, Mexico City, Mexico Walid Leonardo Dajer-Fadel Resident in Cardiothoracic Surgery, General Hospital of Mexico, Mexico City, Mexico José Palafox Chief, Thoracic Surgery Unit, Center for Respiratory and Allergic Diseases, Xalapa, Mexico

Successful thoracoscopic thymectomy in an infant

References 1. Lawal TA, Gosemann JH, Kuebler JF, Glüer S, Ure BM. Thoracoscopy versus thoracotomy improves midterm musculoskeletal status and cosmesis in infants and children. Ann Thorac Surg. 2009;87(1):224-8.

2. Fuchs J, Kirschner HJ, Warmann SW, Schellinger K, Baden W, Szavay P. Thoracoscopic anatomical lung resection in children [Article in German]. Zentralbl Chir. 2007;132(3):247-50.

3. Garey CL, Laituri CA, Valusek PA, St Peter SD, Snyder CL. Management of anterior mediastinal masses in children. Eur J Pediatr Surg. 2011;21(5):310-3.

4. Bataineh ZA, Zoeller C, Dingemann C, Osthaus A, Suempelmann R, Ure B. Our experience with single lung ventilation in thoracoscopic paediatric surgery.

Eur J Pediatr Surg. 2012;22(1):17-20.

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5. Palafox D, Palafox J. The usefulness of thoracoscopic thymectomy for myasthenia gravis [Article in Spanish].

Rev Med Hosp Gen Mex. 2012;75(1):9-13 6. de Lijster MS, Bergevoet RM, van Dalen EC, Michiels EM, Caron HN, Kremer LC, et al. Minimally invasive surgery versus open surgery for the treatment of solid abdominal and thoracic neoplasms in children. Cochrane Database Syst Rev. 2012;1:CD008403.

7. Ure BM, Schmidt AI, Jesch NK. Thoracoscopic surgery in infants and children. Eur J Pediatr Surg. 2005;15(5):314-8.

8. Wagner AJ, Cortes RA, Strober J, Grethel EJ, Clifton MS, Harrison MR, et al. Long-term follow-up after thymectomy for myasthenia gravis: thoracoscopic vs open. J Pediatr Surg. 2006;41(1):50-4; discussion 50-4.

9. Seguier-Lipszyc E, Bonnard A, Evrard P, Garel C, De Ribier A, Aigrain Y, et al. Left thoracoscopic thymectomy in children. Surg Endosc. 2005;19(1):140-2.

10. Sardenberg RA, Abadalla RZ, Abreu IR, Evaristo EF, Younes RN. Robotic thymectomy for myasthenia gravis.

J Bras Pneumol. 2011;37(5):694-6.

Submitted: 25 July 2012. Accepted, after review: 01 October 2012.

J Bras Pneumol. 2013;39(2):251-253

Letter to the Editor Underdiagnosis of respiratory diseases during an economic downturn and the need for spirometry as a screening test Subdiagnóstico de doenças respiratórias durante uma desaceleração econômica e necessidade do uso da espirometria como teste de triagem

Filio Kotrogianni, Foteini Malli, Konstantinos I Gourgoulianis

To the Editor: In a very interesting paper published recently in the Brazilian Journal of Pulmonology, Queiroz et al.(1) reported a COPD underdiagnosis rate of 71.4% in a primary health care setting. In addition, the authors observed that only 5.6% of the subjects previously diagnosed with COPD had undergone pulmonary function tests (PFTs). We would like to recount our experience concerning the underutilization of diagnostic tools, such as spirometry, and the consequent underestimation of respiratory diseases. The underdiagnosis of major health problems, such as asthma and COPD, has to be noted, especially in a period during which access to health care is no longer a universal, inalienable right, because of the recent economic downturn.

Greece is currently dealing with a major financial crisis, which has had disheartening effects on every aspect of life, including not only access to health care but also the quality of the health care services available. In particular, the reduction in family income and the inability of individuals to afford health insurance coverage, has limited the use of high-quality health care services. The total government expenditure on (budget for) health care has been also affected by the economic crisis. The World Health Organization reported that, due to the economic downturn, patients in Greece are either seeking medical assistance at public health care facilities or deferring health care completely.(2) As a result, an increasing number of patients remain undiagnosed even if they are symptomatic or have specific risk factors for a particular disease, such as COPD. Our group, in cooperation with the Hellenic Thoracic Society, evaluated 267 individuals (183 males; mean age: 53.5 ± 14.3 years). All of the participants completed a questionnaire that included demographic and clinical data, as well as information about any previous PFTs. J Bras Pneumol. 2013;39(2):254-255

The participants then underwent spirometry in accordance with international recommendations.(3) Of the 267 individuals studied, 167 (62.5%) had never undergone PFTs. Therefore, for the majority of the participants, this project constituted the first evaluation of their pulmonary function. Of the 167 participants who had never undergone PFTs, 84 were current smokers and 48 were former smokers. More importantly, 55.1% presented with at least one respiratory symptom (such as dyspnea, expectoration, and wheezing). Despite presenting with these risk factors for a major respiratory disease, those participants had never sought medical attention. In addition, of the 167 participants who had never undergone PFTs, 32 (19.2%) showed abnormal spirometric results and 110 (65.6%) presented with respiratory symptoms, such as cough, dyspnea, and decreased exercise tolerance.

The underdiagnosis of COPD depends on various factors that might be affected by the current economic crisis, such as the problematic access to health care facilities due to financial problems, the lack of diagnostic facilities, and the absence of skilled, experienced staff. In addition, the low level of education associated with the economic downturn might result in a lack of information concerning risk factors and could even prevent a significant number of patients from identifying their symptoms.

Spirometry is an inexpensive, noninvasive test of ventilatory function and plays a critical role in the diagnosis of respiratory diseases. However, screening the general population would not be feasible. One group of authors suggested that patients with a high probability of having COPD be identified through the use of symptom-based questionnaires and subsequently screened with PFTs as needed. Delayed diagnoses and a large number of unnecessary spirometric tests would thus be avoided.(4)

Underdiagnosis of respiratory diseases during an economic downturn and the need for spirometry as a screening test

During a financial crisis, when governments cannot invest in public health care and people can barely afford special examinations, consequently neglecting their health, spirometry should be accessible to all symptomatic patients in order to promote early diagnosis and prevent the progression of the disease, thereby reducing health costs. Screening tools, such as spirometry, should be made available to subjects at risk for respiratory diseases, such as elderly patients and smokers, with the aim of reducing the underdiagnosis of such diseases, which can be adequately treated when detected early.

Filio Kotrogianni Resident in Respiratory Medicine, Respiratory Medicine Department, University Hospital of Larissa, Larissa, Greece

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Konstantinos I Gourgoulianis Professor of Respiratory Medicine, Faculty of Medicine, University of Thessaly, Larissa, Greece

References 1. de Queiroz MC, Moreira MA, Rabahi MF. Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiânia, Brazil. J Bras Pneumol. 2012; 38(6):692-9.

2. World Health Association. The Financial Crisis and Global Health. Report of a High-Level Consultation, 19 January 2009. Geneva: World Health Organization; 2009.

3. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3): 1107-36.

4. Thorn J, Tilling B, Lisspers K, Jörgensen L, Stenling A, Stratelis G. Improved prediction of COPD in at-risk patients using lung function pre-screening in primary care: a real-life study and cost-effectiveness analysis.

Prim Care Respir J. 2012;21(2):159-66.

Foteini Malli Resident in Respiratory Medicine, Respiratory Medicine Department, University Hospital of Larissa, Larissa, Greece

Submitted: 14 February 2013. Accepted, after review: 25 February 2013.

J Bras Pneumol. 2013;39(2):254-255

Letter to the Editor Authors’ reply Resposta dos autores

To the Editor: We would like to thank the authors Filio Kotrogianni, Foteini Malli, and Konstantinos I Gourgoulianis for their interest in our article, which honors us and encourages us to continue to pursue this line of research. A disease as serious as COPD, which is still considered to be of secondary importance in some parts of the world, should not be neglected.

In their letter, we have noted that the problem of the underutilization of spirometry also happens in their country, which supports our assertion that this does not occur only in developing countries.

It is of note that most of the smokers studied in their report had respiratory symptoms, and most of those with abnormal spirometry results were symptomatic from a respiratory standpoint.

This reinforces the concept of active surveillance, suggested by the Global Initiative for Chronic Obstructive Lung Disease, in 2013, rather than spirometry screening for COPD. In Brazil, most patients first seek medical attention at primary health care facilities, which, consequently, should be prepared to prevent, diagnose, and treat the most common and relevant diseases in the community. Our study and the letter from our colleagues in Greece reveal the need to improve the early detection and diagnosis of COPD, which would reduce its impact and severity. In addition, they alert us to the need for health education for smokers and patients with COPD, so that they understand the nature of their disease, the risk factors for disease progression, their role in fighting the disease,

J Bras Pneumol. 2013;39(2):256-256

and the role played by health care professionals.

Such information can assist health care managers in optimizing the training of primary health care workers regarding the diagnosis of COPD and to increase the availability of diagnostic spirometry.

Considering the prospect of an increase in the prevalence of COPD worldwide, studies such as ours demonstrate the need for action in the context of primary health care in order to increase the awareness of clinicians regarding their responsibility in the initial clinical diagnosis.

Despite being inexpensive, diagnostic spirometry is available at few health care facilities, making it difficult to make a definitive diagnosis of COPD in Brazil. The use of spirometry should therefore be expanded.

Maria Conceição de Castro Antonelli Monteiro de Queiroz Attending Physician, Pulmonology Department, Federal University of Goiás School of Medicine Hospital das Clínicas, Goiânia, Brazil Maria Auxiliadora Carmo Moreira Associate Professor, Federal University of Goiás School of Medicine, Goiânia, Brazil Marcelo Fouad Rabahi Adjunct Professor, Federal University of Goiás School of Medicine, Goiânia, Brazil

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Review and Update articles: Review and Update articles are written at the request of the Editorial Board, which may occasionally accept unsolicited manuscripts that are deemed to be of great interest. The text should not exceed 5000 words, excluding references and illustrations (figures or tables). The total number of illustrations should not exceed eight. The number of references should not exceed 60.

Pictorial essays: Pictorial essays are also submitted only at the request of the Editors or after the authors have consulted and been granted permission by the Editorial Board. The text accompanying such essays should not exceed 3000 words, excluding the references and tables.

No more than 12 illustrations (figures and tables) may be used, and the number of references may not exceed 30.

Case Reports: Case Reports should not exceed 1500 words, excluding title page, abstract, references and illustrations. The text should be composed of: Introduction, Case Report, Discussion and References. It is recommended that any and all information that might identify the patient be withheld, and that only those laboratory exams that are important for the diagnosis and discussion be presented.

The total number of illustrations (figures or tables) should not exceed three, and the number of references should be limited to 20. When the number of cases presented exceeds three, the manuscript will be classified as a Case Series, and the same rules applicable to an original article will be applied.

Brief Communications: Brief communications should not exceed 1500 words, excluding references and tables.

The total number of tables and figures should not exceed two, and the references should be limited to 20. The text should be unstructured.

Letters to the Editor: Letters to the Editor should be succinct original contributions, not exceeding 800 words and containing a maximum of 6 references. Comments and suggestions related to previously published materials or to any medical theme of interest will be considered for publication.

Tables and Figures: All tables and figures should be in black and white, on separate pages, with legends and captions appearing at the foot of each. All tables and figures should be submitted as files in their original format. Tables should be submitted as Microsoft Word files, whereas figures should be submitted as Microsoft Excel, TIFF or JPG files. Photographs depicting surgical procedures, as well as those showing the results of exams or biopsies, in which staining and special techniques were used will be considered for publication in color, at no additional cost to the authors. Dimensions, units and symbols should be based on the corresponding guidelines set forth by the Associação Brasileira de Normas Técnicas (ABNT, Brazilian Association for the Establishment of Technical Norms), available at: http://www.abnt.org.br.

Legends: Legends should accompany the respective figures (graphs, photographs and illustrations) and tables. Each legend should be numbered with an Arabic numeral corresponding to its citation in the text.

In addition, all abbreviations, acronyms, and symbols should be defined below each table or figure in which they appear.

References: References should be listed in order of their appearance in the text and should be numbered consecutively with Arabic numerals. The presentation should follow the Vancouver style, updated in October of 2004, according to the examples below. The titles of the journals listed should be abbreviated according to the style presented by the List of Journals Indexed in the Index Medicus of the National Library of Medicine, available at: http:// www.ncbi.nlm.nih.gov/entrez/journals/loftext.noprov.html.

A total of six authors may be listed. For works with more than six authors, list the first six, followed by ‘et al.’

Examples: Journal Articles 1. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs AC et al. Prediction of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomized study. Eur Respir J. 1999;14(6):1204-13.

Abstracts 2. Singer M, Lefort J, Lapa e Silva JR, Vargaftig BB. Failure of granulocyte depletion to suppress mucin production in a murine model of allergy [abstract]. Am J Respir Crit Care Med. 2000;161:A863.

Chapter in a Book 3. Queluz T, Andres G. Goodpasture’s syndrome. In: Roitt IM, Delves PJ, editors. Encyclopedia of Immunology.

1st ed. London: Academic Press; 1992. p. 621-3.

Official Publications 4. World Health Organization. Guidelines for surveillance of drug resistance in tuberculosis. WHO/Tb, 1994;178:1-24.

Theses 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 [thesis]. São Paulo: Universidade Federal de São Paulo; 1998.

Electronic publications 6. Abood S. Quality improvement initiative in nursing homes: the ANA acts in an advisory role. Am J Nurs [serial on the Internet]. 2002 Jun [cited 2002 Aug 12]; 102(6): [about 3 p.]. Available from: http://www. nursingworld.org/AJN/2002/june/Wawatch.htm

Homepages/URLs 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/

Other situations: In other situations not mentioned in these author instructions, authors should follow the recommendations given by the International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Updated October 2004. Available at http://www.icmje.org/.

All correspondence to the Jornal Brasileiro de Pneumologia should be addressed to: Prof. Dr. Carlos Roberto Ribeiro de Carvalho Editor-Chefe do Jornal Brasileiro de Pneumologia SCS Quadra 01, Bloco K, Salas 203/204 - Ed. Denasa.

CEP: 70.398-900 - Brasília - DF, Brazil Telefones/Fax: 0xx61-3245-1030, 0xx61-3245-6218 Jornal Brasileiro de Pneumologia e-mail address: jpneumo@jornaldepneumologia.com.br (Editorial assistant: Luana Campos) Online submission of articles: www.jornaldepneumologia.com.br

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