JBP - Volume 43, number 6, November/December 2017 by Jornal Brasileiro Pneumologia

ISSN 1806-3713

Volume 43, Number 6

November | December 2017

www.jbp.org.br

Volume 43, Number 6 November | December 2017

HIGHLIGHT

Tuberculosis treatment

Idiopathic pulmonary fibrosis

Lung cancer

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Published once every two months J Bras Pneumol. v.43, number 6, p. 401-500 November/December 2017 EDITOR-IN-CHIEF

Rogerio Souza - Universidade de São Paulo, São Paulo - SP

DEPUTY EDITOR

Bruno Guedes Baldi - Universidade de São Paulo, São Paulo - SP

Associação Brasileira de Editores Científicos

EXECUTIVE EDITORS

Caio Júlio Cesar dos Santos Fernandes - Universidade de São Paulo - São Paulo - SP Carlos Roberto Ribeiro de Carvalho - Universidade de São Paulo, São Paulo - SP Carlos Viana Poyares Jardim - Universidade de São Paulo, São Paulo - SP

ASSOCIATE EDITORS

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

Afrânio Lineu Kritski - Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ Andre Luis Pereira de Albuquerque - Universidade de São Paulo - São Paulo - SP Bruno Hochhegger - Universidade Federal do Rio Grande do Sul - Porto Alegre – RS Edson Marchiori - Universidade Federal Fluminense, Niterói - RJ Fernanda Carvalho de Queiroz Mello - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Frederico Leon Arrabal Fernandes - Universidade de São Paulo - São Paulo - SP Giovanni Battista Migliori - Director WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate - Italy Giovanni Sotgiu - University of Sassari, Sassari - Italy Irma de Godoy - Universidade Estadual Paulista, Botucatu - SP Marcelo Alcântara Holanda - Universidade Federal do Ceará - Fortaleza - CE Pedro Caruso - Universidade de São Paulo - São Paulo - SP Pedro Rodrigues Genta - Universidade de São Paulo - São Paulo - SP Renato Tetelbom Stein - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre - RS Ricardo de Amorim Corrêa - Universidade Federal de Minas Gerais - Belo Horizonte - MG Ricardo Mingarini Terra - Universidade de São Paulo - São Paulo - SP Simone Dal Corso - Universidade Nove de Julho - São Paulo – SP Tomás Pulido - Instituto Nacional de Cardiología Ignacio Chávez - México Ubiratan de Paula Santos - Universidade de São Paulo, São Paulo - SP Veronica Amado - Universidade de Brasília, Brasília - DF

EDITORIAL COUNCIL

Alberto Cukier - Universidade de São Paulo, São Paulo – SP Álvaro A. Cruz - Universidade Federal da Bahia, Salvador, BA Ana C. Krieger - Weill Cornell Medical College - New York – USA Ana Luiza Godoy Fernandes - Universidade Federal de São Paulo, São Paulo - SP Antonio Segorbe Luis - Universidade de Coimbra, Coimbra - Portugal Ascedio Jose Rodrigues - Universidade de São Paulo - São Paulo - SP Brent Winston - University of Calgary, Calgary - Canada Carlos Alberto de Assis Viegas - Universidade de Brasília, Brasília - DF Carlos Alberto de Castro Pereira - Universidade Federal de São Paulo, São Paulo - SP Carlos M. Luna - Hospital de Clinicas, Universidad de Buenos Aires, Buenos Aires - Argentina Carmen Silvia Valente Barbas - Universidade de São Paulo, São Paulo - SP Celso Ricardo Fernandes de Carvalho - Universidade de São Paulo, São Paulo - SP Dany Jasinowodolinski - Universidade de São Paulo, São Paulo - SP Denis Martinez - Universidade Federal do Rio Grande do Sul, Porto Alegre - RS Douglas Bradley - University of Toronto, Toronto, ON - Canadá Emílio Pizzichini - Universidade Federal de Santa Catarina, Florianópolis - SC Fábio Biscegli Jatene - Universidade de São Paulo, São Paulo - SP Frank McCormack - University of Cincinnati School of Medicine, Cincinnati, OH - USA Geraldo Lorenzi Filho - Universidade de São Paulo, São Paulo - SP Gilberto de Castro Junior - Universidade de São Paulo, São Paulo - SP Gustavo Javier Rodrigo - Hospital Central de las Fuerzas Armadas, Montevidéu – Uruguay Ilma Aparecida Paschoal - Universidade de Campinas, Campinas - SP C. Isabela Silva Müller - 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 Alberto Neder - Queen’s University - Ontario, Canada José Antonio Baddini Martinez - Universidade de São Paulo, Ribeirão Preto - SP José Dirceu Ribeiro - Universidade de Campinas, Campinas - SP José Miguel Chatkin - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre - RS José Roberto de Brito Jardim - Universidade Federal de São Paulo, São Paulo - SP José Roberto Lapa e Silva - Universidade Federal do Rio de Janeiro, Rio de Janeiro - RJ Kevin Leslie - Mayo Clinic College of Medicine, Rochester, MN - USA Luiz Eduardo Nery - Universidade Federal de São Paulo, São Paulo - SP Marc Miravitlles - University Hospital Vall d’Hebron - Barcelona, Catalonia, Spain Marisa Dolhnikoff - Universidade de São Paulo, São Paulo - SP Marli Maria Knorst - Universidade Federal do Rio Grande do Sul, Porto Alegre - RS Mauro Musa Zamboni - Instituto Nacional do Câncer, Rio de Janeiro - RJ Nestor Muller - Vancouver General Hospital, Vancouver, BC - Canadá Noé Zamel - University of Toronto, Toronto, ON - Canadá Oliver Augusto Nascimento - Universidade Federal de São Paulo - São Paulo - SP Paul Noble - Duke University, Durham, NC - USA Paulo Francisco Guerreiro Cardoso - Universidade de São Paulo, São Paulo - SP Paulo Manuel Pêgo Fernandes - Universidade de São Paulo, São Paulo - SP Peter J. Barnes - National Heart and Lung Institute, Imperial College, London - UK Renato Sotto Mayor - Hospital Santa Maria, Lisboa - Portugal Richard W. Light - Vanderbili University, Nashville, TN, USA Rik Gosselink - University Hospitals Leuven - Bélgica Robert Skomro - University of Saskatoon, Saskatoon - Canadá Rubin Tuder - University of Colorado, Denver, CO - USA Sérgio Saldanha Menna Barreto - Universidade Federal do Rio Grande do Sul, Porto Alegre - RS Sonia Buist - Oregon Health & Science University, Portland, OR - USA Talmadge King Jr. - University of California, San Francisco, CA - USA Thais Helena Abrahão Thomaz Queluz - Universidade Estadual Paulista, Botucatu - SP Vera Luiza Capelozzi - Universidade de São Paulo, São Paulo - SP

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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.

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BTS Board of Directors (2017-2018 biennium): President: Fernando Luiz Cavalcanti Lundgren - PE Secretary-General: Benedito Francisco Cabral Júnior - DF CFO: Simone Chaves Fagondes - RS Scientific Director: Ana Luisa Godoy Fernandes - SP Director, Communications: Fernanda Miranda de Oliveira - GO Director, Education and Professional Practice:: Irma de Godoy - SP Director, Professional Advocacy: Marcelo Gervilla Gregório - SP President, BTS Congress 2018: Marcelo Fouad Rabahi - GO President Elect (2019/2020 biennium): José Miguel Chatkin - RS Editor-in-Chief of the Brazilian Journal of Pulmonology: Rogério de Souza - SP AUDIT COMMITTEE: Active Members: Ronaldo Rangel Travassos Júnior - PB, Eduardo Felipe Barbosa Silva - DF, Filadélfia Passos Travassos Martins - CE Alternates: Leandro Genehr Fitscher - RS, Ciléa Aparecida Victória Martins - ES, Eduardo Pamplona Bethlem - RJ COORDINATORS, BTS DEPARTMENTS: Thoracic Surgery – Darcy Ribeiro Pinto Filho -RS Sleep–disordered Breathing – Pedro Rodrigues Genta -SP Respiratory Endoscopy – Mauro Musa Zamboni -RJ Pulmonary Function – Silvia Carla Sousa Rodrigues -SP Imaging – Pablo Rydz Pinheiro Santana -SP Lung Diseases – Vera Luiza Capelozzi -SP Pediatric Pulmonology – Marina Buarque de Almeida -SP COORDINATORS, BTS SCIENTIFIC COMMITTEES: Asthma – Maria Alenita de Oliveira - SP Lung Cancer – Gustavo Faibischew Prado - SP Pulmonary Circulation – Marcelo Basso Gazzana -SP Advanced Lung Disease – Paulo Henrique Ramos Feitosa -DF Interstitial Diseases – José Antônio Baddini Martinez -SP Environmental and Occupational Respiratory Diseases – Carlos Nunes Tietboehl-Filho -RS COPD – Frederico Leon Arrabal Fernandes -SP Epidemiology – Juliana Carvalho Ferreira - SP Cystic Fibrosis – Rodrigo Abensur Athanazio – SP Respiratory Infections and Mycoses – Mônica Corso Pereira - SP Pleura – Roberta Karla Barbosa de Sales -SP Smoking – Maria da Penha Uchoa Sales - CE Intensive Care – Eduardo Leite Vieira Costa -SP Tuberculosis – Denise Rossato Silva -RS 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. Assistant Managing Editor: Luana Maria Bernardes Campos. E-mail: jpneumo@jornaldepneumologia.com.br Circulation: 4.000 copies Distribution: Free to members of the BTS and libraries Printed on acid-free paper SUPPORT:

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.43, number 6, p. 401-500 November/December 2017

EDITORIAL 401 - Idiopathic pulmonary fibrosis in Brazil: challenges for epidemiological characterization and management Bruno Guedes Baldi 403 - Evolution in the management of non-small cell lung cancer in Brazil Caio Júlio Cesar dos Santos Fernandes 405 - Noninvasive positive airway pressure: from critically ill patients to physical exercise in outpatients Vinicius Zacarias Maldaner da Silva, Alfredo Nicodemos Cruz Santana

CONTINUING EDUCATION: IMAGING 407 - Tree-in-bud pattern Edson Marchiori, Bruno Hochhegger, Gláucia Zanetti

Contents

CONTINUING EDUCATION: SCIENTIFIC METHODOLOGY 408 - Understanding diagnostic tests. Part 2. Cecilia Maria Patino, Juliana Carvalho Ferreira

ORIGINAL ARTICLE 409 - Impact of continuous positive airway pressure on the pulmonary changes promoted by immersion in water Danize Aparecida Rizzetti, Janayna Rodembuch Borba Quadros, Bruna Esmerio Ribeiro, Letícia Callegaro, Aline Arebalo Veppo, Giulia Alessandra Wiggers, Franck Maciel Peçanha 416 - Tuberculosis infection among primary health care workers Thamy Carvalho Lacerda, Fernanda Mattos de Souza, Thiago Nascimento do Prado, Rodrigo Leite Locatelli, Geisa Fregona, Rita de Cássia Duarte Lima, Ethel Leonor Maciel 424 - Accuracy of closed pleural biopsy in the diagnosis of malignant pleural effusion Renata Báez-Saldaña, Uriel Rumbo-Nava, Araceli Escobar-Rojas, Patricia Castillo-González, Santiago León-Dueñas, Teresa Aguirre-Pérez, María Eugenia Vázquez-Manríquez 431 - Survival in a cohort of patients with lung cancer: the role of age and gender in prognosis Juliana Pereira Franceschini, Sérgio Jamnik, Ilka Lopes Santoro 437 - Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country Marcelo Fouad Rabahi, José Laerte Rodrigues da Silva Júnior, Marcus Barreto Conde

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Published once every two months J Bras Pneumol. v.43, number 6, p. 401-500 November/December 2017

445 - Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014 Eduardo Algranti, Cézar Akiyoshi Saito, Diego Rodrigues Mendonça e Silva, Ana Paula Scalia Carneiro, Marco Antonio Bussacos 451 - Niemann-Pick disease type B: HRCT assessment of pulmonary involvement Heloisa Maria Pereira Freitas, Alexandre Dias Mançano, Rosana Souza Rodrigues, Bruno Hochhegger, Pedro Paulo Teixeira e Silva Torres, Dante Escuissato, Cesar Augusto Araujo Neto, Edson Marchiori 456 - Validation of the STOP-Bang questionnaire as a means of screening for obstructive sleep apnea in adults in Brazil Ricardo Luiz de Menezes Duarte, Lorena Barbosa de Moraes Fonseca, Flavio José Magalhães-da-Silveira, Erika Aparecida da Silveira, Marcelo Fouad Rabahi 464 - Effects of simple long-term respiratory care strategies in older men with COPD Fabrício Zambom-Ferraresi, Pilar Cebollero,Javier Hueto, María Hernández, José Cascante, María Milagros Antón

REVIEW ARTICLE

Contents

472 - Tuberculosis treatment Marcelo Fouad Rabahi, José Laerte Rodrigues da Silva Júnior, Anna Carolina Galvão Ferreira, Daniela Graner Schuwartz Tannus-Silva, Marcus Barreto Conde

LETTER TO THE EDITOR 487 - Omalizumab in patients with severe uncontrolled asthma: well-defined eligibility criteria to promote asthma control Regina Maria de Carvalho-Pinto, Rosana Câmara Agondi, Pedro Giavina-Bianchi, Alberto Cukier, Rafael Stelmach 490 - Primary sclerosing epithelioid fibrosarcoma of the pleura Erlon de Ávila Carvalho, Daniel Oliveira Bonomi, Astunaldo Júnior Macedo Pinho, Paulo Guilherme Oliveira Salles, Henrique Cunha Vieira

SUBJECT INDEX FOR V.43 (1-6) 492 - Índice remissivo de assuntos do volume 43 (1-6) 2017

AUTHOR INDEX FOR V.43 (1-6) 494 - Índice remissivo de autores do volume 43 (1-6) 2017

REVIEWERS FOR V.43 (1-6) 497 - Relação de revisores do volume 43 (1-6) 2017

J Bras Pneumol. 2017;43(6):401-402 http://dx.doi.org/10.1590/S1806-37562017000060003

EDITORIAL

Idiopathic pulmonary fibrosis in Brazil: challenges for epidemiological characterization and management Bruno Guedes Baldi1 Idiopathic pulmonary fibrosis (IPF) is characterized as a progressive fibrosing disease of variable evolution, restricted to the lungs, and classified within the group of idiopathic interstitial lung diseases.(1,2) Although great advances have been made in recent years, which have allowed a better understanding of the pathophysiology of the disease, as well as the determination of more restricted diagnostic criteria and the approval of two antifibrotic medications (pirfenidone and nintedanib) for its treatment, various related aspects need to be optimized, especially in Brazil.(1,5) In the current issue of the JBP, Algranti et al. reported an increase in IPF-related mortality in Brazil between 1979 and 2014.(6) Although their results reflect the global trend and are quite interesting, due to the long evaluation period, there are some points that deserve to be highlighted. As discussed by the authors, some factors may explain the results found, such as the increase in the life expectancy of the population and the increase in the availability of HRCT, the increase in the number of patients and the greater specificity of the diagnosis of the disease being determined in recent years. In addition, the more restrictive criteria for the diagnosis of IPF were defined in 2000 and readjusted in 2011.(1,7) In this context, the evaluation of the data in the initial period of the study might have caused that various patients with IPF to be misdiagnosed; in fact, those patients might have had other fibrosing lung diseases that surely have a better prognosis than does IPF, which might have contributed to underestimating mortality in the earliest stages. This is reinforced by the fact that approximately 10% of the deaths occurred in individuals under 50 years of age, the diagnosis of IPF being less likely in this age group. Therefore, the disease mortality has certainly increased in recent years; however, that rate might be overestimated.(6) As described in a recently published article, robust data on the incidence, prevalence, and mortality of IPF in Brazil are yet to be determined, which, in addition to their epidemiological importance, are economically important so that the costs to provide the drugs that have been approved for the treatment of the disease can be estimated.(8) Therefore, it is essential that future studies should be conducted in order to determine the epidemiological data of IPF in our country in a more reliable way, especially from the moment when the diagnostic criteria were better established. In this context, the creation of a Brazilian national case registry database for IPF is urgently needed.

The number of referral centers for the treatment of interstitial lung diseases is still scarce in Brazil. In those centers, multidisciplinary discussions involving pulmonologists, surgeons, radiologists, and pathologists are essential to optimize the diagnostic approach, since several fibrosing lung diseases take part in the differential diagnosis of IPF, such as hypersensitivity pneumonitis (HP) and connective tissue diseases, among others.(1,9-12) In a recent study by Lynch et al.,(13) a new tomographic classification for IPF was presented. In accordance with that classification system, probable usual interstitial pneumonia was characterized by the presence of reticular opacities and traction bronchiolectasis, with basal and peripheral predominance, no honeycombing, and no other characteristics suggestive of an alternative diagnosis. According to those authors, this tomographic pattern has a high predictive value for IPF in individuals over 60 years of age, smokers or former smokers, with no suggestion for other potential causes of interstitial fibrosing lung diseases, such as chronic HP or connective tissue disease, dispensing with lung biopsy for diagnostic confirmation.(13) This new classification system, in which lung biopsy is not mandatory for the diagnostic confirmation of IPF, creates a trend towards an increase in the number of patients diagnosed with the disease, resulting in greater risks for patients with other fibrosing lung diseases, such as chronic HP and fibrotic nonspecific interstitial pneumonia, to be misdiagnosed with IPF. This aspect is extremely relevant in Brazil, considering the high prevalence of chronic HP, even with a tomographic pattern of probable usual interstitial pneumonia, and the indeterminate frequency of IPF in our country; therefore, this new tomographic criterion should be carefully used in our population with fibrosing lung diseases.(9,14) Recently, two antifibrotic drugs, pirfenidone and nintedanib, have been approved by the Brazilian National Health Oversight Agency for the treatment of IPF in Brazil, since they reduce the functional decline associated with the disease.(2-5) However, there is a need to provide the access to and greater availability of these medications in our country, based on government funding. Another aspect that is a cause for concern in Brazil is the limited number of referral centers for (unilateral or bilateral) lung transplantation, a therapeutic alternative for patients with IPF that will determine an increase in survival, as well as functional improvement and better quality of life in these patients.(1,2,15,16) Other critical factors that influence this issue is the late referral of patients to referral centers for lung transplantation and the shortage of lung donors,

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which has been below the number of candidates on a waiting list.(15) In summary, despite the evolution in knowledge of the pathophysiology of IPF and its diagnostic and therapeutic approach, there are several aspects that need to be improved notably in Brazil, including: 1) to broaden the information regarding the disease; 2) to create a Brazilian national case registry database in order to try to obtain more robust data on the incidence, prevalence, and mortality of IPF; this database is about

to become available soon, and professionals should be aware of the importance of entering their data into the database system; 3) to widen the availability of and the experience with the use of antifibrotic drugs; and 4) to increase the number of referral centers for the multidisciplinary approach to fibrosing lung diseases and lung transplantation. With these improvements, it will be possible to characterize Brazilian national epidemiological data related to the disease more accurately, including the perspective of determining the impact of antifibrotic drugs on mortality.

REFERENCES 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. https://doi. org/10.1164/rccm.2009-040GL 2. Baddini-Martinez J, Baldi BG, Costa CH, Jezler S, Lima MS, Rufino R. Update on diagnosis and treatment of idiopathic pulmonary fibrosis. J Bras Pneumol. 2015;41(5):454-66. https://doi.org/10.1590/S180637132015000000152 3. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al. An official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015;192(2):e3-19. https://doi.org/10.1164/rccm.201506-1063ST 4. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22): 2083-92. https://doi.org/10.1056/NEJMoa1402582 5. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82. https://doi.org/10.1056/ NEJMoa1402584 6. Algranti E, Saito CA, Silva DR, Carneiro AP, Bussacos MA. Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014. J Bras Pneumol. 2017;43(6):xxx-xxx. 7. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-64. 8. Baddini-Martinez J, Pereira CA. How many patients with idiopathic pulmonary fibrosis are there in Brazil? J Bras Pneumol. 2015;41(6):5601. https://doi.org/10.1590/s1806-37562015000000165

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9. Pereira CA, Gimenez A, Kuranishi L, Storrer K. Chronic hypersensitivity pneumonitis. J Asthma Allergy. 2016;9:171-81. https://doi.org/10.2147/JAA.S81540 10. Gomes PS, Shiang C, Szarf G, Coletta EN, Pereira CA. Pleuroparenchymal fibroelastosis: report of two cases in Brazil. J Bras Pneumol. 2017;43(1):72-75. https://doi.org/10.1590/s180637562016000000045 11. Oliveira MR, Pereira DA, Dias OM, Kairalla RA, Carvalho CR, Baldi BG. Idiopathic pulmonary fibrosis can be a transient diagnosis. J Bras Pneumol. 2016;42(1):74-5. https://doi.org/10.1590/S180637562016000000003 12. Pereira DA, Dias OM, Almeida GE, Araujo MS, Kawano-Dourado LB, Baldi BG, et al. Lung-dominant connective tissue disease among patients with interstitial lung disease: prevalence, functional stability, and common extrathoracic features. J Bras Pneumol. 2015;41(2):15160. https://doi.org/10.1590/S1806-37132015000004443 13. Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respir Med. 2017 pii: S22132600(17)30433-2. https://doi.org/10.1016/S2213-2600(17)30433-2 14. Torres PPTS, Rabahi MF, Moreira MAC, Meirelles GSP, Marchiori E. Usual interstitial pneumonia: typical, possible, and â&#x20AC;&#x153;inconsistentâ&#x20AC;? patterns. J Bras Pneumol. 2017;43(5):393-398. https://doi. org/10.1590/s1806-37562016000000368 15. Camargo PC, Teixeira RH, Carraro RM, Campos SV, Afonso Junior JE, Costa AN, et al. Lung transplantation: overall approach regarding its major aspects. J Bras Pneumol. 2015;41(6):547-53. https://doi. org/10.1590/s1806-37562015000000100 16. Rubin AS, Nascimento DZ, Sanchez L, Watte G, Holand AR, Fassbind DA, et al. Functional improvement in patients with idiopathic pulmonary fibrosis undergoing single lung transplantation. J Bras Pneumol. 2015;41(4):299-304. https://doi.org/10.1590/S180637132015000000057

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EDITORIAL

Evolution in the management of non-small cell lung cancer in Brazil Caio Júlio Cesar dos Santos Fernandes1,2

Lung cancer, and its most prevalent variant—non-small cell lung cancer (NSCLC)—is responsible for 85% of all lung cancer cases(1) and is a significant cause of death in the world, as well as in Brazil. It is estimated that, in 2012, approximately 1.6 million deaths occurred due to NSCLC worldwide.(2) In Brazil, in the same year, 23,493 deaths were identified due to this condition.(3) Although the absolute numbers are alarming, lung cancer mortality has been changing over the years. In the mid-1950s, lung cancer became the leading cause of cancer-related deaths in males, and, from the 1980s on, the same phenomenon has occurred in female patients. Since then, there has been a gradual reduction in the number of deaths from lung cancer, mainly due to the decrease in smoking.(4) A series of improvements in the treatment of patients with NSCLC, such as advances in surgical and radiotherapy techniques, in the perioperative care, and in the systemic treatment, have also helped, in some degree, to reduce the mortality rates of the disease. In fact, the advances in chemotherapy are really remarkable. In the past decade, the identification of molecular mechanisms of tumors allowed a better adaptation of chemotherapy concerning the patient, maximizing its effectiveness and reducing its side effects, both in patients with metastatic disease and in those presenting with recurrence after the initial surgical treatment or radiotherapy. Today, specific therapies are available for patients with EGFR, anaplastic lymphoma kinase (ALK), and oncogene 1 (ROS1) gene mutations. (5) Even when gene mutations are not identified, patients can be submitted to immunotherapy as the first line of treatment when the expression of programmed death ligand 1(PD-L1) is identified in at least 50% of the tumor cells.(6) In Brazil, however, most of these therapeutic advances are yet to be available on a large scale; even so, there has been a decrease in the absolute number of deaths due to NSCLC in the country. By 2017, it is estimated that the number of deaths in males and females, respectively, will decrease by 7.5% and 4.8% when we compare it with recent data from 2012.(3) Would there be Brazilian national data that justify this reduction? Recent epidemiological data show that, despite being smaller, the medium-term prognosis of patients with NSCLC is still rather bleak, with a five-year mortality rate of 86%. (7) However, various advances in this area have also been described in Brazil. Recent studies have evaluated the introduction of new surgical techniques, such as videoassisted thoracic surgery, video-assisted thoracoscopy,(8,9), and robotics(10) in our country. Improvements in early

diagnosis have also been described in our setting, with the use of endoscopic ultrasonography for mediastinal staging,(11,12) as well as for the management of more peripheral suspicious lesions(13) that were not previously amenable to a minimally invasive approach. Health care in thoracic oncology referral centers has also been shown to have a positive impact on the prognosis of patients with NSCLC in Brazil, when compared with that in general hospitals.(7) Finally, advances in the management of complications not directly related to the progression of the disease, such as venous thromboembolism,(14) has also benefited this population in a very significant way. In the present issue of JBP, Franceschini et al.(15) provide relevant information on the epidemiology of patients with NSCLC in Brazil. In their retrospective cohort involving 790 patients from a tertiary center in the city of São Paulo, Brazil, who were followed between 2000 and 2012, the distribution of patients with NSCLC was heterogeneous: in younger patients (< 72 years of age) and in women, the predominant histological type was adenocarcinoma. In men older than 72 years of age, the predominant histological type was epidermoid carcinoma. Although NSCLC is still more prevalent in males, the number of women with the disease has been increasing. These data are consistent with those in another cohort study recently published in the JBP.(16) In that study, involving 1,030 patients with NSCLC submitted to surgical treatment between 1986 and 2015, the prevalence of adenocarcinoma in women increased from 11.9%—in the period between 1986 and 1985—to 24.0%—in the period between 2006 and 2015. These data are also consistent with those in the international literature, such as in a cohort study in the USA.(17) Thus, females, younger individuals, and never smokers (who potentially present with genetic mutations that can be treated with specific therapies) have become more and more important in the global and national NSCLC scenario, and, therefore, they should be better understood and evaluated. Another relevant aspect reported by Franceschini et al.(15) concerns mortality. No differences regarding mortality were found in the different age groups evaluated. The elderly patient is, by definition, more fragile, mainly due to the presence of comorbidities. Thus, some international consensuses suggest specific approaches for the elderly population with NSCLC.(18) Epidemiological data in Brazil showing that the elderly population does not necessarily have a worse prognosis than has the general population should stimulate the use of this type of protocol, so that these patients can benefit from the advances in the

1. Serviço de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. 2. Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira, São Paulo (SP) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

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treatment of NSCLC, with a better adapted therapeutic approach. More and more national data on NSCLC patients have become available, and this is a fact to be celebrated. It is very important that international evidence, as well as technological and pharmacological innovations,

on the management of NSCLC be disseminated; however, it is fundamental that we should be aware of our reality on this topic, so that, by recognizing our vulnerabilities and demands, we will be able to offer these innovations to our patients in a more efficient, safe, and cost-effective manner.

REFERENCES 1. Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32(4):66992. https://doi.org/10.1016/j.ccm.2011.08.005 2. Brambilla E, Travis W. Lung cancer. In: Stewart BW, Wild CP, editors, World Cancer Report 2014. Geneva: World Health Organization; 2014. 3. Carioli G, La Vecchia C, Bertuccio P, Rodriguez T, Levi F, Boffetta P, et al. Cancer mortality predictions for 2017 in Latin America. Ann Oncol. 2017;28(9):2286-2297. https://doi.org/10.1093/annonc/ mdx301 4. Jemal A, Simard EP, Dorell C, Noone AM, Markowitz LE, Kohler B, et al. Annual Report to the Nation on the Status of Cancer, 19752009, featuring the burden and trends in human papillomavirus(HPV)associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105(3):175-201. https://doi.org/10.1093/jnci/djs491 5. Sholl LM. Biomarkers in lung adenocarcinoma: a decade of progress. Arch Pathol Lab Med. 2015;139(4):469-80. https://doi.org/10.5858/ arpa.2014-0128-RA 6. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-35. https://doi.org/10.1056/NEJMoa1504627 7. Souza MC, Cruz OG, Vasconcelos AG. Factors associated with disease-specific survival of patients with non-small cell lung cancer. J Bras Pneumol. 2016;42(5):317-325. https://doi.org/10.1590/S180637562015000000069 8. Terra RM, Kazantzis T, Pinto-Filho DR, Camargo SM, Martins-Neto F, GuimarĂŁes AN, et al. Anatomic pulmonary resection by videoassisted thoracoscopy: the Brazilian experience (VATS Brazil study). J Bras Pneumol. 2016;42(3):215-21. https://doi.org/10.1590/S180637562015000000337 9. Soder SA, Barth F, Perin FA, Felicetti JC, Camargo JJP, Camargo SM. Anatomic pulmonary resection via video-assisted thoracic surgery: analysis of 117 cases at a referral center in Brazil. J Bras Pneumol. 2017;43(2):129-133. https://doi.org/10.1590/s180637562015000000352 10. Terra RM, Araujo PH, Lauricella LL, Campos JR, Costa HF, PegoFernandes PM. Robotic pulmonary lobectomy for lung cancer

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treatment: program implementation and initial experience. J Bras Pneumol. 2016;42(3):185-90. https://doi.org/10.1590/S180637562015000000212 11. Figueiredo VR, Cardoso PF, Jacomelli M, Demarzo SE, Palomino AL, Rodrigues AJ, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for lung cancer staging: early experience in Brazil. J Bras Pneumol. 2015;41(1):23-30. https://doi.org/10.1590/S180637132015000100004 12. Steinhauser Motta JP, Kempa AT, Pinto Cardoso A, Paschoal ME, Raggio Luiz R, Lapa E Silva JR, et al. Endobronchial ultrasound in real life: primary diagnosis and mediastinal staging of lung cancer in patients submitted to thoracic surgery. BMC Pulm Med. 2016;16(1):101. https://doi.org/10.1186/s12890-016-0264-7 13. Jacomelli M, Demarzo SE, Cardoso PF, Palomino AL, Figueiredo VR. Radial-probe EBUS for the diagnosis of peripheral pulmonary lesions. J Bras Pneumol. 2016;42(4):248-253. https://doi.org/10.1590/s180637562015000000079 14. Fernandes CJ, Alves Junior JL, Gavilanes F, Prada LF, Morinaga LK, Souza R. New anticoagulants for the treatment of venous thromboembolism. J Bras Pneumol. 2016;42(2):146-54. https://doi. org/10.1590/S1806-37562016042020068 15. Franceschini JP, Jamnik S, Santoro IL. Survival in a cohort of patients with lung cancer: the role of age and gender in prognosis. J Bras Pneumol. 2017;43(6):xxx-xxx. https://doi.org/10.1016/j. jtho.2016.11.327 16. Tsukazan MTR, Vigo A, Silva VDD, Barrios CH, Rios JO, Pinto JAF. Lung cancer: changes in histology, gender, and age over the last 30 years in Brazil. J Bras Pneumol. 2017;43(5):363-367. https://doi. org/10.1590/s1806-37562016000000339 17. Richards TB, Henley SJ, Puckett MC, Weir HK, Huang B, Tucker TC, et al. Lung cancer survival in the United States by race and stage (2001-2009): Findings from the CONCORD-2 study. Cancer. 2017;123 Suppl 24:5079-5099. https://doi.org/10.1002/cncr.31029 18. Dalwadi SM, Szeja SS, Bernicker EH, Butler EB, Teh BS, Farach AM. Practice Patterns and Outcomes in Elderly Stage I Non-Smallcell Lung Cancer: A 2004 to 2012 SEER Analysis. Clin Lung Cancer. 2017. pii: S1525-7304(17)30316-9.

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EDITORIAL

Noninvasive positive airway pressure: from critically ill patients to physical exercise in outpatients Vinicius Zacarias Maldaner da Silva1, Alfredo Nicodemos Cruz Santana2 TO THE EDITOR: Noninvasive positive airway pressure (PAP) is frequently used in subjects treated in respiratory, emergency, and critical care medicine. Pulmonologists usually remember bilevel PAP (BiPAP) as an important therapeutic option in acute, severe COPD exacerbations (hypercapnic acidosis: pH ≤ 7.35 and PaCO2 > 45 mmHg). In this scenario, BiPAP reduces intubation rate and mortality.(1) Another life-threatening situation treated with continuous PAP (CPAP) is cardiogenic pulmonary edema, which also reduces the need for intubation and mortality.(1) The use of PAP also presents good results in outpatients. A common indication of home CPAP use is in obstructive sleep apnea patients, reducing daytime sleepiness and risk of traffic accident, as well as improving blood pressure control and quality of life. BiPAP also has a role in outpatients with amyotrophic lateral sclerosis or COPD. (2,3) In amyotrophic lateral sclerosis outpatients, home BiPAP is usually initiated when there are complaints of orthopnea, VC < 50% of the predicted value, or abnormal nocturnal oximetry.(2) In this clinical conundrum, BiPAP has a positive impact in quality of life and survival (median survival increase: ~200 days). Additionally, in stable severe COPD outpatients, home BiPAP decreases readmission and death rates within one year (absolute risk reduction = 17.0%). In this scenario, stable severe COPD outpatients are usually defined as those who had been previously hospitalized who had used BiPAP due to hypercapnic COPD exacerbation and maintained PaCO2 > 53 mmHg, as well as PaO2 < 55 mmHg (or PaCO2 > 53 mmHg; PaO2 < 60 mmHg; and oxygen saturation < 90% during > 30% of sleep time, or presented with polycythemia or pulmonary hypertension), 2-4 weeks after hospital discharge.(3) In the present issue of JBP, a group of authors evaluated the effect of CPAP use in the respiratory function of healthy women (18-40 years old) immersed in water at xiphoid process level.(4) First, it is necessary to emphasize that the immersion in water of the human body causes an increase in venous return, central venous pressure, and pulmonary capillary pressure, as well as a reduction in MIP, MAP, VC, and FEV1.(4) Consequently, this technique has been used as a model of cardiogenic pulmonary edema in the study.(4) Good results were obtained when the sample of

young healthy women immersed in water received CPAP at 10 cmH2O, reversing the restrictive lung pattern. (4) Therefore, the use of CPAP at that pressure might be beneficial to subjects performing rehabilitation/physical exercise with water immersion. In real life, such subjects generally have osteoarthritis, an aging-related condition. In turn, aging is associated with a higher prevalence of heart failure (HF)—classically manifested as pulmonary edema signs and symptoms. Consequently, CPAP has the potential to reverse reductions in FEV1 and FVC caused by water immersion in subjects with HF, potentially enabling these subjects to be submitted to the technique in a better way, especially if they have been classified as New York Heart Association functional class IV (not included in previous studies).(5) The abovementioned idea is based on the fact that PAP reduces respiratory muscle work and exercise-related dyspnea. This occurs due to intrathoracic pressure increase. Furthermore, with respiratory muscle unloading, oxygen supply and demand are balanced, benefiting HF patients during high intensity exercise.(6) In addition, a meta-analysis showed that PAP application before the six-minute walk test in HF patients increased the walking distance.(7) PAP also appears to improve the cardiac function in HF patients. During a regular cardiac rehabilitation program, acute cardiovascular adjustments occur to supply activated muscles adequately. Resistance exercise training increases ventilatory effort, making inspiratory pleural pressure higher and, consequently, increasing left ventricular (LV) transmural pressure gradient and LV afterload.(8) However, PAP attenuates pleural pressure variations during the effort, reducing LV afterload and improving the heart contractile performance. Another hemodynamic behavior change on PAP use is LV preload decrease (reduction in venous return and a reduction in LV filling). Consequently, LV performance in HF patients is improved.(6) In conclusion, the potential role of CPAP in rehabilitation/ physical exercise programs using water immersion in subjects with HF needs to be further investigated in future studies. We need to remember that, in the study by Rizzetti et al.,(4) subjects with cardiopulmonary disease or older than 40 years of age were excluded.

REFERENCES 1. Rochwerg B, Brochard L, Elliott MW, Hess D, Hill NS, Nava S, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017;50(2). pii: 1602426. https:// doi.org/10.1183/13993003.02426-2016

2. Nicolini A, Banfi P, Grecchi B, Lax A, Walterspacher S, Barlascini C, et al. Non-invasive ventilation in the treatment of sleep-related breathing disorders: A review and update. Rev Port Pneumol. 2014;20(6):324-35. https://doi.org/10.1016/j.rppneu.2014.03.009

1. Hospital de Base do Distrito Federal, Escola Superior de Ciências da Saúde –ESCS – Brasília (DF) Brasil. 2. Hospital Regional da Asa Norte, Escola Superior de Ciências da Saúde – ESCS – Brasília (DF) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

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3. Murphy PB, Rehal S, Arbane G, Bourke S, Calverley PMA, Crook AM, et al. Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation: A Randomized Clinical Trial. JAMA. 2017;317(21):2177-2186. https://doi.org/10.1001/jama.2017.4451 4. Rizzetti DA, Quadros JRB, Ribeiro BE, Callegaro L, Veppo AA, Wiggers GA, et al. Impact of continuous positive airway pressure on the pulmonary changes promoted by immersion in water. J Bras Pneumol. 2017;43(6):409-415. 5. Cider A, Sveälv BG, Täng MS, Schaufelberger M, Andersson B. Immersion in warm water induces improvement in cardiac function in patients with chronic heart failure. Eur J Heart Fail. 2006;8(3):30813. https://doi.org/10.1016/j.ejheart.2005.08.001

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6. da Silva VZ, Lima A, Cipriano GB, da Silva ML, Campos FV, Arena R, et al. Noninvasive ventilation improves the cardiovascular response and fatigability during resistance exercise in patients with heart failure. J Cardiopulm Rehabil Prev. 2013;33(6):378-84. https://doi. org/10.1097/HCR.0000000000000019 7. Bündchen DC, Gonzáles AI, Noronha MD, Brüggemann AK, Sties SW, Carvalho TD. Noninvasive ventilation and exercise tolerance in heart failure: A systematic review and meta-analysis. Braz J Phys Ther. 2014;18(5):385-94. https://doi.org/10.1590/bjpt-rbf.2014.0039 8. O’Donnell DE, D’Arsigny C, Raj S, Abdollah H, Webb KA. Ventilatory assistance improves exercise endurance in stable congestive heart failure. Am J Respir Crit Care Med. 1999;160(6):1804-11. https://doi. org/10.1164/ajrccm.160.6.9808134

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CONTINUING EDUCATION: IMAGING

Tree-in-bud pattern Edson Marchiori1, Bruno Hochhegger2, Gláucia Zanetti1

A 34-year-old female patient presented to the outpatient clinic with complaints of fever, cough, and weight loss (8 kg in the last 3 months). She had a history of having undergone resection of a uterine adenocarcinoma 2 years prior. A chest CT showed branching opacities, which characterize the tree-in-bud (TIB) pattern, in the middle lobe and the left lower lobe, as well as left lung volume reduction and consolidation with cavitation in the lingula (Figure 1). The TIB pattern represents centrilobular branching opacities, most pronounced in the lung periphery, resembling the budding of certain plants. Although, in most cases, the TIB pattern represents filling of bronchioles with mucus, pus, blood, or other materials, with or without dilatation, it may also be related to peribronchovascular connective tissue thickening or filling and dilatation of pulmonary arterioles. Although the TIB pattern is more commonly observed in bronchiolar infections (bronchopneumonia, infectious bronchiolitis, and endobronchial dissemination of tuberculosis), it has a broader differential diagnosis that includes bacterial infections, fungal infections (allergic bronchopulmonary aspergillosis), or viral infections; as well as bronchiectasis; idiopathic conditions (obliterative bronchiolitis and panbronchiolitis) or congenital conditions (cystic fibrosis); aspiration or inhalation of foreign material; and peripheral pulmonary vascular disease, especially due to endovascular metastatic spread of certain tumors.

In our patient, the main differential diagnosis was between pulmonary tuberculosis and endovascular metastatic spread of the previously resected uterine tumor (neoplastic embolism). Pulmonary tumor embolism is the occlusion of pulmonary arteries and arterioles by spreading neoplastic cells. It occurs more frequently in patients with lung, gastrointestinal, liver, breast, or uterine cancer. The possibility of tumor embolism should be considered when a patient with known malignancy develops dyspnea. A suggestive CT finding of neoplastic embolism is dilatation of the affected vessels due to growth of the tumor emboli, a finding that was not observed in our patient. In tuberculosis, the finding of a TIB pattern is a strong indication of disease activity, as well as of the presence of cavitation. A concomitant finding of adjacent bronchial wall thickening is also a strong indication of bronchial inflammation, suggesting an infectious process. In our patient, sputum smear microscopy was positive for AFB, and culture revealed Mycobacterium tuberculosis. The final diagnosis was pulmonary tuberculosis. Radiologists and pulmonologists need to be aware of the broad range of etiologies for the TIB pattern in order to properly guide further investigation. A combination of patient history, clinical and laboratory findings, and associated CT findings is usually sufficient to reach a final diagnosis.

Figure 1. In A, axial CT scan of the chest with lung window settings at the level of the subcarinal region, showing left lung volume reduction and consolidation with cavitation in the lingula. Note also centrilobular branching opacities (tree-in-bud pattern) in the middle lobe and the left lower lobe. In B, image enhancement (maximum intensity projection) demonstrating the tree-in-bud pattern.

RECOMMENDED READING 1. Fraser RS, Müller NL, Colman NC, Pare PD, editors. Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: WB Saunders Company; 1999. 1. Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 2. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre (RS) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

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Understanding diagnostic tests. Part 2. Cecilia Maria Patino1,2, Juliana Carvalho Ferreira1,3

PRACTICAL SCENARIO Investigators studied the diagnostic accuracy of serum procalcitonin levels in diagnosing parapneumonic pleural effusions (PPE) and differentiating it from other causes of pleural effusions. They found that procalcitonin had a positive predictive value (PPV) of 66% and a negative predictive value (NPV) of 91%.(1) PPV AND NPV OF DIAGNOSTIC TESTS In the previous article(2) we discussed two common features of diagnostics tests, sensitivity and specificity, which are important characteristics that describe the accuracy of a test. In this article, we focus on important features of a diagnostic test that help us understand how well a new test diagnoses a disease based on the results of the gold standard: PPV and NPV. The PPV of a diagnostic test is the proportion of individuals who test positive to the new test and have the disease according to the gold standard (the proportion of true positives). When a diagnostic test has a high PPV, there is a high probability that a patient has the disease being investigated when the patient has a positive test. The NPV of a diagnostic test is the proportion of individuals who test negative to the new test and do not have the disease according to the gold standard (the proportion of true negatives). When a test has a high NPV, there is a high probability that a patient does not have the disease being investigated when the patient has a negative test. In our example, the PPV was 66% (39/59), and the NPV was 91% (81/89), according to the results of the new test among 148 individuals (Table 1). The PPV and the NPV of a new test depend on the prevalence of the disease in the population; thus, their results will change across populations with higher or lower prevalence of the disease when compared with

Table 1. Diagnostic performance of serum procalcitonin testing for identifying parapneumonic pleural effusion.

PCT+ PCTTotal

PPE + a = 39 c=8 47

Total b = 20 d = 81 101

59 89 148

Data obtained from He et al.(1) PCT: procalcitonin; PPE: parapneumonic pleural effusion. Sensitivity = a/(a + c); specificity = b/(b + d); Positive predictive value (light gray row) = a/(a+b); and negative predictive value (dark gray row) = d/(d+c).

the population where the test is first reported. If the prevalence of the disease is high in a given population, PPV increases and NPV decreases. Thus, the results of predictive values are not fixed characteristics of the test and cannot be generalized across populations with different prevalences of the disease.(3) There is an easy way to calculate PPV and NPV, based on Bayes’ theorem, using previously reported results and taking into account the local disease prevalence.(2) PPV and NPV are also important indicators when screening the general population. A screening test with high sensitivity and specificity may still have low PPV if the prevalence of the disease is low in that population. For example, when screening for cancer in asymptomatic adults, if the NPV of the test is high, negative results are helpful to rule out the presence of the disease; however, if the PPV is low, a positive result has a higher probability of being a false positive. PPV and NPV are more useful than sensitivity and specificity for clinicians because they estimate the probability of the disease (or its absence), given the test result. In the next, final part of this series about diagnostic tests, we will discuss likelihood ratios and ROC curves.

REFERENCES 1. He C, Wang B, Li D, Xu H, Shen Y. Performance of procalcitonin in diagnosing parapneumonic pleural effusions: A clinical study and meta-analysis. Medicine (Baltimore). 2017;96(33):e7829. https://doi. org/10.1097/MD.0000000000007829 2. Ferreira JC, Patino CM. Understanding diagnostic tests. Part 1.

J Bras Pneumol. 2017;43(5):330. https://doi.org/10.1590/S180637562017000000330 3. Altman DG, Bland M. Diagnostic tests. 2: predictive values. BMJ. 1994;309(6947):102. https://doi.org/10.1136/bmj.309.6947.102

1. Methods in Epidemiologic, Clinical, and Operations Research–MECOR–program, American Thoracic Society/Asociación Latinoamericana del Tórax, Montevideo, Uruguay. 2. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (CA) USA. 3. Divisão de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

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ORIGINAL ARTICLE

Impact of continuous positive airway pressure on the pulmonary changes promoted by immersion in water Danize Aparecida Rizzetti1, Janayna Rodembuch Borba Quadros1, Bruna Esmerio Ribeiro1, Letícia Callegaro1, Aline Arebalo Veppo2, Giulia Alessandra Wiggers1, Franck Maciel Peçanha1 1. Curso de Fisioterapia, Universidade Federal do Pampa – UNIPAMPA – Uruguaiana (RS) Brasil. 2. Residência Multiprofissional em Saúde, Universidade Federal do Pampa – UNIPAMPA – Uruguaiana (RS) Brasil. Submitted: 24 March 2017. Accepted: 15 October 2017 Study conducted under the auspices of the Curso de Fisioterapia, Universidade Federal do Pampa – UNIPAMPA – Uruguaiana (RS) Brasil.

ABSTRACT Objective: To determine whether different levels of CPAP improve the lung volumes and capacities of healthy subjects immersed in water. Methods: This was a randomized clinical trial, conducted between April and June of 2016, involving healthy female volunteers who were using oral contraceptives. Three 20-min immersion protocols were applied: control (no CPAP); CPAP5 (CPAP at 5 cmH2O); and CPAP10 (CPAP at 10 cmH2O). We evaluated HR, SpO2, FVC, FEV1, the FEV1/FVC ratio, peak expiratory flow rate (PEFR), and FEF25-75%) at three time points: pre-immersion; 10 min after immersion; and 10 min after the end of each protocol. Results: We evaluated 13 healthy volunteers. The CPAP10 protocol reversed the restrictive pattern of lung function induced by immersion in water, maintaining pulmonary volumes and capacities for a longer period than did the CPAP5 protocol. Conclusions: When the hemodynamic change causing a persistent lung disorder, only the application of higher positive pressures is effective in maintaining long-term improvements in the pulmonary profile. Keywords: Physical therapy modalities; Noninvasive ventilation; Continuous positive airway pressure.

INTRODUCTION Immersion in water results in physiological alterations to various systems, including the musculoskeletal, renal, respiratory, and cardiovascular systems.(1) The hydrostatic pressure compresses the thoracic cavity, reducing its circumference, which promotes cranial displacement of the diaphragm.(2) In healthy individuals, the cardiovascular effects, which include increases in venous return, blood volume, and central venous pressure, result in increased cardiac output, greater left atrial diameter, and higher cardiac volume.(3-5) Cardiorespiratory changes induced by immersion in water reduce the end-expiratory volume and the length-tension ratio of the respiratory muscles, decreasing their capacity to generate and maintain adequate force, thus reducing MIP and MEP.(2) Such changes also increase pulmonary capillary pressure, which worsens lung function, reducing VC, FEV1, and functional residual capacity, thereby leading to the development of a restrictive pattern of lung function. (2,3,6) In fact, in clinical practice, many cardiopulmonary diseases induce a restrictive pattern as a consequence of pulmonary congestion, via mechanisms similar to those promoted by immersion in water. The therapeutic arsenal used by physiotherapists in the treatment of pulmonary congestion and its respiratory complications includes respiratory exercises, incentive spirometry, and noninvasive positive-pressure ventilation

(NPPV).(7,8) In a study involving the induction of restrictive pulmonary characteristics by immersion in water, Vepo et al.(9) found that neither respiratory exercises nor incentive spirometry were effective in normalizing lung function during the immersion. Applying NPPV in the continuous positive airway pressure (CPAP) mode has been shown to improve the hemodynamic status of patients with pulmonary congestion due to heart failure, reducing cardiac preload and afterload, thus increasing lung compliance and lung volumes, as well as reducing the work of breathing.(10) Other studies have shown that, in patients with heart disease, NPPV reduces venous return, pulmonary capillary pressure, and central venous pressure, consequently normalizing pulmonary function.(11,12) Some therapeutic approaches do not reverse the restrictive pattern of lung function during the maintenance of hemodynamic changes in this model of pulmonary congestion induced by immersion in water, and there is evidence that NPPV, in CPAP mode, constitutes an important therapeutic tool for the treatment of this condition. It is therefore imperative to investigate the effects that NPPV has on the hemodynamic changes that induce the restrictive pattern characteristic of pulmonary congestion. Therefore, the objective of this study was to determine whether the use of NPPV in CPAP mode at various pressures improves lung volumes and capacities in healthy subjects immersed in water.

Correspondence to:

Danize Aparecida Rizzetti. BR-472, km 592, Caixa Postal 118, CEP 97500-970, Uruguaiana, RS, Brasil. Tel.: 55 55 3413-4321. E-mail: danize.rizzetti@gmail.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

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METHODS

Study design and subject selection This was a randomized clinical trial, conducted between April and June of 2016 at a federal university in the Brazilian state of Rio Grande do Sul. All procedures were performed in accordance with Brazilian National Health Council Resolution no. 466/12, and the study was approved by the research ethics committee of the institution (CAEE no. 56861216.7.0000.5323). All participating subjects gave written informed consent. The sample, determined by sample size calculation for the analysis of quantitative variables of a proportion of a population of infinite size, considering a 95% confidence level, a 5% maximum error of estimation, and an estimated prevalence of 50%, was composed of volunteers who met the following criteria: being healthy; being female; being between 18 and 40 years of age; using oral contraceptives during the study period (to ensure homogeneity of the sample, considering that the use of oral contraceptives stabilizes the levels of female sex hormones, thus avoiding possible changes in lung function due to hormonal fluctuations occurring during the various phases of the menstrual cycle); and having given written informed consent. We excluded subjects who, for any reason, did not participate in all stages of the study; subjects who were unable to perform the maneuvers involved in the assessment and the NPPV; subjects who showed some alteration during spirometry; subjects who presented cardiovascular, respiratory, neurological, or musculoskeletal diseases; subjects who were on medication (except oral contraceptives); and subjects who were smokers or former smokers.

Data collection The volunteers were submitted to anamnesis (regarding general health status, associated diseases, and medication use) and physical examination (to determine weight, height, and body mass index), performed by a single evaluator according to the standardized criteria established by the International Society for the Advancement of Kinanthropometry. (13) The subjects also underwent cardiopulmonary evaluation, in which HR, SpO2, systolic blood pressure, and diastolic blood pressure were determined in accordance with the recommendations made in the Fourth Brazilian Guidelines for the Management of Hypertension.(14) We analyzed pulmonary function by spirometry (Koko Legend®; nSpire Health Inc., Hertford, UK), in accordance with the criteria established by the American Thoracic Society/European Respiratory Society(15) and the Brazilian Thoracic Association,(16) using the predicted values for FVC, FEV1, and the FEV1/ FVC ratio, as well as for the peak expiratory flow rate (PEFR) and FEF25-75%, determined by Pereira et al.(17) We measured slow vital capacity with a respirometer (Wright Mark 8; Ferraris Respiratory, Louisville, CO, USA). We also measured MIP and MEP, using a manometer (MV 120; Comercial Médica, São Paulo, 410

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Brazil), as described by Neder et al.(18) These evaluations were performed while the subjects were seated, as recommended in the Brazilian Thoracic Association guidelines.(16)

Intervention protocols Each volunteer was immersed in water up to the level of the xiphoid process, after which NPPV, in CPAP mode (BiPAP®; Respironics, Murrysville, PA, USA), was applied via face mask. In this immersion model, the reduction in pulmonary function is mainly due to cardiovascular alterations, which, in healthy individuals, simulate a restrictive pattern of lung function, as is typically observed in certain cardiorespiratory complications, such as pulmonary congestion.(9) Vepo et al.(9) employed this model and reported that, by 10 min after immersion in water, subjects showed reductions in FVC and FEV1 induced by hemodynamic changes, including increased blood volume and higher central venous pressure. All subjects participated in three NPPV immersion protocols, with an interval of at least 24 h between each application, in a sequence defined by block randomization, as shown in Figure 1. The protocols lasted for 20 min each and were given the following designations: control—during spontaneous breathing, at rest and without ventilatory support; CPAP5—CPAP of 5 cmH2O, according to Reis et al.(19); and CPAP10—CPAP of 10 cmH2O, according to Bellone et al.(20) During the application of each protocol, the variables FC, SpO2, FVC, FEV1, FEV1/FVC ratio, PEFR, and FEF25-75% were evaluated at the following time points (Figure 1): before immersion in water (pre-immersion); at 10 min after immersion in water; and at 10 min after the end of the protocol (i.e., 40 min after the initiation of the protocol).

Statistical analysis The results are expressed as means and standard deviations. The Shapiro-Wilk test was used in order to determine the distribution of the data, which was found to be normal for all of the variables analyzed. The data were analyzed by one-way repeated-measures ANOVA and Fisher’s post-hoc test, as appropriate. Values of p < 0.05 were considered significant. The program GraphPad Prism, version 6.01 (GraphPad Inc., San Diego, CA, USA) was used for the statistical analyses and for the creation of the graphics. RESULTS Of the 15 volunteers evaluated, 2 were excluded: for presenting with spirometric changes at the initial evaluation (n = 1); and for not participating in all of the stages of data collection (n = 1). The final sample therefore comprised 13 volunteers, with a mean age of 23.6 ± 5.5 years. As can be seen in Table 1, the anthropometric characteristics of the volunteers were within the limits of normality for age and gender, as were the cardiovascular and respiratory parameters evaluated before the application of the protocols.

Rizzetti DA, Quadros JRB, Ribeiro BE, Callegaro L, Veppo AA, Wiggers GA, Peçanha FM

SUBJECT SELECTION

STAGE I PRE-IMMERSION EVALUATION (n = 15) 1 SUBJECT EXCLUDED STAGE II IMMERSION PROTOCOLS (n = 14) 1 SUBJECT EXCLUDED

CONTROL (NO NPPV) (n = 13)

PRE-IMMERSION

CPAP5 (NPPV FOR 20 MIN) (n = 13)

10 MIN AFTER IMMERSION

AT REST IN IMMERSION

CPAP10 (NPPV FOR 20 MIN) (n = 13)

POST-PROTOCOL

20-MIN PROTOCOL IN IMMERSION

10 MIN AFTER PROTOCOL

AT REST IN IMMERSION

CONTROL/CPAP5/CPAP10 PI

I10’

HR SpO2 FVC FEV1 FEV1/FVC PEFR FEF25-75%

I30’

I40’ HR SpO2 FVC FEV1 FEV1/FVC PEFR FEF25-75%

Figure 1. Study design and outline of the application of non-invasive positive pressure ventilation protocols (VNIPP). CPAP: continuous positive airway pressure; and PEFR: peak expiratory flow rate.

At 10 min after immersion in water, all of the subjects showed reductions in FVC and FEV1, suggesting a restrictive alteration to the pulmonary pattern, as previously observed by Vepo et al.(9) Those reductions persisted at 10 min after the end of the control protocol and at 10 min after the end of the CPAP5 protocol. However, the pulmonary changes induced by immersion were normalized after application of the CPAP10 protocol (Figure 2). The FEV1/FVC ratio also showed a reduction at 10 min after immersion, in all subjects and in all three protocols. In accordance with the reductions in FVC and FEV1, the reduction in the FEV1/FVC ratio persisted at 10 min after the application of the control and CPAP5 protocols, as well as being reversed after the application of the CPAP10 protocol (Figure 3). The

PEFR and FEF25-75% values were also decreased at 10 min after immersion in water. At 10 min after the end of the CPAP5 and CPAP10 protocols, the PEFR values were normalized, although neither protocol was able to normalize the FEF25-75% values (Table 2). In the cardiorespiratory evaluation, a reduction in HR was observed at 10 min after immersion in water, and that reduction persisted at all of the evaluation time points, for all of the protocols. However, no changes were observed for SpO2, which remained at basal values after immersion and at all other evaluation time points, for all of the protocols (Table 2). DISCUSSION In the present study, we demonstrated that the application of CPAP at 10 cmH2O can restore the J Bras Pneumol. 2017;43(6):409-415

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Table 1. Initial physical, respiratory and cardiovascular evaluation of the subjects evaluated (n = 13).a

Parameter Value Age, years 23.6 ± 5.5 Height, m 1.60 ± 0.02 Weight, kg 63.7 ± 11.6 23.6 ± 3.5 BMI, kg/m2 HR, bpm 76.2 ± 6.4 SBP, mmHg 120.5 ± 8.6 DBP, mmHg 71.9 ± 7.7 98.4 ± 0.8 SpO2, % 98.5 ± 26.3 MIP, cmH2O 103.1 ± 26.5 MEP, cmH2O SVC, L 3.3 ± 0.3 SVC, % of predicted 82.2 ± 3.0 FVC, L 3.9 ± 0.6 FVC, % of predicted 98.9 ± 11.4 3.5 ± 0.5 FEV1, l 99.9 ± 10.7 FEV1, % of predicted 0.9 ± 0.1 FEV1/FVC 98.0 ± 7.0 FEV1/FVC, % PEFR, L/min 8.4 ± 1.7 PEFR, % of predicted 106.2 ± 16.3 4.4 ± 1.1 FEF25-75%, L/min 95.2 ± 19.9 FEF25-75%, % of predicted BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; SVC: slow vital capacity; PEFR: peak expiratory flow rate. aValues expressed as mean ± SD. restrictive pattern of lung function induced by immersion in water in healthy individuals, maintaining pulmonary volumes and capacities at normal levels for a longer period when compared with CPAP at 5 cmH2O. To our knowledge, this is the first study suggesting that, in situations in which a hemodynamic change that causes a restrictive pattern of lung function persists, the application of higher positive pressures is an effective means of maintaining improvements in the pulmonary profile. Hemodynamic changes during immersion in water occur in part by hemodilution due to the transfer of fluid—from the interstitial spaces to the intravascular spaces—within the lower limbs.(5,21) In the respiratory system, those changes promote reductions in pulmonary volumes and capacities, characteristic of a restrictive pattern.(22) In clinical practice, pulmonary complications due to cardiovascular changes lead to a restrictive pulmonary pattern, mainly due to the increase in intrathoracic blood volume. In patients with heart disease, pulmonary congestion, which is characterized by elevated pulmonary and systemic venous pressures, is usually related to ventricular dysfunction and a reduction in cardiac output.(23,24) Left untreated, pulmonary congestion can progress to pulmonary edema, which constitutes a medical emergency.(23-25) The model of a restrictive pattern of lung function used in the present study, as previously described by 412

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Vepo et al.,(9) uses immersion in water to promote increased central blood volume in healthy subjects and, consequently, hemodynamic changes similar to those developed in patients with pulmonary congestion. Thus, this model allows the analysis and clarification of the effects of CPAP exclusively on changes in lung volumes and capacities promoted by isolated hemodynamic factors, avoiding the risk that associated diseases will influence the findings. After applying CPAP to subjects immersed in water, we found that only the use of a CPAP level of 10 cmH2O provided sustained improvements in lung volumes and capacities. This suggests that when the hemodynamic changes that contribute to congestive pulmonary disease are not controlled, higher positive pressures are required in order to maintain improvements in lung function. Likewise, Vepo et al.(9) observed no improvements in lung volumes and capacities when respiratory exercises and incentive spirometry were applied in subjects immersed in water, suggesting that these techniques do not provide the expected benefits when the primary hemodynamic change is not controlled or reversed. Although pharmacotherapy, with diuretics and vasodilators, is an essential tool in combating fluid retention and relieving the respiratory symptoms of pulmonary congestion,(24,26,27) the use of pharmacotherapy in combination with positive pressure has become increasingly more widespread as a means of normalizing the hemodynamic status of patients with pulmonary congestion and of preventing its recurrence. Therefore, CPAP is a mode of ventilation applied in a wide spectrum of clinical situations(28) and is often indicated for patients in critical condition, such as those with acute cardiogenic pulmonary edema (ACPE). In such cases, the Brazilian Guidelines on Mechanical Ventilation(28) recommend the use of CPAP at 5-10 cmH2O, which justifies the choice of pressures employed in the present study. The pulmonary benefits derived from CPAP are due, in large part, to the elevation of intrathoracic pressure and consequent reduction of left ventricular afterload promoted by the pressurization of the airways. That pressurization consequently increases cardiac output, promoting improvements in lung volumes and capacities, thus reducing respiratory distress.(11,12) The hemodynamic effects of CPAP have been fully elucidated for the population of patients with pulmonary hypertension due to left ventricular dysfunction. However, our study demonstrated that, when the cause of the hemodynamic imbalance persists, the improvement in pulmonary function is maintained only when higher CPAP is applied to the airways, regardless of the pulmonary improvements observed immediately after application of the technique. Although numerous studies have involved the application of CPAP for the treatment of cardiogenic pulmonary edema, using the same range of positive pressures employed in the present study, those studies have varied in terms of the effects that such pressures

Rizzetti DA, Quadros JRB, Ribeiro BE, Callegaro L, Veppo AA, Wiggers GA, Peçanha FM

B Control *

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I10’ I40’ Time point CPAP5

2 1

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CPAP10

FEV1 (L)

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Figure 2. FVC and FEV1 in the control protocol (in A and D, respectively), the CPAP5 (5 cmH2O) protocol (in B and E, respectively), and the CPAP10 (10 cmH2O) protocol (in C and F, respectively), at the time points evaluated (data expressed as mean ± SD). CPAP: continuous positive airway pressure; PI: pre-immersion; I10’: 10 min after immersion; I40’: 10 min after the end of the (20-min) protocol. *p < 0.05 vs. PI (one-way repeated-measures ANOVA and Fisher’s post-hoc test).

FEV1/FVC ratio

0.8

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0.8 0.6 0.4 0.2 0.0

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Figure 3. FEV1/FVC ratio in the control protocol (in A), the CPAP5 (5 cmH2O) protocol (in B), and the CPAP10 (10 cmH2O) protocol (in C), at the time points evaluated (data expressed as mean ± SD). CPAP: continuous positive airway pressure; PI: pre-immersion; I10’: 10 min after immersion; I40’: 10 min after the end of the (20-min) protocol. *p < 0.05 vs. PI (one-way repeated-measures ANOVA and Fisher’s post-hoc test). Table 2. Cardiovascular and respiratory parameters evaluated in the immersion protocols.a

Parameter HR, bpm SpO2, % PEFR, L/min FEF25-75%, L/min

Control CPAP5 PI I10’ I40’ PI I10’ I40’ PI 93.5 ± 78.8 ± 79.8 ± 101.3 ± 84.2 ± 80.4 ± 98.5 ± 15.1 11.2* 10.5* 13.9 10.4* 13.5* 14.4 98.8 ± 1.0 98.5 ± 1.1 98.8 ± 0.9 98.3 ± 0.6 98.6 ± 0.9 98.8 ± 0.7 98.5 ± 1.7 7.06 ± 1.3 7.0 ± 1.3* 6.9 ± 1.2 7.5 ± 1.1 7.2 ± 1.2* 7.3 ± 1.1 7.1 ± 1.0 4.1 ± 0.7 3.9 ± 0.8* 3.8 ± 0.7* 4.3 ± 0.7 3.9 ± 0.6* 3.8 ± 0.6* 3.9 ± 0.8

CPAP10 I10’ I40’ 82.2 ± 78.4 ± 8.7* 12.1* 98.5 ± 1.2 98.3 ± 1.9 6.6 ± 1.3* 6.9 ± 1.2 3.9 ± 0.8 3.8 ± 0.7

CPAP5: CPAP of 5 cmH2O; CPAP10: CPAP of 10 cmH2O; PI: pre-immersion; I10’: 10 min after immersion; I40’: 10 min after the end of the (20-min) protocol; and PEFR: peak expiratory flow rate. aValues expressed as mean ± SD. *p < 0.05 vs. PI (one-way repeated-measures ANOVA and Fisher’s post-hoc test).

were found to have on mortality, ICU admission, and length of hospital stay, as well as in terms of the reported advantages of CPAP over conventional therapy.(20,29,30) It is known that CPAP increases survival and precludes the need for endotracheal intubation in patients with

ACPE. (29-31) However, in a randomized controlled study involving patients with ACPE, no differences were found between the patients receiving conventional oxygen therapy and those receiving CPAP in terms of the short- or long-term mortality rates.(32) The J Bras Pneumol. 2017;43(6):409-415

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divergences across studies are probably attributable to differences among the patient samples in terms of the associated clinical factors and the pharmacological interventions administered in combination with the CPAP. Both situations prevent the isolated analysis of the effects of CPAP on respiratory changes resulting from hemodynamic disturbances. The reductions we observed in the other spirometric parameters, such as FEF25-75% and PEFR, after immersion in water, were also reported by Vepo et al.(9) Those authors reported that FEF25-75% is directly dependent on the FVC values, its reduction therefore being expected during immersion. In addition, this parameter is known to be related to the distal airway permeability,(33) and it is reduced in proportion with the increase in intrathoracic blood volume and pulmonary capillary pressure observed in this model. Regarding the cardiorespiratory parameters investigated, we demonstrated a reduction in HR in all of the protocols applied, which corroborates the findings of Kaneko et al.,(34) who employed a combination of CPAP and drug therapy in patients with ACPE. However, in our study, we were unable to associate that change with the application of positive airway pressure, because the same HR behavior was also observed in the control protocol. It has been suggested that the change observed results exclusively from immersion

in water.(35,36) The application of CPAP at 10 cmH2O has been shown to be superior to the conventional treatment for improving hypoxemia in patients with ACPE.(37) However, our study did not find significant differences between the CPAP protocols or the time points evaluated in terms of the SpO2, which could be related to the fact that our subjects were healthy and presented with normal SpO2 values. It should be noted that our subjects reported fatigue after the application of the CPAP10 protocol, which might be attributable to the fact that they had normal pulmonary function and therefore had a lower tolerance to higher positive airway pressures. That might have limited the performance of the study participants during the spirometric evaluation performed immediately after the application of CPAP. In summary, the findings of the present study suggest that the use of higher CPAP pressures is effective in maintaining improvements in lung volumes and capacities in situations in which the hemodynamic change causing the restrictive lung pattern persists. Our findings underscore the importance of adequately controlling the primary hemodynamic cause of pulmonary congestion, so that the combination of physiotherapeutic techniques and clinical practice will provide the maximum possible improvement of the respiratory changes present in this condition, for a longer period of time.

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21. Larsen AS, Johansen LB, Stadeager CJ, Warberg NJ, Christensen NJ, Norsk P. Volume-homeostatic mechanisms in humans during graded water immersion. J Appl Physiol (1985). 1994;77(6):2832-9. 22. Hsia CC. Cardiopulmonary limitations to exercise in restrictive lung disease. Med Sci Sports Exerc. 1999;31(1 Suppl):S28-32. https://doi. org/10.1097/00005768-199901001-00005 23. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart failure syndromes: an essential target of evaluation and treatment. The Am J Med. 2006;119(12 Suppl 1):S3-S10. https://doi. org/10.1016/j.amjmed.2006.09.011 24. Felker GM, Mentz RJ. Diuretics and ultrafiltration in acute decompensated heart failure. J Am Coll Cardiol. 2012;59(24):214553. https://doi.org/10.1016/j.jacc.2011.10.910 25. Bitter T, Fox H, Schmalgemeier H, Wellmann B, Zwenke A, Spiesshöfer J, et al. Acute improvement of pulmonary hemodynamics does not alleviate Cheyne-Stokes respiration in chronic heart failure-a randomized, controlled, double-blind, crossover trial. Sleep Breath. 2016; 20(2):795-804. https://doi.org/10.1007/s11325-015-1300-1 26. Vazir A, Cowie MR. Decongestion: Diuretics and other therapies for hospitalized heart failure. Indian Heart J. 2016; 68 Suppl 1:S61-8. https://doi.org/10.1016/j.ihj.2015.10.386 27. Klein L. Treating hemodynamic congestion is the key to prevent heart failure hospitalizations. JACC Heart Fail. 2016;4(5):345-7. https://doi. org/10.1016/j.jchf.2016.03.004 28. Barbas CS, Isola AM, Farias AM, Cavalcanti AB, Gama AM, Duarte AC, et al. Brazilian recommendations of mechanical ventilation 2013. Part I. Rev Bras Ter Intensiva. 2014;26(2):89-121. https://doi. org/10.5935/0103-507X.20140017 29. Masip J, Betbesé AJ, Páez J, Vecilla F, Cañizares R, Padró J, et al. Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: a randomised trial. Lancet. 2000;356(9248):2126-32. https://doi. org/10.1016/S0140-6736(00)03492-9 30. Crane SD, Elliott MW, Gilligan P, Richards K, Gray AJ. Randomised controlled comparison of continuous positive airways pressure,

bilevel non-invasive ventilation, and standard treatment in emergency department patients with acute cardiogenic pulmonary oedema. Emerg Med J. 2004;21(2):155-61. https://doi.org/10.1136/ emj.2003.005413 31. Peter JV, Moran JL, Phillips-Hughes J, Graham P, Bersten AD. Effect of non-invasive positive pressure ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-analysis. Lancet. 2006;367(9517):1155-63. https://doi.org/10.1016/S01406736(06)68506-1 32. Liesching T, Nelson DL, Cormier KL, Sucov A, Short K, Warburton R, et al. Randomized trial of bilevel versus continuous positive airway pressure for acute pulmonary edema. J Emerg Med. 2014; 46(1):130-40. https://doi.org/10.1016/j.jemermed.2013.08.015 33. Dompeling E, van Schayck CP, Molema J, Akkermans R, Folgering H, van Grunsven PM, et al. A comparison of six different ways of expressing the bronchodilating response in asthma and COPD; reproducibility and dependence of prebronchodilator FEV1. Eur Respir J. 1992;5(8):975-81. 34. Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med. 2003; 348(13):1233-41. https://doi.org/10.1056/NEJMoa022479 35. Srámek P, Simecková M, Janský L, Savlíková J, Vybíral S. Human physiological responses to immersion into water of different temperatures. Eur J Appl Physiol. 2000;81(5):436-42. https://doi. org/10.1007/s004210050065 36. de Oliveira Ottone V, de Castro Magalhães F, de Paula F, Avelar NC, Aguiar PF, da Matta Sampaio PF, et al. The effect of different water immersion temperatures on post-exercise parasympathetic reactivation. PLoS One. 2014;9(12):e113730. https://doi.org/10.1371/ journal.pone.0113730 37. Rasanen J, Heikkilä J, Downs J, Nikki P, Väisänen I, Viitanen A. Continuous positive airway pressure by face mask in acute cardiogenic pulmonary edema. Am J Cardiol. 1985;55(4):296-300. https://doi.org/10.1016/0002-9149(85)90364-9

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J Bras Pneumol. 2017;43(5):416-423 http://dx.doi.org/10.1590/S1806-37562016000000211

ORIGINAL ARTICLE

Tuberculosis infection among primary health care workers Thamy Carvalho Lacerda1,2,3, Fernanda Mattos de Souza1, Thiago Nascimento do Prado1,2,4,5, Rodrigo Leite Locatelli1,2, Geisa Fregona1,3, Rita de Cássia Duarte Lima2,5, Ethel Leonor Maciel1,2,5 1. Laboratório de Epidemiologia, Universidade Federal do Espírito Santo, Vitória (ES) Brasil. 2. Programa de Pós-Graduação em Saúde Coletiva, Universidade Federal do Espírito Santo, Vitória (ES) Brasil. 3. Hospital Universitário Cassiano Antonio de Moraes – HUCAM − Universidade Federal do Espírito Santo, Vitória (ES) Brasil. 4. Programa de Pós-Graduação em Enfermagem, Universidade Federal do Espírito Santo, Vitória (ES) Brasil. 5. Departamento de Enfermagem, Universidade Federal do Espírito Santo, Vitória (ES) Brasil. Submitted: 16 July 2016. Accepted: 4 May 2017. Study carried out at the Universidade Federal do Espírito Santo, Vitória (ES) Brasil.

ABSTRACT Objective: To estimate the prevalence of and determine the risk factors associated with latent Mycobacterium tuberculosis infection (LTBI) among primary health care workers in the city of Vitória, Brazil. Methods: This was a cross-sectional study with data collected through a survey regarding socio-demographic, occupational, clinical, and exposure characteristics, as well as knowledge about tuberculosis, conducted between 2011 and 2012. All participants underwent a tuberculin skin test (TST), and TSTs were read at 72 h by a trained professional. Results: A total of 218 primary health care workers participated in the study. The prevalence of TST positivity at the ≥ 10-mm and ≥ 5-mm cut-off points was, respectively, 39.4% (95% CI: 32.9-45.9) and 54.1% (95% CI: 47.4-60.7). Regarding occupational categories, community health agents had the highest proportion of TST positivity, regardless of the cut-off point (≥ 10 mm: 47.5%; and ≥ 5 mm: 60.5%). Regarding factors associated with TST results, “having had a previous TST” showed a statistically significant association with TST positivity at the ≥ 10-mm and ≥ 5-mm cut-off points (OR = 2.5 [95% CI: 1.17-5.30] and OR = 2.18 [95% CI: 1.23-3.87], respectively). Conclusions: The prevalence of LTBI was found to be high among the primary health care workers in this sample. Therefore, we recommend the establishment of a periodic screening program for LTBI and implementation of effective biosafety policies for the prevention of this infection among primary health care workers. Keywords: Health personnel; Tuberculin test; Latent tuberculosis; Primary health care.

INTRODUCTION The principles and guidelines of the Brazilian Unified Health Care System, which have been developed with the purpose of organizing this system and the health care facilities, have decentralization as one of their cornerstones. From this perspective, primary health care, because of its dynamism and capillarity, is the preferred gateway and center of communication between the users and the public health care network. The Family Health Program (FHP) strategy is the model of care that guides and reorganizes this scope of care regarding different adverse health events and health care needs, including public policies aimed at a serious and complex public health problem: tuberculosis.(1,2) Despite being one of the leading causes of morbidity and mortality in the world,(3) tuberculosis continues to be a neglected issue in low- and middle-income countries and a major public health problem.(4) Among tuberculosis risk groups are health care workers, this group being one of the most vulnerable, as has been demonstrated in some studies.(5-7) Tuberculosis risk has been associated with duration of occupational exposure to patients with tuberculosis, delay in diagnosis and in laboratory confirmation of tuberculosis, occupational

category, and activities in certain settings, as well as with a lack of administrative, environmental control, and personal protective measures.(5) In 2004, the Brazilian National Ministry of Health emphasized the integration of the activities of the Brazilian National TCP into all facilities within the Brazilian Unified Health Care System. Following the TCP guidelines in relation to “longitudinality” in the fight against tuberculosis,(8) control measures were decentralized and redirected to primary care, which, in this case, would be the responsibility of the FHP strategy and the Community Health Agent Program. For this reason, it has been hypothesized that, although studies have been conducted that confirmed a greater chance of infection in the hospital setting,(5,9-12) health care workers who work in primary care and act as a gateway to services for patients with suspected tuberculosis and those diagnosed with tuberculosis would also have a greater likelihood of infection, as has been demonstrated in other studies.(13-15) Therefore, the present study was designed with the objective of estimating the prevalence of and analysing the risk factors associated with latent Mycobacterium tuberculosis infection (LTBI) among primary health care workers in the city of Vitória, Brazil.

Correspondence to:

Ethel Leonor Noia Maciel. Laboratório de Epidemiologia, Universidade Federal do Espírito Santo, Avenida Marechal Campos, 1468, Maruípe, CEP 29040-090, Vitória, ES, Brasil. Tel./Fax: 55 27 3335-7287. E-mail: ethel.maciel@gmail.com Financial support: This study received financial support from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; MCT/CNPq/CT-Saúde / MS/SCTIE/DECIT Mandate no. 067/2009) and the Fundação de Amparo à Pesquisa do Espírito Santo (FAPES, Foundation for the Support of Research in the State of Espírito Santo; Process no. 59060603/2012).

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ISSN 1806-3713

Lacerda TC, Souza FM, Prado TN, Locatelli RL, Fregona G, Lima RCD, Maciel EL

METHODS This was a cross-sectional study in which the target population was health care workers—community health agents (CHAs), nursing assistants/technicians, nurses, and physicians—affiliated with the primary health care network and the tuberculosis control programs (TCPs) in the city of Vitória, Brazil. The inclusion criteria were belonging to the aforementioned occupational categories and having a negative HIV rapid test result. The exclusion criteria were being known to be infected with HIV, having received prophylaxis for LTBI, having received treatment for tuberculosis, or being pregnant. Loss to follow-up was defined as failure to return for tuberculin skin test (TST) reading on the scheduled date. For calculating the sample size, we adopted a prevalence of tuberculosis infection of 30% among the health care workers, given that, in the literature, this prevalence rate ranged from 10% to 40%.(8) The lowest projected prevalence was 20%, with a test power of 90% and a loss of 10%, totaling 230 health care workers for the final analysis. The primary health care clinics (PHCCs) were selected by simple random sampling, being listed in their respective health categories—traditional PHCC, PHCC with an FHS program, PHCC with a Community Health Agent Program, and PHCC with a TCP. Participation of health care workers was conditioned on their agreeing to participate and giving written informed consent. All health care workers included in the study underwent chest X-ray and medical evaluation to assess epidemiological and clinical aspects with the aim of excluding the possibility of active tuberculosis, in accordance with instructions from the Brazilian National Ministry of Health.(1) Participants were administered a questionnaire collecting data on socio-demographic characteristics, clinical characteristics, and knowledge about tuberculosis, as well as undergoing a diagnostic test, the TST, for the identification of LTBI. For the test, 0.1 mL (2 tuberculin units) of PPD RT23 (State Serum Institute, Copenhagen, Denmark) was administered i.d. in the middle third of the volar aspect of the left forearm. TSTs were read 72 h after injection, by measuring the maximum transverse diameter of the area of palpable induration with a millimeter ruler.(1) It was not possible to investigate the booster effect among the study participants. TSTs were administered by a professional trained by the Espírito Santo State Department of Health and certified by the State Tuberculosis Program. An HIV rapid test (HIV Rapid Check; Infectious Disease Center, Federal University of Espírito Santo, Vitória, Brazil) was used as a screening procedure and an exclusion criterion, being performed in accordance with the manufacturer’s instructions. To assess the questionnaire’s face validity for collecting data for the research project, a pilot study was conducted at the Maruípe Health Care Clinic, in the city of Vitória, Brazil, in which a nurse who

participated in the process of development of that instrument administered it to 10 health care workers invited to this assessment. As a result of this step, we made changes to the questions regarding the physical structure of the PHCCs. The independent variables considered in this study included gender (male or female); age group (19-30, 31-40, 41-50, or 51-70 years); occupation (CHA, nursing assistant or technician, nurse, or physician); working at a PHCC that has a TCP in place (no or yes); length of time working in the current position in primary care (< 5 years or ≥ 5 years); working in primary care only (no or yes); having ever worked in a setting with a high risk of TB (no or yes); having received some training/ education on tuberculosis (no or yes—if yes, less than 5 years ago or 5 years ago or more and appraisal of the contribution of such training to clinical practice [good, fair, or poor]); frequency of seeking information on tuberculosis (never, sometimes, or always); frequency of availability of personal protective equipment (PPE) at the PHCC (never, sometimes, or always); easy access to PPE at the PHCC (no or yes); frequency of PPE use during the care of patients with respiratory symptoms (never, sometimes or always); having a BCG vaccination scar (no or yes); having ever had close contact with someone with tuberculosis (no or yes); having comorbidities or being on immunosuppressive drugs (no or yes); smoking (no, yes, or former smoker); and drinking (no or yes). The outcome variable was the TST result, in mm, as recommended by the Brazilian National Ministry of Health.(1) As an evaluation method, we established cut-off points of 10-mm and 5-mm induration at 72 hours for TST positivity, with TST results being grouped for comparison as follows: TST reactions < 10 mm and < 5 mm (negative TST); and TST reactions ≥ 10 mm and ≥ 5 mm (positive TST).(1) All information was coded and stored anonymously in a dedicated database created with Windows® Excel. Data were collected on case report forms. The chi-square test was used for proportion differences, and the Student’s t-test or the Mann-Whitney test was used for mean differences, when appropriate. To estimate associations with M. tuberculosis infection, we used ORs, which were calculated with 95% CIs. In the bivariate analysis, a p value of ≤ 0.20 was considered to indicate a statistically significant difference, whereas in the multivariate analysis we used a p value of ≤ 0.05. For sample size calculation and statistical analysis, we used Stata statistical software, version 13 (StataCorp LP, College Station, TX, USA). The present study was previously authorized by the Vitória Municipal Health Department and was approved by the Human Research Ethics Committee of the Federal University of Espírito Santo Health Sciences Center (CEP no. 007/2010). RESULTS Over the data collection period, the number of health care workers affiliated with the primary health care J Bras Pneumol. 2017;43(5):416-423

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network in the city of Vitória, Brazil, was 911. Of those, as shown in the flowchart in Figure 1, 568 worked at the health care facilities selected for the study and were therefore potentially eligible. However, only 231 voluntarily agreed to participate in the study. The distribution of the eligibility and participation samples of health care workers, by PHCC, is shown in Table 1. Of the 231 volunteer participants, 5 (2.1%) were lost because they failed to present at 72 h for TST reading, 5 (2.1%) had received treatment for LTBI, and 3 (1.3%) had been treated for active tuberculosis. All of those 13 were excluded from the study. Therefore, the study sample consisted of 218 participants who underwent screening. Active tuberculosis was not diagnosed in any of the health care workers included in the study, and none were recommended to receive LTBI prophylaxis. The prevalence of LTBI among the 218 participants, according to the TST results at the ≥ 10-mm and ≥ 5-mm cut-off points, respectively, was 39.4% (95% CI: 32.9-45.9) and 54.1% (95% CI: 47.4-60.7). Regarding the general characteristics of the health care workers included in the study, 200 (91.7%) were female, and 197 (90.3%) had a BCG vaccination scar. The mean age of the participants was 43 years (95% CI: 41.7-44.4), with normal distribution. Figure 1 presents the study flowchart showing the distribution of the health care workers by TST cut-off points (≥ 10 mm and ≥ 5 mm). Regarding occupational categories, we found that 99 (45.3%) and 103 (47.5%) of those who had positive TST results at

the ≥ 10-mm and ≥ 5-mm cut-off points, respectively, were CHAs. The mean length of time working in the current position in primary care was approximately 8 years (95% CI: 7.38-8.95). Bivariate analysis (Tables 2 and 3) for the TST cut-off point of ≥ 5 mm revealed that the variables length of time ≥ 5 years working in the current position in primary care (p = 0.04), having had a previous TST (p = < 0.01), being a smoker (p = 0.01), and being an alcoholic (p = 0.13) were associated with positive TST results. For the TST cut-off point of ≥ 10 mm, age group (p = 0.09), appraisal of the training/education on tuberculosis (p = 0.16), having had a previous TST (53.1%; p = < 0.01), and being a smoker (p = 0.03) were the variables that showed a statistically significant association with positive TST results. Although BCG vaccination coverage was high among these health care workers (Table 3), this variable was not found to be significantly associated with positive TST results, regardless of the cut-off point. Logistic regression analysis (Table 4) showed that only “having had a previous TST” maintained a statistically significant association with positive TST results at the ≥ 10-mm (OR = 2.5; 95% CI: 1.17-5.30) and ≥ 5-mm cut-off points (OR = 2.18; 95% CI: 1.23-3.87). DISCUSSION The hypothesis of high exposure to M. tuberculosis is corroborated by the increase in the prevalence of LTBI, from 39.4% to 54.1%, among primary health

Table 1. Distribution of the eligibility and participation samples of primary health care workers in the city of Vitória, Brazil, 2012.

Health category

Health care facility

Unidade de Saúde Maruípe Unidade de Saúde Geny Grijó (Centro) Traditional PHCC Unidade de Saúde Ilha de Santa Maria Unidade de Saúde Dr. Carlito Von Schielgen (Jabour) Unidade de Saúde Raul Oliveira Nunes (Jardim Camburi) PHCC with a CHAP Unidade de Saúde Dr. Jolindo Martins (Bairro República) Unidade de Saúde Avelina Maria Lacerda Gonçalves (Bairro do Quadro) PHCC with an FHP Unidade de Saúde Maria Rangel dos Passos (Consolação) strategy Unidade de Saúde Santo André Unidade de Saúde Dr. Manoel Rocha Coutinho (Ilha do Príncipe) Unidade de Saúde Dr. Bolivar de Abreu (Forte São João) Unidade de Saúde Dr. José Moysés (Santa Luíza) Unidade de Saúde Thomaz Tommasi (Community Medicine/Bonfim) Unidade de Saúde Grande Vitória Unidade de Saúde Dr. Affonso Schawb (Fonte Grande) Unidade de Saúde Dr. Luiz Castellar da Silva (Jesus de Nazareth) Total 16 PHCC with a TCP

Total number of eligible health care workers 83 40 15 26 51 52 10

Total number of health care workers interviewed 15 15 11 14 7 16 9

52 24 20 37 49 31

27 19 6 16 30 13

43 15 20

19 3 11

568

231

PHCC: primary health care clinic; PCT: Tuberculosis Control Program; CHAP: Community Health Agent Program; and FHP: Family Health Program.

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Lacerda TC, Souza FM, Prado TN, Locatelli RL, Fregona G, Lima RCD, Maciel EL

568 primary health care workers were potentially eligible for the study.

Excluded from the analysis were 5 primary health care workers who failed to present at 72 h for TST reading. 5 primary health care workers who had received treatment for LTBI. and 3 primary health care workers who had received treatment for active TB.

2 231 primary health care workers gave WIC.

218 primary health care workers were included in the analysis.

TST cut-off point of 10 mm

+TST 86 (39.4%)

−TST 132 (60.6%)

TST cut-off point of 5 mm

−TST 100 (45.9%)

+TST 118 (54.1%)

6 39 (45.3%) CHA

34 (39.5%) N ASST/TECH

9 (10.5%) N

4 (4.6%) PHY

56 (47.5%) CHA

44 (37.3%) N ASST/TECH

11 (9.3%) N

7 (5.9%) PHY

Figure 1. Flowchart of study participation and of tuberculin skin test results in primary health care workers in the city of Vitória, Brazil, 2012. WIC: written informed consent; TST: tuberculin skin test; LTBI: latent Mycobacterium tuberculosis infection; TB: tuberculosis; CHA: community health agent; N ASST/TECH: nursing assistant or technician; N: nurse; e PHY: physician. TST cut-off points were established at ≥ 10-mm and ≥ 5-mm induration for positive tests (+TST) and at < 10-mm and < 5-mm induration for negative tests (−TST).

care workers in the city of Vitória, Brazil, given the Brazilian National Ministry of Health’s new proposal that takes the TST cut-off point of ≥ 5 mm into account.(1) Other studies conducted in Brazil have also reported a high prevalence of LTBI among primary health care workers.(13,15-18) The present study had some limitations. First, cross-sectional studies are limited in their ability to identify causal associations; therefore, a longitudinal study would be more appropriate to determine TST conversion rates and associated factors.(19) The second limitation regarded logistical problems, which made it impossible to repeat the TST among the health care workers who were nonreactors at first and, consequently, to evaluate the booster effect. It is recommended that this effect be evaluated, since individuals infected with M. tuberculosis may have a decreased ability to react to the TST over time, because of loss of response of memory T lymphocytes, which would lead some people to have a negative response to the TST even when they are infected with this agent.(20,21) Therefore, this

evaluation aims to reactivate the immune response to tuberculin by memory cells, by reinforcing the stimulus with a second injection of tuberculin one to three weeks after the first TST.(20) The strengths of the present study were that a pilot study was conducted before the data collection period; TST administration and reading were standardized, as was recognition of BCG scars, all of which were performed by the same researcher; and information on HIV status was available, being obtained from the results of the rapid test administered to all participants. Regarding the prevalence of LTBI by occupational category, the present study revealed that the highest proportion of TST positivity, regardless of the cut-off point, was among CHAs. CHAs are both part of the same community as their patients and simultaneously part of the health care team that assists patients with tuberculosis. This may lead CHAs to neglect or even ignore, for various reasons, the protective measures that they should adopt in their institutional relationship with individuals with the disease.(14,18) This leads us J Bras Pneumol. 2017;43(5):416-423

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Table 2. Distribution of socio-demographic and epidemiological characteristics of the primary health care workers who participated in the study (N = 218).

Variable

Gender Male Female Age group, years 19-30 31-40 41-50 51-70 Occupation CHA N ASST/TECH N PHY Works at an HCC that has a TCP in place No Yes Does not know Length of time working in the current position in primary care, years <5 ≥5 Works in primary care only No Yes Has worked in a setting with a high risk of TB No Yes Has received training/education on TB No Yes Less than 5 years ago 5 years ago or more Assesses the contribution of training to clinical practice as Good Fair Poor Frequency of seeking information on TB Never Sometimes Always

TST ≥ 10 mm +TST −TST n (%) n (%) 8 (44.4) 10 (55.6) 78 (39.0) 122 (61.0)

0.65

TST ≥ +TST n (%) 11 (61.1) 107 (53.5)

5 mm −TST n (%) 7 (38.9) 93 (46.5)

0.53

5 (20.0) 26 (36.6) 33 (47.8) 22 (41.5)

20 (80.0) 45 (63.4) 36 (52.2) 31 (58.5)

0.09

10 (40.0) 35 (49.3) 42 (60.9) 31 (58.5)

15 (60.0) 36 (50.7) 27 (39.1) 22 (41.5)

0.22

39 (36.1) 34 (46.0) 9 (47.4) 4 (23.5)

69(63.9) 40 (54.0) 10 (52.6) 13 (76.5)

0.24

56 (51.8) 52 (48.1) 44 (59.5) 30 (40.5) 11 (57.9) 8 (42.1) 7 (41.2) 10 (58.8)

0.50

55 (38.0) 25 (47.2) 6 (30.0)

90 (62.0) 28 (52.8) 14 (70.0)

0.33

76 (52.4) 69 (47.6) 32 (60.4) 21 (39.6) 10 (50.0) 10 (50.0)

22 (33.3) 64 (42.1)

44 (66.7) 88 (57.9)

0.22

29 (43.9) 37 (56.0) 89 (58.5) 63 (41.4)

0.04

48 (37.5) 38 (42.2)

80 (62.5) 52 (57.8)

0.48

69 (53.9) 59 (46.0) 49 (54.4) 41 (45.6)

0.93

56(36.8) 30(45.4)

96(63.2) 36 (54.6)

0.23

82 (53.9) 70 (46.0) 36 (54.5) 30 (45.4)

0.93

32 (36.8)

55 (63.2)

0.64

46 (52.9) 41 (47.1)

0.54

41 (43.2) 13 (37.1)

54 (56.8) 22 (62.9)

20 (47.6) 24 (34.3) 9 (56.2)

22 (52.4) 46 (65.7) 7 (43.7)

0.16

22 (52.4) 20 (47.6) 38 (54.3) 32 (45.7) 11 (68.7) 5 (31.2)

0.51

11 (52.4) 54 (35.8) 19 (43.2)

10 (47.6) 97 (64.2) 25 (56.8)

0.27

15 (71.4) 6 (28.6) 79 (52.3) 72 (47.7) 22 (50.0) 22 (50.0)

0.22

0.56

50 (52.6) 45 (47.4) 22 (62.9) 13 (37.1)

TST: tuberculin skin test; CHA: community health agent; N ASST/TECH: nursing assistant or technician; N: nurse; PHY: physician; TCP: Tuberculosis Control Program; TB: tuberculosis; HCC: health care clinic. TST cutoffs were established at ≥ 10-mm and ≥ 5-mm induration for positive tests (+TST) and at < 10-mm and < 5-mm induration for negative tests (−TST).

to wonder whether being acquainted with and living near the clientele, together with limited information and knowledge, can be factors causing neglect, embarrassment, and limitation on the part of CHAs to integrate appropriate protective measures against tuberculosis into their professional routine and resulting in a lack of protection.(22) In addition, several risk factors 420

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have been associated with the high prevalence of TST positivity among health care workers.(6,7,14,15) Here, we found that those health care workers who had had a previous TST were more likely to test positive in the second test, regardless of the cut-off point. We believe that this finding may indicate a longer length of time working in health care and, consequently, their having

Lacerda TC, Souza FM, Prado TN, Locatelli RL, Fregona G, Lima RCD, Maciel EL

Table 3. Distribution of occupational characteristics of the primary health care workers in the study population (N = 218).

Variable

Frequency of availability of PPE at the PHCC Never Sometimes Always Easy access to PPE at the PHCC No Yes Frequency of PPE use during the care of patients with respiratory symptoms Never Sometimes Always Has a BCG vaccination scar No Yes Has had close contact with someone with TB No Yes Has had a previous TST No Yes Has comorbidities or is on immunosuppressive drugs No Yes Smoker No Yes Former smoker Drinker No Yes

TST ≥ 10 mm +TST −TST n (%) n (%)

TST ≥ 5 mm +TST −TST n (%) n (%)

38 (38.4) 17 (37) 31 (42.5)

61 (61.6) 29 (63) 42 (57.5)

0.80

52 (52.5) 24 (52.2) 42 (57.5)

47 (47.5) 22 (47.8) 31 (42.5)

0.77

10 (45.5) 38 (39.2)

12 (54.5) 59 (60.8)

0.58

14 (63.6) 52 (53.6)

8 (36.4) 45 (46.4)

0.39

60 (37.3) 16 (44.4) 9 (50.0)

101 (62.7) 20 (55.6) 9 (50.0)

0.46

87 (54.0) 19 (52.8) 11 (61.1)

74 (46.0) 17 (47.2) 7 (38.9)

0.83

10 (47.6) 76 (38.6)

11 (52.4) 121 (61.4)

0.42

11 (52.4) 107 (54.3)

10 (47.6) 90 (45.7)

0.86

69 (37.5) 16 (48.5)

115 (62.5) 17 (51.5)

0.23

97 (52.7) 20 (60.6)

87 (47.3) 13 (39.4)

0.40

35 (29.2) 51 (53.1)

85 (70.8) 45 (46.9)

< 0.01

53 (44.2) 63 (65.6)

67 (55.8) < 0.01 33 (34.4)

64 (40.5) 22 (36.7)

94 (59.5) 38 (63.3)

0.60

89 (56.3) 29 (48.3)

69 (43.7) 31 (51.7)

59 (36.9) 9 (75.0) 18 (39.1)

101 (63.1) 3 (25.0) 28 (60.9)

78 (48.7) 10 (83.3) 30 (65.2)

82 (51.2) 2 (16.7) 16 (34.8)

47 (36.7) 38 (43.2)

81 (63.3) 50 (56.8)

64 (50.0) 53 (60.2)

64 (50.0) 35 (39.8)

0.03

0.33

0.29

0.01

0.13

TST tuberculin skin test; PPE: personal protective equipment; PHCC: primary health care clinic; and TB: tuberculosis. TST cutoffs were established at ≥ 10-mm and ≥ 5-mm induration for positive tests (+TST) and at < 10-mm and < 5-mm induration for negative tests (−TST). *Pearson’s chi-square test.

had a TST more than once. However, TST conversion is defined not only by a positive result in the second TST but also by an increase in induration of 10 mm between the first and the second TST. Given this premise, LTBI prophylaxis should be started for health care workers who meet the two criteria above.(1) In our study, it was not possible to assess TST conversion, since the health care workers did not present a record of the quantitative results of the previous TST. False-positive TST results may occur when health care workers have been previously sensitized by BCG vaccination or by exposure to environmental mycobacteria, since some of the antigens present in this vaccine and in these microorganisms make up the antigenic mixture that is present in PPD RT-23,(3) which could lead to cross-reactivity with the test.(23) However, having a BCG vaccination scar, which was present in nearly all of the health care workers participating in this study, did not show a statistically significant

association with positive TST results, regardless of the cut-off point. Obtaining information on biosafety was a distinguishing aspect of the present study, as well as being of fundamental importance to the impact of health surveillance, particularly with regard to the health of workers. Although N95 masks are known to be a type of PPE, they are not used by the vast majority of health care workers, which can be explained by the unavailability of PPE at the facilities, as was reported by most of the health care workers participating in this study. However, in addition to implementing personal protective measures, which include having PPE available for use, primary health care clinics should also introduce administrative and environmental control measures, such as making simple changes in the organization of health care services; training health care workers; reorganizing the care pathway of patients with active tuberculosis; keeping any long-stay environment J Bras Pneumol. 2017;43(5):416-423

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Table 4. Logistic regression for identification of factors associated with positive tuberculin skin test results (≥ 10-mm and ≥ 5-mm induration) among the primary health care workers in the study population (N = 218).

Variable

Age group, years 19-30 31-40 41-50 51-70 Length of time working in the current position in primary care, years <5 ≥5 Assesses the contribution of training to clinical practice as Good Fair Poor Smoker No Yes Former smoker Alcoholic No Yes Has had a previous TST No Yes

Adjusted OR Reference 1.78 2.42 1.95

TST ≥ 10 mm p 95% CT

0.44 0.24 0.40

0.40-7.84 0.54-10.85 0.40-9.53

Reference 0.65 1.47

0.32 0.52

0.28-1.50 0.44-4.97

Reference 2.78 1.21

0.28 0.69

0.43-17.83 0.45-3.24

Reference 2.50

0.01

1.17-5.30

TST ≥ 5 mm p

95% CI

Reference 1.48

0.20

0.80-2.73

Reference 4.34 1.87

0.06 0.08

0.89-21.12 0.92-3.80

Reference 1.23

0.48

0.68-2.19

Reference 2.18

< 0.01

1.23-3.87

Adjusted OR

TST: tuberculin skin test. *Pearson’s chi-square test.

for patients with possible respiratory symptoms as ventilated as possible; having exhaust systems, filters, or fans; and destining an appropriate place for sputum collection and, when available, identifying it accordingly. These measures, taken together, are necessary to ensure that people with symptoms suggestive of tuberculosis can be readily identified and, if infected, be cared for at an appropriate time and place and subsequently treated.(1) In addition, we emphasize that these administrative and environmental measures are considered the most important for preventing the transmission of M. tuberculosis.(3) In summary, the present study showed that the prevalence of LTBI was high among the primary health care workers in this sample and that recommending preventive therapy for this infection may raise reflections and questions, given that reducing the TST cut-off point to 5 mm will possibly result in the detection of a larger number of infected individuals, who would be referred for treatment, leading to new visits and additional costs to the health care system. In addition, it should be taken into account that widespread BCG

vaccination coverage and exposure to environmental mycobacteria could be associated with positive TST results at this cut-off point. Therefore, we recommend the establishment of a periodic screening program to detect and monitor LTBI among primary health care workers, as well as the implementation of effective administrative, environmental, and personal protective measures to prevent LTBI in those at risk of exposure to M. tuberculosis. Such measures are necessary, since they contribute to the achievement of the goals established by the World Health Organization,(24) especially in relation to the first pillar of the End TB Strategy, in which integrated, patient-centered care and prevention include systematic screening of high-risk groups for M. tuberculosis, as well as treatment for LTBI. The results obtained in the present study, together with those of a multicenter study, will contribute to the development of the Brazilian National Plan for the Control of M. tuberculosis infection, as envisaged by the World Health Organization and recommended by the Brazilian National Ministry of Health.

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Lacerda TC, Souza FM, Prado TN, Locatelli RL, Fregona G, Lima RCD, Maciel EL

3. World Health Organization. Global tuberculosis control--epidemiology, strategy, financing. Geneva: WHO; 2009. 4. World Health Organization. Guidelines on the Management of Latent Tuberculosis Infection [monograph on the internet]. Geneva: World Health Organization; 2015 [cited 2016 Oct 1]. [Adobe Acrobat document, 38p.]. Available from: http://apps.who.int/medicinedocs/ documents/s21682en/s21682en.pdf 5. Joshi R, Reingold AL, Menzies D, Pai M. Tuberculosis among healthcare workers in low- and middle-income countries: a systematic review. PLoS Med. 2006,3(12):e494. https://doi.org/10.1371/journal. pmed.0030494 6. Menzies D, Joshi R, Pai M. Risk of tuberculosis infection and disease associated with work in health care settings. Int J Tuberc Lung Dis. 2007;11(6):593-605. 7. Zwerling A, van den Hof S, Scholten J, Cobelens F, Menzies D, Pai M. Interferon-gamma release assays for tuberculosis screening of healthcare workers: a systematic review. Thorax. 2012;67(1):62-70. https://doi.org/10.1136/thx.2010.143180 8. Sociedade Brasileira de Pneumologia e Tisiologia. II Diretrizes brasileiras para tuberculose. J Bras Pneumol. 2004;30(Suppl 1):S3S56. 9. Silva VM, Cunha AJ, Oliveira JR, Figueira MM, Nunes ZB, DeRiemer K, et al. Medical students at risk of nosocomial transmission of Mycobacterium tuberculosis. Int J Tuberc Lung Dis. 2000;4(5):420-6. 10. Maciel EL, Viana MC, Zeitoune RC, Ferreira I, Fregona G, Dietze R. Prevalence and incidence of Mycobacterium tuberculosis infection in nursing students in Vitória, Espírito Santo. Rev Soc Bras Med Trop. 2005;38(6):469-72. https://doi.org/10.1590/S003786822005000600004 11. Maciel EL, Meireles W, Silva AP, Fiorotti K, Dietze R. Nosocomial Mycobacterium tuberculosis transmission among healthcare students in a high incidence region, in Vitória, State of Espírito Santo. Rev Soc Bras Med Trop. 2007;40(4):397-9. https://doi.org/10.1590/ S0037-86822007000400004 12. de Oliveira SM, Honner MR, Paniago AM, Aguiar ES, Venâncio da Cunha R. Prevalence of mycobacterium tuberculosis among professionals in a university hospital, Mato Grosso do Sul, 2004. Rev Lat Am Enfermagem. 2007;15(6):1120-4. https://doi.org/10.1590/ S0104-11692007000600010 13. Rodrigues PM, Moreira TR, Moraes AK, Vieira Rda C, Dietze R, Lima Rde C, et al. Mycobacterium tuberculosis infection among community health workers involved in TB control. J Bras Pneumol, 2009;35(4):351-8. https://doi.org/10.1590/S180637132009000400009 14. Moreira TR, Zandonade E, Maciel EL. Risk of tuberculosis infection

among community health agents. Rev Saude Publica. 2010;44(2):3328. https://doi.org/10.1590/S0034-89102010000200014 15. de Souza FM, do Prado TN, Pinheiro Jdos S, Peres RL, Lacerda TC, Loureiro RB, et al. Comparison of interferon-γ release assay to two cut-off points of tuberculin skin test to detect latent Mycobacterium tuberculosis infection in primary health care workers. PLoS One. 2014;9(8):e102773. https://doi.org/10.1371/journal.pone.0102773 16. Machado PC, Valim AR, Maciel EL, Prado TN, Borges TS, Daronco A, et al. Comparison of tuberculin test and interferon-gamma release assay for diagnosing latent tuberculosis in Community Health Workers, State of Rio Grande do Sul, Brazil, 2012 [Article in Portuguese]. Epidemiol Serv Saude. 2014;23(4):675-81. https://doi. org/10.5123/S1679-49742014000400009 17. Borges TS, Sonda EC, Daronco A, Battisti F, Santos MM, Valim AR et al. Prevalence of latent Mycobacterium tuberculosis infection among professionals of the primary healthcare network. Braz J Health Promot. 2014;27(2):269-75. 18. Rogerio WP, Prado TN, Souza FM, Pinheiro Jdos S, Rodrigues PM, Sant’anna AP, et al. Prevalence of infection with Mycobacterium tuberculosis and associated factors in community health workers in Brazil based on the tuberculin skin test [Article in Portuguese]. Cad Saude Publica. 2015;31(10):2199-210. https://doi.org/10.1590/0102311X00152414 19. Silva VM, Cunha AJ, Kritski AL. Risco de infecção pelo Mycobacterium tuberculosis entre alunos da Faculdade de Medicina da Universidade Federal do Rio de Janeiro. J Bras Pneumol. 2004;30(4):459-66. https://doi.org/10.1590/S1806-37132004000500010 20. Luna JA. Guía de la tuberculosis para médicos especialistas. Paris: Unión Internacional Contra la Tuberculosis y Enfermedades Respiratorias; 2003. 21. Oliveira SM, Honer MR, Paniago AM, Aguiar ES, Cunha RV. Booster effect on tuberculin skin tests at a university hospital in Mato Grosso do Sul [Article in Portuguese]. Rev Bras. Saude Ocup. 2008;33(117):726. https://doi.org/10.1590/S0303-76572008000100008 22. World Health Organization. WHO policy on TB infection control in health care facilities, congregate settings and households. Geneva: World Health Organization; 2009. 23. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis. 2006;10(11):1192-204. 24. World Health Organization. The End TB Strategy. Global strategy and targets for tuberculosis prevention, care and control after 2015 [monograph on the internet]. Geneva: World Health Organization; 2015 [cited 2016 Oct 1]. [Adobe Acrobat document, 2p.]. Available from: http://www.who.int/tb/post2015_TBstrategy.pdf

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J Bras Pneumol. 2017;43(5):424-430 http://dx.doi.org/10.1590/S1806-37562016000000323

ORIGINAL ARTICLE

Accuracy of closed pleural biopsy in the diagnosis of malignant pleural effusion Renata Báez-Saldaña1,2, Uriel Rumbo-Nava1, Araceli Escobar-Rojas2, Patricia Castillo-González1, Santiago León-Dueñas1, Teresa Aguirre-Pérez1, María Eugenia Vázquez-Manríquez3 1. Servicio Clínico de Neumología Oncológica, Instituto Nacional de Enfermedades Respiratorias, Ciudad de México, México. 2. División de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México. Ciudad de México, México. 3. Servicio de Anatomía Patológica, Instituto Nacional de Enfermedades Respiratorias, Ciudad de México, México. Submitted: 21 October 2016. Accepted: 4 May 2017. Study carried out at the Servicio Clínico de Neumología Oncológica, Instituto Nacional de Enfermedades Respiratorias, Ciudad de México, México.

ABSTRACT Objective: Previous studies have demonstrated that closed pleural biopsy (CPB) has a sensitivity of less than 60% for diagnosing malignancy. Therefore, controversy has recently emerged regarding the value of CPB as a diagnostic test. Our objective was to assess the accuracy of CPB in diagnosing malignancy in patients with pleural effusion. Methods: This was a prospective 8-year study of individuals who underwent CPB to establish the etiology of pleural effusion. Information on each patient was obtained from anatomopathological reports and medical records. When CPB findings showed malignancy or tuberculosis, the biopsy was considered diagnostic, and that was the definitive diagnosis. In cases in which biopsy histopathological findings were nonspecific, a definitive diagnosis was established on the basis of other diagnostic procedures, such as thoracoscopy, thoracotomy, fiberoptic bronchoscopy, biochemical and cellular measurements in pleural fluid, and/or microbiological tests. The accuracy of CPB was determined with 2 × 2 contingency tables. Results: A total of 1034 biopsies from patients with pleural effusion were studied. Of those, 171 (16.54%) were excluded from the accuracy analysis either because of inadequate samples or insufficient information. The results of the accuracy analysis were as follows: sensitivity, 77%; specificity, 98%; positive predictive value, 99%; negative predictive value, 66%; positive likelihood ratio, 38.5; negative likelihood ratio, 0.23; pre-test probability, 2.13; and post-test probability, 82. Conclusions: CPB is useful in clinical practice as a diagnostic test, because there is an important change from pre-test to post-test probability. Keywords: Biopsy; Pleural effusion, malignant/diagnosis; Pleural effusion, malignant/ epidemiology.

INTRODUCTION Previous evidence has demonstrated that the performance of blind closed pleural biopsy (CPB) as a diagnostic test for malignancy is poor, since the reported sensitivity is less than 60%; therefore, in some countries, CPB is considered obsolete and its use tends to disappear.(1,2) Currently, the interventional pulmonologist has two options for obtaining histological samples of pleural tissue: CPB or medical thoracoscopy. The first is an old technique,(3,4) and the second is currently considered the gold standard(2); however, both procedures have advantages and disadvantages. The CPB described by Cope and Abrams(3,4) in the mid-20th century is an alternative method of obtaining pleural tissue without the need for a surgical procedure. Its use for more than 5 decades is attributed to its ease of performance, its low cost, the tolerability by the patient, and the fact that, within a short period of time, it allows a decision about the management of the case.(5) Nevertheless, it is a purely diagnostic procedure, which does not bring any gains in terms of treatment or symptom relief to the patient as occurs with medical thoracoscopy or video-assisted thoracoscopy.

At our institution, approximately 400 new cases of intrathoracic malignancy are diagnosed every year, and, of those, approximately 40% have pleural effusion. The initial approach to pleural effusion is to perform a thoracentesis so that the pleural fluid can be analyzed biochemically and cytologically. In cases of nondiagnostic thoracentesis and in the presence of lymphocytic exudate, a definitive diagnosis is established by histopathological analysis of samples obtained by image-guided or non-image-guided CPB or by video-assisted thoracoscopy. Because at our hospital we continue to perform CPB in cases of lymphocytic exudative pleural effusion of unknown etiology, the objective of the present study was to assess the accuracy of CPB in establishing a diagnosis of malignancy in patients under investigation for pleural effusion. METHODS This was a prospective study of patients with pleural effusion who underwent CPB to establish the etiology of the effusion, over an 8-year period at a referral hospital for respiratory diseases in Mexico City. The study was approved by the Research Ethics Committee of the Instituto Nacional de Enfermedades Respiratorias.

Correspondence to:

Renata Báez-Saldaña. Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, C.P. 14080, Ciudad de México, México. Tel.: 52 55 5487-1700, ext. 5284. E-mail: baezrd@unam.mx Financial support: None.

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Báez-Saldaña R, Rumbo-Nava U, Escobar-Rojas A, Castillo-González P, León-Dueñas S, Aguirre-Pérez T, Vázquez-Manríquez ME

Before CPB, pleural fluid analysis including biochemical measurements such as protein, lactic dehydrogenase, and cholesterol levels was performed to classify the effusion as an exudate or transudate(6); in addition, other measurements such as glucose, adenosine deaminase, and pH levels were performed, as were cell counts and cytological studies. CPB was performed by different pulmonologists with 5 to 15 years of experience and by second- or third-year residents in pulmonary medicine of the emergency and inpatient departments. When CPB was performed by residents, these residents were always directed and supervised by the pulmonologist in charge of the patient. The diagnostic procedure was performed with a Cope(3) or Abrams(4) needle in patients with submassive or massive pleural effusion, in a hospitalization procedure room or in the emergency department. With the patient in a sitting position, his/her arms resting on a table, at shoulder level, the entry point was determined on the affected side. In general, the entry point was located between the posterior axillary line and the line of the inferior angle of the scapula, in the fifth intercostal space. With aseptic technique and local anesthesia (lidocaine 2%) of the skin, subcutaneous cellular tissue, intercostal muscle, and underlying region of the parietal pleura, a thoracentesis was performed to ensure that the pleural space had been entered; subsequently, a 3- to 5-mm incision was made with a scalpel blade on the skin and subcutaneous tissue to facilitate the insertion of the biopsy needle along and above the superior border of the inferior rib, so as to avoid damage to the intercostal neurovascular bundle. The Abrams needle consists of three parts: an outer 11-gauge cannula (3 mm in outer diameter); an inner 13-gauge stylet that facilitates transparietal insertion; and a 13-gauge hooked needle for taking the biopsy. When the stylet needle was withdrawn, there was an outflow of pleural fluid, which confirmed successful entry into the pleural cavity. With the cannula in the pleural space, the trocar needle was inserted through it into the pleural space, the notch of the trocar being positioned opposite the said needle grip. To collect a sample of parietal pleura, the said notch engaged the pleura, and with a rotating movement of the trocar needle, the required sample was cut off and taken. These steps were repeated as many times as the number of samples desired. The Cope needle consists of four parts: an 11-gauge outer cannula 3 mm in diameter; a 13-gauge hooked biopsy trocar; a beveled trocar; and an inner stylet. After a syringe was attached to the hooked biopsy trocar, the inner stylet was inserted into the beveled trocar, and both were inserted through the outer cannula into the pleural space. The hooked biopsy trocar, to whose outer end a syringe had been attached, was inserted through the outer cannula into the pleural space. Entry into the pleural space was confirmed by aspiration of fluid into the syringe. The parietal pleura was hooked with the biopsy trocar, and, with a slight outward pulling motion, the biopsy was taken.

With either needle, between 4 and 8 samples were taken clockwise at 3, 6, and 9 o’clock, but never at 12 o’clock to avoid damage to the intercostal neurovascular bundle. The biopsies were placed in 3.7% formaldehyde solution for histopathological examination, which was performed by different pathologists from the pathology department with more than 10 years of experience in diagnosing pulmonary, pleural, and mediastinal diseases. Initially, the biopsies were analyzed morphologically, and, subsequently, they were evaluated immunohistochemically, with appropriate antibody panels for the diagnosis of different neoplastic and non-neoplastic diseases. The identification of the cases in which CPB was performed was obtained from the records of the anatomical pathology department of the hospital. Information regarding each patient, such as general characteristics, history, clinical profile, radiological findings, and results of cytological and cytochemical study of pleural fluid, was obtained from the inpatient medical records. When CPB results showed malignancy or tuberculosis, the biopsy was considered diagnostic, and that was the definitive diagnosis in the medical record. In cases of lymphocytic exudates with CPB histopathological findings of nonspecific inflammatory changes (nonspecific chronic inflammation or reactive mesothelial hyperplasia), a definitive diagnosis was established on the basis of other diagnostic procedures, which, for these cases, were the following: invasive procedures such as thoracoscopy, thoracotomy, fiberoptic bronchoscopy, adenosine deaminase levels, and/or microbiological tests for pyogenic bacteria and for Mycobacterium tuberculosis; or the clinical criterion and specific laboratory studies according to the case. In all cases, CPB histopathological findings were compared with the definitive diagnosis made by the treating physician and 6-month follow-up data, on the basis of medical records. Pleural tuberculosis was defined as the presence of at least one of the following: a finding of granulomas on pleural biopsy; a positive Ziehl-Neelsen staining of pleural fluid or biopsy material; a positive LöwensteinJensen culture of pleural fluid; a positive sputum smear microscopy; or an adenosine deaminase level of > 45 IU in a pleural exudate with a lymphocyte predominance of > 80%. Parapneumonic pleural effusion was defined as the presence of a pleural exudate with a predominance of polymorphonuclear cells in addition to a clinical profile consistent with pneumonia; the case was treated with antibiotics, and there was improvement at discharge.

Statistical analysis For the accuracy analysis of CPB, we used 2 × 2 contingency tables in which the results of the diagnostic test were compared with respect to the presence or absence of any intrathoracic malignant disease and with respect to the presence or absence of mesothelioma alone. J Bras Pneumol. 2017;43(5):424-430

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We calculated sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and pre-test and post-test probabilities.Â (7) RESULTS During the study period, 1,034 CPBs were performed in 1,034 patients with pleural effusion. The mean age of the patients was 57 Âą 17 years, 615 (59.48%) were male, and 419 (40.52%) were female. Malignancy was identified in 466 (45.07%) of the patients, among whom lung adenocarcinoma and mesothelioma were the most common neoplasms, being found in 252 (24.37%) and 105 (10.16%), respectively (Table 1). Of the 1034 CPBs, 171 (16.54%) were excluded from the accuracy analysis: 72 (6.96%) because of inadequate samples, given that no pleural tissue was obtained; and 99 (9.57%) because of lack of information about the case, since case follow-up until the establishment of a definitive diagnosis was impossible. Among the final diagnoses of the 863 cases included in the accuracy analysis, the most common were lung adenocarcinoma, mesothelioma, and undifferentiated carcinoma (Table 2). CPB results, by presence or absence of any intrathoracic malignant disease and by presence or absence of mesothelioma, as well as results for the diagnostic test performance indicators for each case, are described in 2 Ă&#x2014; 2 contingency tables (Tables 3 and 4). Table 1. Histopathological results for 1,034 closed pleural biopsies.

Result Malignant neoplasm Lung adenocarcinoma Mesothelioma Undifferentiated carcinoma Small cell lung cancer Giant cell lung cancer Epidermoid carcinoma Hodgkin and non-Hodgkin lymphoma Other neoplasmsa Total Infectious disease Tuberculosis Parapneumonic pleural effusion Total Other results Nonspecific inflammationb Inadequate biopsy sample (no pleural tissue)c Total

n (%) 252 (24.37) 105 (10.16) 53 (5.12) 19 (1.84) 6 (0.58) 5 (0.48) 11 (1.06) 15 (1.45) 466 (45.07) 116 (11.22) 2 (0.19) 118 (11.41) 378 (36.56) 72 (6.96) 450 (43.52)

Other neoplasms included sarcomas and metastasis from clear cell renal, breast, and ovarian cancer. bIt refers to findings of non-specific acute and chronic inflammation and reactive mesothelial hyperplasia. c These biopsies were excluded from the accuracy analysis. a

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In 38/863 cases (4.40%), there were complications (3 cases had two complications): 30 cases had pneumothorax, of which 19 did not require pleural tube placement and 11 did; 6 patients developed a hematoma at the puncture site; 2 had vasovagal syncope; and 3 developed subcutaneous emphysema in the area surrounding the puncture site. DISCUSSION The results of this study describe, according to modern clinical epidemiology, the performance of CPB in cases of lymphocytic exudative pleural effusion of unknown etiology. This diagnostic test proved useful since it allowed the identification of 77% of the cases of pleural effusion due to any malignancy and 81% of those due to mesothelioma. Lung adenocarcinoma metastatic to the pleura and mesothelioma were the most commonly diagnosed neoplasms by this method. The specificity of the diagnostic test under study was high, since only 2% of the patients with other causes of pleural effusion had a positive result for malignancy and none had a positive result for mesothelioma. Likewise, in a patient with a positive CPB result for neoplastic disease, the actual probability of having a neoplasm was 99% and that of having a mesothelioma was 100%. However, in clinical practice, the confidence with which it is possible to rule out the probability of a thoracic neoplasm, given a normal result or a result with nonspecific inflammatory changes, is very important in a setting where the prevalence of the disease is high, Table 2. Diagnoses of 863 cases with completed followup for identification of a definitive diagnosis, for accuracy analysis of closed pleural biopsy.

Result Malignant neoplasm Lung adenocarcinoma Mesothelioma Small cell lung cancer Hodgkin and non-Hodgkin lymphoma Undifferentiated carcinoma Epidermoid carcinoma Giant cell carcinoma Other neoplasmsa Total Infectious diseases Tuberculosis Parapneumonic pleural effusion Total Other diseases Othersb Idiopathic Total

n (%) 317 (36.73) 130 (15.06) 26 (3.01) 20 (2.32) 41 (4.75) 15 (1.74) 6 (0.70) 32 (3.71) 587 (68.02) 141 (16.34) 50 (5.79) 191 (22.13) 70 (8.11) 15 (1.74) 85 (9.85)

Other neoplasms included sarcomas; metastasis from clear cell renal, breast, and ovarian cancer; germ cell tumors; and papillary thyroid cancer. bOther nonneoplastic diseases included rheumatoid arthritis; systemic lupus erythematosus; renal, hepatic, and cardiogenic failure; pneumoconiosis; pachy pleuritis; and pulmonary thromboembolism.

Báez-Saldaña R, Rumbo-Nava U, Escobar-Rojas A, Castillo-González P, León-Dueñas S, Aguirre-Pérez T, Vázquez-Manríquez ME

Table 3. Closed pleural biopsy results, by presence or absence of any intrathoracic malignant disease, and accuracy analysis.a

Biopsy result Diagnostic biopsy Non-diagnostic biopsy Total

Presence of Absence of malignancy malignancy 450 5 137 271 587 276 Test performance indicator

Sensitivity a/(a + c) = 450/587 Specificity d/(b + d) = 271/276 Positive predictive value a/(a + b) = 450/455 Negative predictive value d/(c + d) = 271/408 Positive likelihood ratio Sensitivity/(1 − specificity) = 77/2 Negative likelihood ratio (1 − sensitivity)/specificity = 23/98 Prevalence (a + c)/(a + b + c + d) = 587/863 Pre-test probability Prevalence/(1 − prevalence) = 68/32 Post-test probability Pre-test probability × positive likelihood ratio = 2.13 × 38.5

Total 455 408 863

77% (95% CI: 74-79) 98% (95% CI: 97-99) 99% (95% CI: 98-100) 66% (95% CI: 63-70) 38.5 0.23 68% (95% CI: 65-71.3) 2.13 82

a: true-positive results; b: false-positive results; c: false-negative results; and d: true-negative results. a Mesothelioma is included. Table 4. Closed pleural biopsy results, by presence or absence of mesothelioma, and accuracy analysis.

Biopsy result Diagnostic biopsy Non-diagnostic biopsy Total

Presence of Absence of mesothelioma mesothelioma 105 0 25 733 130 733 Test performance indicator

Sensitivity a/(a + c) = 105/130 Specificity d/(b + d) = 733/733 Positive predictive value a/(a + b) = 105/105 Negative predictive value d/(c + d) = 733/758 Positive likelihood ratio Sensitivity/(1 − specificity) = 81/99 Negative likelihood ratio (1 − sensitivity)/specificity = 19/100 Prevalence (a + c)/(a + b + c + d) = 130/863 Pre-test probability Prevalence/(1 − prevalence) = 15/85 Post-test probability Pre-test probability × positive likelihood ratio = 0.18 × 82

Total 105 758 863

81% (95% CI: 78-83) 100% 100% 97%(95% CI: 96-98) 82 0.19 15% (95% CI: 13-17) 0.18 14.8

a: true-positive results; b: false-positive results; c: false-negative results; and d: true-negative results.

as is our case, to such an extent that a negative result does not exclude the probability of a neoplasm in 34% of cases. The usefulness of this diagnostic procedure lies in the possibility of excluding malignancy in cases of lymphocytic exudative pleural effusion on the basis of a

biopsy result showing nonspecific chronic inflammation or reactive mesothelial hyperplasia. Our series and other published series report a high number of such results (20%-60%)(8-13); in some such cases malignancy is subsequently confirmed by other methods, those J Bras Pneumol. 2017;43(5):424-430

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Table 5. Performance of different methods of obtaining pleural tissue samples for the diagnosis of intrathoracic malignancy-related pleural effusion.

Reference

Technique

Number of patients

Diagnostic Frequency of performance complications* Studies of diagnosis of malignant pleural effusion Sn: 68% Sp: 99% (8)a Poe et al., 1984 CPB 211 9.9% PPV: 98% NPV: 77% Sn: 51% Sp: 100% (9) CPB 75 11% Chakrabati et al., 2006 PPV: 100% NPV: 100% Sn: 33.9% CPB 658 Sp and PPV: 100% 14.4% Pereyra et al., 2013(10) NPV: 71% CPB vs. 67 Sn: 60% 1/67 (1.5%) Botana et al., 2013(11) US-guided CPB 114 Sn: 77.4% 3/114 (2.5%) Sn: 47% vs. 87% CPB vs. 25 Sp: 100% vs. 100% CPB 1/25 (1) CT-guided CPB Maskell et al., 2013 25 NPV: 44% vs. 80% CT 0 Clinical trial PPV: 100% vs. 100% CPB vs. 36 55.6% 7/36 (19.4%) Son et al., 2014(12) MT 31 93.5 % 0 Clinical trial MT vs. 29 Sn: 86.2% 10.3% Haridas et al., 2014(14) CPB 29 Sn: 62.1 % 17.2% Clinical trial MT vs. 62 Sn: 94.1% 11/62 Metintas et al., 2010(16) CT-guided pleural 62 Sn: 87.5% 14/62 biopsy Sn: 77% CPB for any Sp: 98% Present study 863 4.40% malignancy PPV: 99% NPV: 66% Studies of diagnosis of mesothelioma RTLA vs. 188 Sn: 98% 4.8% Boutin et al., 1993(15) CPB 145 Sn: 21% ---Sn: 77% Sp: 88% No severe US-guided biopsy 70 Heilo et al., 1999(13) PPV: 100% complications NPV: 57% US- or CT-guided Sn: 86% (17) 53 2/53 Adams et al., 2001 biopsy Sp: 100% Sn: 81% CPB for Sp: 100% Present study 863 4.40% mesothelioma PPV: 100% NPV: 97% CPB: closed pleural biopsy; Sn: sensitivity: Sp: specificity; PPV: positive predictive value; NPV: negative predictive value; US: ultrasound; MT: medical thoracoscopy; and RTLA: rigid thoracoscopy under local anesthesia. aDiagnoses of malignancy and tuberculosis are included. being false-negatives for malignancy. In the present study, 378 biopsies (36.56%) showed nonspecific inflammatory changes, and, in the accuracy analysis, 137/587 (23.34%) corresponded to false-negative results for malignancy. The explanation for such false-negative results lies in the fact that neoplasms disseminate in patches in the pleura in cases of intrathoracic malignancy, the effusion is due to obstruction of pleural or mediastinal lymphatics, or the disease involves only the visceral 428

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pleura. Among the neoplasms for which false-negative CPB results occurred most often were several varieties of intrathoracic sarcomas and neoplasms of mediastinal and metastatic extrathoracic origin, such as metastasis from clear cell renal, breast, and ovarian cancer, germ cell tumors, and papillary thyroid cancer. On the basis of the positive likelihood ratio, a patient with a lymphocytic pleural exudate and a CPB result positive for malignancy will be 38.5 times more likely to have a malignant chest disease compared with a patient

Báez-Saldaña R, Rumbo-Nava U, Escobar-Rojas A, Castillo-González P, León-Dueñas S, Aguirre-Pérez T, Vázquez-Manríquez ME

with the same characteristics but with a negative CPB result. Finally, there was a large difference between pre- and post-test probability, 2.13 and 82, respectively, which suggests clinically important displacement. A similar trend was observed for mesothelioma. Previous studies on the performance of CPB in diagnosing malignancy, whether addressing CPB alone or comparing it with image-guided or medical thoracoscopy-guided techniques, have demonstrated that CPB with Cope or Abrams needles allows the diagnosis of 21% to 62% of cases of neoplasm-related pleural effusion(1,8-12,14,15) (Table 5). When pleural biopsy is performed under image guidance, whether ultrasound or computed tomography, it consistently shows better performance, with sensitivity between 77% and 87.5%,(1,11,13,16,17) and when there is pleural thickening greater than 1 cm, sensitivity increases to 95%, a value similar to that achieved when biopsy is obtained with thoracoscopy.(16) In general, specificity and positive predictive values are high for CPB and for that performed under image guidance. In our study, sensitivity for neoplastic disease (77%) was higher than that reported in previous studies and was within the range reported for image-guided pleural biopsy (Table 5), and, similar to previous studies, specificity and positive predictive value were high in the present study. This is probably due to the fact that the place where our study was conducted is a referral hospital for respiratory diseases and many of the cases present with advanced stages of the disease. Medical thoracoscopy and video-assisted thoracoscopy are considered the gold-standard methods of obtaining biopsies in cases of neoplasm-related pleural effusion. (5) For medical thoracoscopy, evidence shows sensitivity ranging from 86.2 to 93.5%(12,14,16) (Table 5). There have been few studies assessing the accuracy of CPB in diagnosing mesothelioma. One study compared the performance of CPB with that of surgical thoracoscopy and found sensitivity of 21% vs. 98 %.(15) When biopsy is performed under image guidance such as ultrasound or computed tomography, sensitivity increases to 77% and 86%, respectively(13,17) (Table 5). The above results contrast with those of the present study, since the CPB performance indicator values for the diagnosis of mesothelioma were high and even similar to image-guided biopsy results.(13,17) This performance can be explained in part by the fact that many of the cases had pleural thickening.

Our study confirms the safety of CPB and its accessibility even to pulmonologists in training. The frequency of complications was 4.40% (Table 5), similar to that reported in the literature(2); on the other hand, we demonstrated the performance of CPB in a routine work setting, given that biopsy collection and histopathological analysis were performed independently by different health care workers. At our institution, CPB is still part of the diagnostic algorithm of patients with lymphocytic exudative pleural effusion for identification of etiology, although we have video-assisted thoracoscopy, whose performance is much better than that of CPB and which in addition facilitates performing therapeutic procedures, such as pleurodesis to prevent effusion recurrence, concurrently with biopsy collection; however, video-assisted thoracoscopy takes more time and resources and may be a risk factor in patients with high anesthetic risk. Medical thoracoscopy is not yet available at our institution, and image-guided pleural biopsy is not often performed because it requires equipment, whether ultrasound or computed tomography equipment, and trained personnel. Currently at our institution we are attempting to generalize the performance of CPB under image guidance, whether ultrasound or computed tomography, as well as to implement the use of medical thoracoscopy. One of the limitations of the present study is that cytology results, culture results, and radiographic findings such as pleural thickening were not included in the analysis, being considered only in including cases in the study and in the definitive diagnosis. Another potential limitation is the number of cases excluded from the analysis, which can undoubtedly affect the test performance indicators; nevertheless, we consider that we have a good sample size that includes more than 80% of all cases reported during the study period and therefore estimate that the change in the test performance indicators would be modest and would not ostensibly affect the trend of results. In conclusion, at the facility where the present study was conducted, CPB proved to be valid, accurate, and precise in establishing the diagnosis of intrathoracic malignancy in patients with pleural effusion. CPB is useful in clinical practice as a diagnostic test, because there is an important change from pre-test to post-test probability.

REFERENCES 1. Maskell NA, Gleeson FV. Davies RJ. Standard pleural biopsy versus CT-guided cutting-needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial. Lancet. 2003;361(9366):1326-30. https://doi.org/10.1016/S01406736(03)13079-6 2. Dixon G, de Fonseka D, Maskell N. Pleural controversies: image guided biopsy vs. thoracoscopy for undiagnosed pleural effusions? J Thorac Dis. 2015;7(6):1041-51. 3. Cope C. New pleural biopsy needle; preliminary study. JAMA. 1958;167(9):1107-8. https://doi.org/10.1001/ jama.1958.72990260005011a

4. Abrams LD. A pleural-biopsy punch. Lancet. 1958;1(7010):30-1. https://doi.org/10.1016/S0140-6736(58)92521-2 5. Koegelenberg CF, Diacon AH. Pleural controversy: closed needle pleural biopsy or thoracoscopy-which first? Respirology. 2011;16(5):738-46. https://doi.org/10.1111/j.14401843.2011.01973.x 6. Light RW. Clinical practice. Pleural effusion. N Engl J Med. 2002;346(25):1971-7. https://doi.org/10.1056/NEJMcp010731 7. Straus SE, Richardson WS, Glasziou P, Haynes RB. Diagnóstico y cribado. In: Straus SE, Richardson WS, Glasziou P, Haynes RB. 3rd edition, Medicina basada en la evidencia. Elsevier España; 2006; J Bras Pneumol. 2017;43(5):424-430

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p. 67-100. 8. Poe R, Israel RH, Utell MJ, Hall WJ, Greenblatt DW, Kallay MC. Sensitivity, specificity, and predictive values of closed pleural biopsy. Ann Intern Med. 1984;144(2):325-8. https://doi.org/10.1001/ archinte.1984.00350140139020 9. Chakrabarti B, Ryland I, Sheard J, Warburton CJ, Earis JE. The role of the Abrams percutaneous pleural biopsy in the investigation of exudative pleural effusions. Chest. 2006;129(6):1549-55. https://doi. org/10.1378/chest.129.6.1549 10. Pereyra MF, San-José E, Ferreiro L, Golpe A, Antúnez J, GonzálezBarcala FJ, et al. Role of blind closed pleural biopsy in the management of pleural exudates. Can Respir J. 2013;20(5):362-6. https://doi.org/10.1155/2013/731352 11. Botana-Rial M, Leiro-Fernández V, Represas-Represas C, GonzálezPiñeiro A, Tilve-Gómez A, Fernández-Villar A. Thoracic ultrasoundassisted selection for pleural biopsy with Abrams needle. Repir Care. 2013;58(11):1949-54. https://doi.org/10.4187/respcare.02378 12. Son HS, Lee SH, Darlong LM, Jung J, Sun K, Kim KT, et al. Is there a role for a needle thoracoscopic pleural biopsy under local anesthesia for pleural effusions? Korean J Thorac Cardiovasc Surg.

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2014;;47(2):124-8. https://doi.org/10.5090/kjtcs.2014.47.2.124 13. Heilo A, Stenwig AE, Solheim OP. Malignant pleural mesothelioma: US-guided histologic core-needle biopsy. Radiology. 1999; 211(3):657-9. https://doi.org/10.1148/radiology.211.3.r99jn03657 14. Haridas N, Suraj KP, Rajagopal TP, James PT, Chetambath R. Medical Thoracoscopy vs Closed Pleural Biopsy in Pleural Effusions: A Randomized Controlled Study. J Clin Diagn Res. 2014;8(5):MC01-4. 15. Boutin C, Rey F. Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 1: Diagnosis. Cancer. 1993;72(2):389-93. https://doi.org/10.1002/10970142(19930715)72:2<389::AID-CNCR2820720213>3.0.CO;2-V 16. Metintas M, Ak G, Dundar E, Yildirim H, Ozkan R, Kurt E, et al. Medical thoracoscopy vs CT scan-guided Abrams pleural needle biopsy for diagnosis of patients with pleural effusions: a randomized, controlled trial. Chest. 2010;137(6):1362-8. https://doi.org/10.1378/ chest.09-0884 17. Adams RF, Gleeson FV. Percutaneous image-guided cutting-needle biopsy of the pleura in the presence of a suspected malignant effusion. Radiology. 2001;219(2):510-4. https://doi.org/10.1148/ radiology.219.2.r01ma07510

J Bras Pneumol. 2017;43(6):431-436 http://dx.doi.org/10.1590/S1806-37562016000000298

ORIGINAL ARTICLE

Survival in a cohort of patients with lung cancer: the role of age and gender in prognosis Juliana Pereira Franceschini1, Sérgio Jamnik1, Ilka Lopes Santoro1 1. Disciplina de Pneumologia, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP) Brasil. Submitted: 21 September 2016. Accepted: 10 July 2017. Study carried out in the Disciplina de Pneumologia, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP) Brasil.

ABSTRACT Objective: To determine the demographic and clinical characteristics of patients with non-small cell lung cancer (NSCLC), as well as their disease course, by age group and gender. Methods: This was a retrospective cohort study of patients diagnosed with NSCLC from 2000 to 2012 and followed until July 2015 in a tertiary referral hospital in the city of São Paulo, Brazil. Based on the 25th and 75th percentiles of the age distribution, patients were stratified into three age groups: < 55 years; ≥ 55 and < 72 years; and ≥ 72 years. Survival time was evaluated during the follow-up period of the study. Functions of overall and gender-specific survival stratified by age groups (event: all-cause mortality) were calculated using the Kaplan-Meier method. Differences among survival curves were assessed via the log-rank test. Results: We included 790 patients with the following age distribution: < 55 years, 165 patients; ≥ 55 and < 72 years, 423; and ≥ 72 years, 202. In the entire sample, there were 493 men (62.4%). Adenocarcinoma was the most common histological pattern in the < 72-year age groups; 575 patients (73%) presented with advanced disease (stages IIIB-IV). The median 5-year survival was 12 months (95% CI: 4-46 months), with no significant differences among the age groups studied. Conclusions: NSCLC remains more common in men, although we found an increase in the proportion of the disease in women in the < 55-year age group. Adenocarcinoma predominated in women. In men, squamous cell carcinoma predominated in the ≥ 72year age group. Most patients presented with advanced-stage disease at diagnosis. There were no statistical differences in survival between genders or among age groups. Keywords: Lung neoplasms; Age groups, Sex; Survival.

INTRODUCTION Changes in the demographic structure of the Brazilian population indicate a process of population aging. According to data from the Brazilian Institute of Geography and Statistics, the proportion of elderly individuals increased from 7.2% in 2000 to 11.7% in 2015, currently consisting of a contingent of more than 23 million people.(1) The demographic transition results in an epidemiological transition, which means that the population’s disease profile has changed to that of chronic diseases. In Brazil, as well as in other countries in the world, lung cancer remains an elderly disease.(2-4) The proportion of lung cancer patients aged 50 or younger is estimated to be at most 12%.(5-9) In addition, lung cancer has ceased to be an almost exclusively male disease and has become increasingly common among women. Furthermore, this neoplasm occurs more frequently in patients with a history of smoking, and the closing gap in smoking rates between men and women is one of the contributing factors to the increase in the incidence of lung cancer in women.(10) There are few studies in the literature that have evaluated the course of non-small cell lung cancer (NSCLC) by age group and gender. Therefore, the objective of the present study was to determine the major demographic

and clinical characteristics of patients with NSCLC, as well as their disease course, by gender and age group. METHODS This was a retrospective cohort study nested within a structured database (which is part of a hospital tumor registry) and involving lung cancer patients followed in a tertiary referral hospital in the city of São Paulo, Brazil. The present study was approved by the local research ethics committee, and all patients gave written informed consent at the time of their entry into the database. The start data of observation was January 1, 2000, and the deadline for inclusion of new cases in the cohort was July 31, 2012; for the purpose of the study, patients were followed until July 31, 2015. We included all patients with a histologically and cytologically proven diagnosis of NSCLC who were treated in the aforementioned hospital. At the time of diagnosis, data on demographic and clinical variables, such as age, gender, functional status (as measured by the Karnofsky performance status), smoking status (never vs. current or former smoker), and smoking history (in pack-years) were collected, as were data on tumor-related variables, such as histological type (adenocarcinoma, squamous

Correspondence to:

Ilka Lopes Santoro. Disciplina de Pneumologia, Universidade Federal de São Paulo, Rua Botucatu, 740, 3º andar, CEP 04023-062, São Paulo, SP, Brasil. Tel./Fax: 55 11 5576-4238 or 55 11 5082-5105. E-mail: ilkasantoro@gmail.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Survival in a cohort of patients with lung cancer: the role of age and gender in prognosis

carcinoma, other), stage (IA-IIIA vs. IIIB-IV), and presence of site-specific metastasis, categorized as intrathoracic or extrathoracic. Based on the 25th and 75th percentiles of the age distribution, patients were stratified into three age groups: < 55 years; ≥ 55 and < 72 years; and ≥ 72 years. Survival time, defined as the time between the date of histological diagnosis and the date of the last event, was recorded during follow-up. A last event was defined as all-cause mortality (date of death), as the patient being alive at the end of the study follow-up, or as the patient being lost to follow-up—this patient was censored at the last date of contact. Data are expressed as mean ± SD or as median (interquartile range). Categorical variables were analyzed with the chi-square test or Fisher’s exact test, and numerical variables were analyzed using one-way ANOVA (complemented by the Bonferroni test) or the Kruskal-Wallis test (complemented by Duncan’s test) depending on the sample distribution. Functions of overall and gender-specific survival stratified by age group were calculated using the Kaplan-Meier method. Differences among survival curves were assessed via the log-rank test. Test results with an α error < 5% (p < 0.05) were considered significant. Data were analyzed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA). RESULTS During the study inclusion period, we identified 790 patients with a diagnosis of NSCLC, 493 (62.4%) of whom were male and 297 (37.6%) of whom were female. The mean age of the entire study sample was 64 ± 11 years, ranging from 27 to 93 years. It is important to emphasize that the female gender had a lower median age and a lower 25th percentile than those of the male gender (62 and 54 vs. 66 and 58 years, respectively). In addition, we observed that 10% of women were less than 50 years of age at the time of diagnosis, whereas only 5% of men were in the youngest age group. Figure 1 illustrates the distribution of the 790 patients studied, divided by gender, in relation to age percentiles. Male patients predominated in all age groups studied; however, the female/male ratio was highest in the youngest age group, and this difference was statistically significant (p = 0.012; Table 1). Although the median Karnofsky performance status was the same for the three age groups, the ≥ 72-year age group had a lower proportion of patients with Karnofsky performance status above the median than did the other age groups (p = 0.007; Table 1). Smoking was confirmed in 664 (84%) of the cases evaluated, with 462 men (94%) and 202 women (68%) being smokers. There was a predominance of smokers among male patients for all age groups. In addition, the female/male ratio of smokers increased inversely 432

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Female gender Male gender

Gender F M

60 Age

Percentile 5 10 25 50 75 90 95 42.00 47.80 54.00 62.00 72.00 77.20 83.00 47.00 52.00 58.00 66.00 72.00 77.00 81.00

Figure 1. Age percentile distribution, by gender, for the 790 patients studied.

proportionally to increasing age group; however, this difference did not reach statistical significance (Table 1). The median smoking history of the entire sample was 45 pack-years (interquartile range: 30-63 pack-years), with patients in the ≥ 72-year age group having a higher mean smoking history than those in the other age groups (p < 0.001). Although women smoked less than men in all age groups, the gender difference in smoking history was lowest in the youngest age group (Table 1). Adenocarcinoma was the most common histological pattern for individuals aged 71 or younger, although this difference did not reach statistical significance (Table 1). In the female gender, adenocarcinoma predominated in all age groups, whereas squamous carcinoma predominated in the oldest age group in the male gender. Although there was a predominance of adenocarcinoma among women, regardless of smoking status, the proportion of adenocarcinoma among neversmoking women was higher (p = 0.04). In the male gender, there was a predominance of adenocarcinoma among never smokers and a predominance of squamous carcinoma among smokers (p = 0.001). A total of 575 patients (73%) were found to have advanced NSCLC (stages IIIB-IV). There was no difference in disease stage distribution among the different age groups studied (Table 1). A total of 368 patients (47%) did not present with metastasis at diagnosis. The ≥ 55- and < 72-year age group had the highest proportion of patients without metastasis, whereas the < 55-year age group had the highest proportion of individuals with extrathoracic metastasis (p < 0.046; Table 1). The most common site of metastasis was the lung, followed by the pleura. Of the extrathoracic sites of metastasis, the brain was the most common. There were no differences in the

Franceschini JP, Jamnik S, Santoro IL

Table 1. Demographic and clinical data of 790 patients with non-small cell lung cancer, by age group.a

Variable

Male gender Karnofsky performance status Smoking Male Female Smoking history, pack-years Male Female Tumor size, cm Histological type Adenocarcinoma Squamous cell carcinoma Other Baseline stage of disease IA-IIIA IIIB-IV Metastasis at T0 M0 M1a M1b Deaths Follow-up, months

< 55 (n = 165) 87 (53) 80.7 ± 14.4 136 (82) 78 (90) 58 (74) 34.7 ± 22.7 39.1 ± 24.5 28.9 ± 18.8 5.1 ± 2.6

Age, years ≥ 55 and < 72 (n = 423) 279 (66) 79.9 ± 14.7 363 (86) 263 (94) 100 (69) 53.3 ± 30.2 57.8 ± 28.8 41.6 ± 30.6 4.7 ± 2.5

≥ 72 (n = 202) 127 (63) 76.4 ± 15.3 165 (82) 121 (95) 44 (59) 63.4 ± 41.4 70.7 ± 42.2 42.2 ± 31.3 4.8 ± 2.3

92 (56) 52 (32) 21 (12)

216 (51) 170 (40) 37 (09)

91 (45) 91 (45) 20 (10)

34 (21) 131 (79)

127 (30) 294 (70)

52 (26) 150 (74)

70 (42) 45 (27) 50 (30) 83 (50) 4.9 [1.3-13.2]

213 (50) 108 (26) 102 (24) 232 (55) 6.5 [2.0-16.3]

85 (42) 71 (35) 46 (23) 105 (52) 4.4 [1.4-12.9]

0.012* 0.007‡ 0.34* 0.21* 0.10* < 0.001‡

0.52‡ 0.13*

0.057*

0.046*

0.56* 0.07†

T0: date on which the diagnosis of lung cancer was confirmed; M0: no metastasis; M1a: lung or pleural/pericardial metastasis; and M1b: adrenal, brain, liver, bone, or other metastasis. aValues expressed as n (%), mean ± SD, or median [interquartile range]. *Chi-square test. ‡One-way ANOVA (complemented by the Bonferroni test). †KruskalWallis test (complemented by Duncan’s test).

distribution of metastasis sites among the age groups (Table 2). The median 5-year survival was 12 months (95% CI: 4-46 months) with a follow-up of at least 3 years (Table 1). There was no significant difference in agegroup specific survival (Figure 2). The same was true for gender-specific survival. DISCUSSION Lung cancer is a disease that predominates in elderly individuals, and, according to the literature, its incidence gradually increases with advancing age. (3,11) However, 21% of the study population were less than 55 years of age at diagnosis, with 10% of women being less than 50 years of age. Group stratification was based on percentiles of the age distribution rather than on the international definition of elderly, which considers the age of 60 years as a cut-off point for developing countries. The percentile-based cut-off point was chosen because we wanted to adjust the patient group distribution to the particular characteristics of our sample. The world literature shows that, although most lung cancer patients in all age groups are male, the gender difference in the number of cases is smaller in younger age groups,(12) which corroborates the results of the present study, since the proportion of women

was highest in the < 55-year age group. Similarly, it is known that, in general, young patients with lung cancer are female, are never smokers, predominantly have adenocarcinoma histology, and are diagnosed at an advanced stage of disease.(13) According to the World Health Organization, women currently represent 20% of smokers worldwide.(14) In the present study, not only was the proportion of female smokers higher in the youngest age group than in the others, but also the gender difference in smoking history was smaller. This is in line with data on smoking in Brazil, which demonstrate that the decline in the number of smokers has been less pronounced among females than males since 1980, when this type of epidemiological research began.(11,15) The decrease in smoking habit observed over the study period was concomitant with national interventions for smoking control, such as pictorial cigarette pack warnings, advertising restriction, laws establishing smoke-free environments, and cigarette price and tax increases.(16,17) Another contributing factor to closing the gap in smoking rates between women and men in the < 55-year age group is the probable greater difficulty experienced by women in quitting smoking.(18-20) This is probably related both to physical factors, such as the relationship between nicotine and female hormones, and to emotional factors associated with mood and J Bras Pneumol. 2017;43(6):431-436

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Survival in a cohort of patients with lung cancer: the role of age and gender in prognosis

affect. In addition, earlier age at smoking initiation and longer-term tobacco consumption translate into greater difficulty in quitting smoking.(11) The increase in smoking among women is one of the factors that may explain the increase in lung cancer mortality in this population.(21,22) In our study, we observed a higher number of women in the < 55-year age group than in the other age groups. The < 55-year age group comprised a higher proportion of patients diagnosed with adenocarcinoma. In general, adenocarcinoma is more weakly related to the smoking habit than is squamous carcinoma,(23,24) which was more common in individuals who were older and had a greater smoking history. There were no differences in survival among the different age groups studied. This may be related to

disease stage at diagnosis, which also did not differ among the age groups, with most individuals presenting with either locally advanced or metastatic disease at diagnosis, which is in agreement with the findings reported in the international literature.(25) With regard to metastasis, we found that, in the oldest age group, the prevalence of brain and adrenal metastasis was lower than in the other age groups studied, although there were no significant differences. International consensus guidelines on cancer treatment are not always applicable to patients in extreme age groups (i.e., young or elderly patients). Therefore, appropriate follow-up of such individuals becomes increasingly important.(26,27) With advancing age, patients are more likely to have comorbidities that may lead to polypharmacy, and, in addition, physiological changes inherent in the aging process may impair renal

Table 2. Distribution of sites of intrathoracic and extrathoracic metastasis for the three groups of patients with nonsmall cell lung cancer, by age group.a

Variable < 55 (n = 165)

Age, years ≥ 55 and < 72 (n = 423)

≥ 72 (n = 202)

Lung Pleura/pericardium

23 (51) 22 (49)

54 (50) 54 (50)

44 (62) 27 (38)

Adrenal Brain Liver Bone Other

8 (16) 18 (36) 7 (14) 13 (26) 4 (8)

17 (17) 38 (37) 19 (19) 24 (24) 4 (4)

4 (9) 11 (24) 14 (30) 14 (30) 3 (7)

M1a

0.24

M1b

0.40

Values expressed as n (%).

Female gender Age group, years < 55 ≥ 55 and < 72 ≥ 72 < 55 − censored cases ≥ 55 and < 72 − censored cases ≥ 72 − censored cases

Age group, years

1.0

< ≥ ≥ < ≥ ≥

0.6

and < 72 − censurados and < 72 − censurados − censored cases

0.8 0.6 0.4

0.0

log-rank = 0.81 0.4

0.2

0.0 0

Survival time (in months)

100

log-rank = 0.96

0.2

Survival probability curve

0.8

55 55 72 55 55 72

Survival probability curve

1.0

0 20 40 60 80 100 Survival time (in months) Male gender Age group, years 1.0 < 55 ≥ 55 and < 72 0.8 ≥ 72 < 55 − censored cases ≥ 55 and < 72 − censored cases 0.6 ≥ 72 − censored cases 0.4

log-rank = 0.57

0.2 0.0 0

100

Survival time (in months)

Figure 2. Overall and gender-specific survival probability curves for non-small cell lung cancer patients stratified by age group.

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and hepatic functions, bringing about changes that affect the pharmacokinetics and pharmacodynamics of medications, with a consequent increase in adverse effects associated with chemotherapy treatment.(3,27) In the present study, functional status in the oldest age group, as measured by the Karnofsky performance status, was lower than that in the other age groups, which may be related to the presence of frailty and comorbidities. The major contribution of the present study is that it described and compared the clinical characteristics of a sample of lung cancer patients of different age groups, with an emphasis on extreme age groups. Among its limitations is the fact that it is a retrospective study conducted in a single tertiary referral center, which may increase the risk of selection bias inherent in the design, with implications for the external validity of the

results, although patient inclusion was consecutive. In addition, it was not possible to determine possible comorbidities in the patients by using objective methods, such as the Charlson comorbidity index. The present study presented the characteristics of lung cancer patients, stratified by age group. On that basis, we conclude that the frequency of NSCLC remains higher among men, although we observed an increase in the proportion of the disease in women in the youngest age group (< 55 years) when compared with the other age groups. Adenocarcinoma was the predominant histological type in women. In men, squamous carcinoma predominated in patients ≥ 72 years of age. Most patients presented with advancedstage disease at diagnosis. There were no statistical differences in survival between genders or among age groups.

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24. Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol. 2007;25(5):561-70. https://doi.org/10.1200/ JCO.2006.06.8015 25. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global

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Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548. https:// doi.org/10.1001/jamaoncol.2016.5688 26. Repetto L, Luciani A. Cancer treatment in elderly patients: evidence and clinical research [Article in Italian]. Recenti Prog Med. 2015;106(1):23-7. 27. Froesch P, Martucci F, Gyรถrik S, Dutly AE, Cafarotti S. Management of non-small cell lung cancer in the elderly. Eur J Intern Med. 2014;25(10):888-94. https://doi.org/10.1016/j.ejim.2014.10.024

J Bras Pneumol. 2017;43(6):437-444 http://dx.doi.org/10.1590/S1806-37562017000000004

ORIGINAL ARTICLE

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country Marcelo Fouad Rabahi1,2, José Laerte Rodrigues da Silva Júnior2,3, Marcus Barreto Conde4,5 1. Faculdade de Medicina, Universidade Federal de Goiás, Goiânia (GO) Brasil. 2. Centro Universitário de Anápolis, Anápolis (GO) Brasil. 3. Universidade de Rio Verde, Aparecida de Goiânia (GO) Brasil. 4. Faculdade de Medicina de Petrópolis, Petrópolis (RJ) Brasil. 5. Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. Submitted: 3 January 2017. Accepted: 18 June 2017. Study carried out at the Faculdade de Medicina, Universidade Federal de Goiás, Goiânia (GO) Brasil.

ABSTRACT Objective: To analyze the impact that the 2009 changes in tuberculosis treatment in Brazil had on the rates of cure, tuberculosis recurrence, mortality, treatment abandonment, and multidrug-resistant tuberculosis (MDR-TB). Methods: An ordinary least squares regression model was used in order to perform an interrupted time series analysis of secondary data collected from the Brazilian Tuberculosis Case Registry Database for the period between January of 2003 and December of 2014. Results: The 2009 changes in tuberculosis treatment in Brazil were found to have no association with reductions in the total number of cases (β = 2.17; 95% CI: −3.80 to 8.14; p = 0.47) and in the number of new cases (β = −0.97; 95% CI: −5.89 to 3.94; p = 0.70), as well as having no association with treatment abandonment rates (β = 0.40; 95% CI: −1.12 to 1.93; p = 0.60). The changes in tuberculosis treatment also showed a trend toward an association with decreased cure rates (β = −4.14; 95% CI: −8.63 to 0.34; p = 0.07), as well as an association with increased mortality from pulmonary tuberculosis (β = 0.77; 95% CI: 0.16 to 1.38; p = 0.01). Although there was a significant increase in MDR-TB before and after the changes (p < 0.0001), there was no association between the intervention (i.e., the changes in tuberculosis treatment) and the increase in MDR-TB cases. Conclusions: The changes in tuberculosis treatment were unable to contain the decrease in cure rates, the increase in treatment abandonment rates, and the increase in MDR-TB rates, being associated with increased mortality from pulmonary tuberculosis during the study period. Keywords: Tuberculosis, pulmonary/epidemiology; Tuberculosis, pulmonary/drug therapy; Tuberculosis, pulmonary/mortality; Interrupted time series analysis; Drug resistance, multiple; Drug compounding.

INTRODUCTION According to the World Health Organization, there were 10.4 million new cases of tuberculosis worldwide in 2015, with 1 million cases among children and 1.2 million cases among people living with HIV.(1) In addition, there were 1.4 million deaths from tuberculosis, 400,000 of which were due to tuberculosis/HIV coinfection; therefore, tuberculosis remains one of the 10 leading causes of death worldwide.(1) Brazil is among the 20 countries that together account for 84% of all incident cases of tuberculosis (in absolute numbers) and 87% of all incident cases of tuberculosis among people living with HIV worldwide.(1) Because of an increase in primary resistance to isoniazid (H) and rifampin (R), the Brazilian National Ministry of Health made a decision to change the basic treatment regimen for tuberculosis, which had been the same since the 1970s.(2-5) Therefore, as of December of 2009, the basic regimen consisted of a fixed-dose, single-tablet combination of R, H, pyrazinamide (Z), and ethambutol (E) for two months, followed by a combination of R and H for four months (2RHZE/4RH regimen).(3,5) In addition,

the daily dose of H was reduced from 400 mg to 300 mg (for individuals weighing 50 kg or more), and that of Z was reduced from 2,000 mg to 1,500 mg (for individuals weighing 50 kg or more).(2-4) By adding E to the previous drug regimen (i.e., RHZ), the Brazilian National Ministry of Health expected to increase cure rates and prevent an increase in multidrug resistance (i.e., resistance to R and H).(3,4) The Brazilian National Ministry of Health also expected that fixed-dose combination (FDC) tablets would increase patient comfort (by reducing the number of tablets to be taken), prevent patients from taking the drugs separately, and reduce treatment abandonment rates, thus increasing treatment adherence.(3) The objective of the present study was to analyze the impact that the 2009 changes in tuberculosis treatment in Brazil had on the rates of cure, treatment abandonment, mortality, and multidrug-resistant tuberculosis (MDR-TB). METHODS We used an ordinary least squares regression model in order to perform an interrupted time series analysis (ITSA) of

Correspondence to:

Marcelo Rabahi. Avenida B, 483, CEP 74605-220, Goiânia, GO, Brasil. Tel.: 55 62 99975-3381. Fax: 55 62 3521-3333. E-mail: mfrabahi@gmail.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

secondary data collected from the Sistema de Informação de Agravos de Notificação da Tuberculose (SINAN-TB, Brazilian Tuberculosis Case Registry Database).(6-8) We collected monthly data for the period between January of 2003 and December of 2014. We used the Stata statistical software package, version 13.1 (StataCorp LP, College Station, TX, USA). ITSA was performed as described by Linden.(9) In brief, regression coefficients were estimated by the ordinary least squares method, producing Newey-West standard errors. Subsequently, the Cumby-Huizinga test was applied to the error distribution in order to test for residual autocorrelation, which was adjusted for by Prais-Winsten regression, when necessary. Seasonality was accounted for by the use of dummy variables in order to define each month of the year, dummy variables being used as adjustment factors in the analysis. Given that an ITSA of a single group does not have a comparable control group, the pre-intervention trend projected for the post-intervention period serves as a counterfactual. Trend analysis was used in order to determine whether there was a statistically significant difference between the pre- and post-intervention slopes outside the intervention period. The following formula was used: Yt = β0 + β1Tt + β2Tt + β3XtTt + ∈t where Yt is an aggregate outcome variable, measured at t equally spaced time points; Tt is time elapsed since the beginning of the study; Xt (indicator) represents the intervention; XtTt is an interaction term; and ∈t is the random error. In the present study, which involved only one group, β0 represents the intercept of the line on the vertical axis (initial level of the outcome variable); β1 is the slope or trajectory of the outcome variable before the intervention; β2 represents the change in the level of outcome immediately after the introduction of the intervention; and β3 represents the difference between the pre- and post-intervention slopes. Therefore, significant values of p at β2 indicate an immediate intervention effect, and significant values of p at β3 indicate an intervention effect over time. Interrupted time series plots show (monthly) study variable data (dots) and data regression (straight line). Figure 1 shows pre-, mid-, and post-intervention data (from January of 2003 to November of 2009, from December of 2009 to December of 2010, and from January of 2011 to December of 2014, respectively), the intervention being tuberculosis treatment changes. We used an intervention time frame (from December of 2009 to December of 2010) rather than an intervention time point because that was the estimated time required to implement the new treatment in all health care facilities in Brazil. In addition, tuberculosis treatment lasts at least six months (being as long as nine months in some cases), and patients whose treatment was started in the month prior to the change would continue to receive the old treatment for at least another five months. If the slope (gradient) of the trend line is the same before and after the intervention (i.e., tuberculosis treatment changes), it means that the trend in the data for the study variable remains the same despite 438

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the intervention. A decrease in the slope of the line after the intervention suggests a downward trend in the data, whereas an increase in the slope of the line after the intervention suggests an upward trend in the data. However, statistical analysis is the only means of determining whether (potential) changes in the data and an upward or downward shift in the regression line after the intervention are significant, i.e., whether they are related to or independent of the intervention. The results of our statistical analysis were expressed as β regression coefficients. The confidence interval was 95%, and the significance level was 5%. Only data on pulmonary tuberculosis were included, given that most of the tuberculosis cases that are diagnosed by sputum smear microscopy, Mycobacterium tuberculosis culture, or a combination of the two are pulmonary tuberculosis cases rather than extrapulmonary tuberculosis cases, which are commonly diagnosed on the basis of patient response to empirical treatment. Given that the new treatment was used only in individuals who were 10 years of age or older, those who were younger than 10 years of age were not included in the analyses. We collected data on the following variables: total number of cases of pulmonary tuberculosis; number of new cases of pulmonary tuberculosis; number of cases of tuberculosis recurrence; number of cases of retreatment after treatment abandonment; treatment outcomes (cure, treatment abandonment, mortality from tuberculosis, and mortality from other causes); number of cases of MDR-TB; number of HIV tests performed; number of cultures for M. tuberculosis; number of positive HIV test results; and number of positive cultures for M. tuberculosis. The SINAN-TB defines cure as the sum of the cases of patients who were discharged and patients who completed the six months of treatment. Up until 2010 (when tuberculosis treatment was changed), tuberculosis recurrence was defined as development of a new tuberculosis case within twelve months after cure. In 2011, the Programa Nacional de Controle da Tuberculose (PNCT, Brazilian National Tuberculosis Control Program) definition of tuberculosis recurrence was changed to “a case of active tuberculosis in a previously treated and cured patient, regardless of the time elapsed since the previous treatment”.(4) Therefore, in 2011, the SINAN-TB and PNCT definitions of tuberculosis recurrence came to be the same (personal communication). Although the previous definition was operational and included cases of exogenous reinfection, it was aimed at identifying cases of true recurrence, caused by the same bacterial strain that caused the first episode of tuberculosis, as a result of incomplete sterilization of the infecting bacilli. As a result of the new definition, the recurrence cases reported after 2010/2011 differed from those reported before that. This introduced a confounding factor that precludes the evaluation of the impact of the intervention on that variable. The rates of cure and treatment abandonment were calculated in relation to the total number of cases of pulmonary tuberculosis

Rabahi MF, Silva Júnior JLR, Conde MB

after exclusion of cases in which the outcome was unknown. Given that this was an ecological study, no research ethics committee approval was required. RESULTS Table 1 shows SINAN-TB data on pulmonary tuberculosis in individuals 10 years of age or older for the 2003-2014 period. Figure 1 shows graphical representations of cure, treatment abandonment, MDR-TB, and mortality rates in the study period. Beginning in 2003, there was a continuous decrease in cure rates and a steady increase in treatment abandonment, mortality, and MDR-TB rates (Figure 1). Figure 2 shows interrupted time series plots demonstrating the impact of the intervention (tuberculosis treatment changes) on tuberculosis-related variables. As can be seen in Figure 2A, there was a statistically significant decrease in the total number of reported cases of tuberculosis before the intervention (p < 0.0001); however, after the intervention, that decrease was no longer significant (p = 0.09). There was a significant decrease in the number of reported new cases of pulmonary tuberculosis before the intervention (p < 0.0001), and that decrease remained significant after the intervention (p = 0.01). However, our ITSA showed that the reductions in the total number of reported cases of tuberculosis (β = 2.17; 95% CI: −3.80 to 8.14; p = 0.47) and in the number of reported new cases of tuberculosis (β = −0.97; 95% CI: −5.89 to 3.94; p = 0.70) occurred independently of the intervention. Figure 2C shows that there were significant decreases in cure rates before and after the intervention (p < 0.0001 for both). Although our statistical analysis showed that those decreases occurred independently of the intervention (β = −4.14; 95% CI: −8.63 to 0.34; p = 0.07), the fact that the value of p was = 0.07 shows a trend toward an association between tuberculosis treatment changes and decreased cure rates. Figure 2D shows that treatment abandonment rates were high throughout the study period regardless of the intervention (β = 0.40; 95% CI: −1.12 to 1.93; p = 0.60). It is of note that there was a significant decrease in treatment abandonment rates during the period in which the intervention was implemented (β = −7.28; 95% CI: −11.6 to 2.93; p = 0.001). As can be seen in Figure 2E, there was no statistical association between tuberculosis treatment changes and MDR-TB cases (β = 0.13; 95% CI: −0.03 to 0.29; p = 0.12). However, there were significant increases in the numbers of MDR-TB cases before and after tuberculosis treatment changes (p < 0.0001 for both). As can be seen in Table 1, the reported number of deaths from tuberculosis was found to have increased from 85 in 2003 to 2,482 in 2007, a finding that suggests that there was an SINAN-TB criterion change or reporting problem. Therefore, we analyzed the total number of deaths (i.e., the sum of deaths from pulmonary tuberculosis and other causes) in the study period (from 2003 to 2014) and performed a separate analysis of

deaths from pulmonary tuberculosis and other causes from 2007 to 2014 (rather than from 2003 to 2014). As can be seen in Figure 2F, the slope of the trend line after the intervention suggests a nonsignificant reduction in the total number of deaths, which might have been due to a significant reduction in the number of deaths from other causes (Figure 2G) between the pre- and post-intervention periods (β = −0.86; 95% CI: −1.50 to −0.21; p = 0.01). In contrast, with regard to mortality from pulmonary tuberculosis (Figure 2H), the slope of the trend line after the intervention (β = 0.39; 95% CI: 0.03 to 0.75; p = 0.04) and statistical analysis comparing the pre- and post-intervention periods (β = 0.77; 95% CI: 0.16 to 1.38; p = 0.01) showed an association between the intervention and increased mortality from pulmonary tuberculosis. DISCUSSION For the 2003-2014 period in Brazil, SINAN-TB data show a decrease in the total number of reported cases of pulmonary tuberculosis, a decrease in the number of reported new cases of pulmonary tuberculosis, and a continuous decrease in cure rates, as well as a steady increase in the rates of recurrence, MDR-TB, and mortality, together with high rates of treatment abandonment. Our ITSA revealed that, in addition to being associated with an increase in the number of deaths from pulmonary tuberculosis, the intervention (the changes in tuberculosis treatment) showed a trend toward an association with a further decline in cure rates, having had no impact on the increase in the number of cases of MDR-TB or on the high rates of treatment abandonment (i.e., having been statistically independent of both). In addition, the possibility of underreporting cannot be ruled out. The tuberculosis incidence rate has decreased since the 1980s, having decreased from 70.4/100,000 population in 1982 to 43.0/100,000 population in 2010. (10-12) This might be due to the Emergency Plan for Tuberculosis Control in 1996-1997, the PNCT in 1998 (which extended coverage, implemented supervised treatment, and created a new way of transferring resources to municipalities), and the provision of antiretroviral therapy to patients with tuberculosis/ HIV coinfection, among many other measures.(10-12) However, the rates of cure, drug resistance, and treatment abandonment have remained below the goal since the 1980s.(3,10-12) Therefore, it is possible that other variables are involved in the decrease in the number of reported cases of pulmonary tuberculosis in Brazil. The tuberculosis incidence rate has been shown to be inversely associated with variables such as per capita income and gross domestic product.(13-16) Therefore, it is possible that economic stability and the increase in gross domestic product in Brazil in the last 25 years have contributed to reducing the number of tuberculosis cases. In this context, the current rates of cure and treatment abandonment (which are far from those recommended by the World Health Organization), together with the current economic J Bras Pneumol. 2017;43(6):437-444

439

440

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2004

75,201

61,980 4,967

4,568

3,247 439

51,486 (79.8) 8,438 (13.1) 4,458 (6.9) 104 (0.2) 4,354 (6.7) 5,869 157 (0.2) 15,131 (20) 5,812 (38) 35,196 (47) 4,565 (13)

2003

75,890

62,497 5,186

4,591

2,823 794

51,891 (79.5) 8,649 (13.2) 4,650 (7.1) 85 (0.1) 4,565 (7.0) 6,216 122 (0.2) 14,077 (19) 5,514 (39) 32,813 (43) 4,697 (14)

52,529 (80.0) 8,018 (12.3) 4,689 (7.2) 262 (0.4) 4,427 (6.8) 5,864 175 (0.3) 16,061 (22) 6,662 (41) 37,513 (50) 4,681 (12)

3,512 396

4,325

61,507 4,716

74,456

2005

50,474 (79.5) 7,953 (12.5) 4,898 (7.7) 1,287 (2.0) 3,611 (5.7) 5,115 195 (0.3) 15,415 (21) 7,289 (47) 38,455 (53) 4,842 (13)

3,514 269

4,250

59,050 4,995

72,078

2006

48,069 (78.6) 7,939 (13.0) 4,916 (8.1) 2,482 (4.1) 2,434 (4.0) 4,795 257 (0.4) 15,316 (22) 7,531 (49) 39,608 (57) 5,243 (13)

3,237 201

3,940

57,045 4,468

68,891

2007

49,710 (78.6) 8,559 (13.5) 4,763 (7.6) 2,382 (3.8) 2,381 (3.8) 5,103 242 (0.4) 15,995 (22) 8,220 (51) 43,298 (61) 5,557 (13)

3,215 167

4,412

59,047 4,528

71,369

2008

49,376 (77.3) 9,200 (14.4) 4,981 (7.8) 2,389 (3.7) 2,592 (4.1) 5,395 350 (0.5) 9,223 (24) 17,348 (53) 45,742 (64) 5,668 (12)

3,226 198

4,626

58,924 4,512

71,486

2009

48,965 (77.1) 9,037 (14.2) 5,020 (7.9) 2,480 (3.9) 2,540 (4.0) 5,088 469 (0.7) 19,940 (28) 10,561 (53) 47,962 (68) 6,167 (13)

2,982 269

4,919

57,567 4,787

70,524

2010

51,195 (77.7) 9,114 (13.8) 5,073 (7.7) 2,317 (3.5) 2,756 (4.2) 5,142 496 (0.8) 21,682 (30) 11,403 (53) 50,983 (70) 6,441 (13)

2,904 199

4,989

58,943 5,365

72,400

2011

48,537 (76.7) 9,223 (14.6) 4,875 (7.7) 2,425 (3.8) 2,450 (3.9) 3,717 633 (1.0) 21,820 (32) 11,824 (54) 50,418 (73) 6,368 (13)

1,894 214

5,235

55,962 5,250

68,763

2012

49,324 (76.1) 9,856 (15.2) 5,065 (7.8) 2,547 (3.9) 2,518 (3.9) 3,886 611 (0.9) 23,221 (33) 12,917 (56) 54,251 (77) 6,564 (12)

1,585 232

6,347

56,980 5,353

70,626

2013

47,319 (75.7) 9,422 (15.1) 5,083 (8.1) 2,525 (4.0) 2,558 (4.1) 4,270 680 (1.1) 22,334 (32) 13,712 (61) 54,257 (77) 6,775 (12)

1,659 191

7,032

56,152 4,995

70,217

2014

TB: tuberculosis; MDR-TB: multidrug-resistant tuberculosis; and Mtb: Mycobacterium tuberculosis. aValues expressed as n or n (%). bThe rates of cure, treatment abandonment, and mortality were calculated in relation to the total number of pulmonary TB cases in which the outcome was known.

TB/HIV coinfection

Total number of HIV tests

Positive Mtb cultures

Total number of Mtb cultures

Transfer MDR-TB

Death from other causesb

Death from TBb

Total number of deathsb

Treatment abandonmentb

Year Type of entry in the database Total number of cases of pulmonary TB New cases of pulmonary TB Recurrence within < 1 year after discharge Retreatment after treatment abandonment Transfer Unknown Pulmonary TB outcome Cureb

Table 1. Annual data on pulmonary tuberculosis in Brazil for the period between January of 2003 and December of 2014.a

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

Rabahi MF, Silva JĂşnior JLR, Conde MB

Cure

Treatment abandonment

79 14

77 76

75 11

MDR-TB

20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14

Mortality

20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14

1.2

8.5

0.8

7.5

0.6

0.4

6.5

0.2

0 03

12 13 20 14 20

07 08 20

Figure 1. Graphical representations of cure, treatmet abandonment, mortality, and multidrug-resistant tuberculosis (MDR-TB) rates in the 2003-2014 period. The vertical axis (ordinate) represents the proportions relative to the total number of cases of pulmonary tuberculosis during the study period. The horizontal axis (abscissa) represents the variable â&#x20AC;&#x153;yearsâ&#x20AC;?. The dashed rectangle represents the transition from the old to the new tuberculosis treatment in Brazil.

crisis in the country, might affect the decrease in the incidence rate of tuberculosis (or even increase it) in the coming years.(1) The 2011 change in the definition of tuberculosis recurrence by the PNCT, whereby any patient who had had tuberculosis was considered to have recurrent tuberculosis regardless of the time elapsed between the first and second episodes, was expected to reduce the number of new cases and increase the total number of reported cases. This might explain why the decrease in the number of reported new cases remained significant after 2010 (p = 0.01), whereas the decrease in the total number of reported cases did not (p = 0.09). By adding a fourth drug (E) to the RHZ regimen, the Brazilian National Ministry of Health expected to increase the cure rate.(3) According to the literature, treatment failure is unlikely to occur in patients with resistance to H treated with the RHZ regimen.(17,18) Therefore, the addition of E to the drug regimen was unlikely to result in a significant increase in the cure rate. However, the continuous decrease in cure rates since 2003 was not attenuated by the 2009/2010 tuberculosis treatment changes. In addition, our ITSA revealed a trend toward an association between the intervention and a further decline in cure rates. The low rate of cure of pulmonary tuberculosis patients can be attributed to a variety of reasons. One reason is treatment failure. There have been reports of bioavailability and absorption problems

affecting FDC formulations of R, particularly in people living with HIV and having a low CD4 count.(19-21) In a systematic review and meta-analysis published in 2013 and comparing FDC formulations and separate drug formulations for the treatment of tuberculosis, the risk of treatment failure or recurrence was found to be higher in the group of patients receiving treatment with FDC formulations (relative risk = 1.28; 95% CI: 0.99-1.70).(22) In Brazil, tuberculosis treatment changes included a change in formulation (from a separate drug formulation to a FDC formulation) and a reduction in the doses of H and Z.(3) In another systematic review, published in 2016, FDC formulations were compared with separate drug formulations and no differences were found between the two regarding treatment failure rates; however, there was a trend toward higher recurrence in the group of patients receiving treatment with FDC formulations (relative risk = 1.28; 95% CI: 1.00-1.64).(23) Given that the change in the definition of tuberculosis recurrence and the intervention occurred in the same period, the impact of the intervention on recurrence rates was not evaluated in the present study. Therefore, it is impossible to determine whether the increase in the number of cases of recurrence is due to the changes in tuberculosis treatment or to the inclusion of a larger number of cases of exogenous reinfection. True tuberculosis recurrence is due to incomplete sterilization of the infecting bacilli, which J Bras Pneumol. 2017;43(6):437-444

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6000

β = –6.42 (95% CI: –11.01 to –1.76) p = 0.01*

5500

New cases

6500

p = 0.24

5500

4500

5000

4000

6000

β = –5.34 (95% CI: –7.39 to –3.29) p < 0.0001*

01/2003 01/2005 01/2007 01/2009 01/2011 01/2013 12/2014

β = –4.14 (95% CI: –8.63 to 0.34) p = 0.07

200 150

01/2011 01/2009 01/2013 12/2014 01/2007 01/2008 01/2010 01/2012 01/2014

Trend

900 1000 1100 800 700 600

β = 0.43 (95% CI: 0.20 to 0.66) p < 0.0001*

p = 0.97

β = –0.05 (95% CI: –0.45 to 0.36) p = 0.82

01/2003 01/2005 01/2007 01/2009 01/2011 01/2013 12/2014 β = 0.77 (95% CI: 0.16 to 1.38) p = 0.01* β = 0.39 (95% CI: –0.85 to 0.09) p = 0.11 p = 0.59

β = 0.83 (95% CI: 0.03 to 0.75) p = 0.04*

250

300

200

β = –8.20 (95% CI: -11.58 to 4.76) p = 0.0001*

Deaths from TB

β = –3.94 (95% CI: –5.70 to –2.19) p < 0.0001* p = 0.33

β = –0.46 (95% CI: –1.01 to 0.09) p = 0.10

150

β = –0.86 (95% CI: –1.50 to –0.21) p = 0.01*

250

300

500

Cases of treatment abandonment

Cases of MDR-TB

20 0 01/2003 01/2005 01/2007 01/2009 01/2011 01/2013 12/2014

F 600

β = 0.35 (95% CI: 0.21 to 0.50) p < 0.0001*

01/2003 01/2005 01/2007 01/2009 01/2011 01/2013 12/2014

550

p = 0.17

Β = 0.83 (95% CI: –0.34 to –2.01) p = 0.16

500

β = 2.23 (95% CI: 0.16 to 0.29) p < 0.0001*

Total number of deaths (from TB and other causes)

β = –0.13 (95% CI: –0.03 to 0.29) p = 0.12

p = 0.001*

450

4500 4000 3500

01/2003 01/2005 01/2007 01/2009 01/2011 01/2013 12/2014

β = 0.40 (95% CI: –0.55 to 1.32) p < 0.39

400

β = –8.20 (95% CI: -11.58 to 4.76) p = 0.0001*

β = –0.40 (95% CI: –1.12 to 1.93) p = 0.60

350

p = 0.63

300

β = –3.94 (95% CI: –5.70 to –2.19) p < 0.0001*

Cases of cure

5000

5500

Deaths from other causes

β = -0.97 (95% CI: -5.89 to 3.94) p = 0.70

5000

β = –4.78 (95% CI: -10.37 to 0.81) p = 0.26 p = 0.09

6500

β = 2.17 (95% CI: –3.80 to 8.14) p = 0.47

β = –6.78 (95% CI: -9.28 to –4.29) p < 0.0001*

Total number of cases

7000

7500

01/2007 01/2009 01/2011 01/2013 12/2014 01/2008 01/2010 01/2012 01/2014

Measured values

Figure 2. Interrupted time series regressions for the following variables: total number of cases of pulmonary tuberculosis (in A); new cases (in B); cases of cure (in C); cases of treatment abandonment (in D); cases of multidrug-resistant tuberculosis (MDR-TB, in E); total number of deaths (in F); deaths from other causes (in G); and deaths from pulmonary tuberculosis (TB, in H). The dots represent the data collected for each variable each month from January of 2003 to December of 2014, and the straight line represents the data trend. The middle column corresponds to the period in which the intervention was implemented (between December of 2009 and December of 2010). *Statistically significant.

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Rabahi MF, Silva Júnior JLR, Conde MB

should be killed by R and Z.(20,24) In order to avoid (true) recurrence, the bioavailability and bioequivalence of FDC tablets should be studied before their use. Reduced cure rates can also be explained by increased treatment noncompliance. The fact that the treatment abandonment rate remained high regardless of the intervention suggests that the decrease in cure rates was independent of that variable. In addition, it shows that, contrary to what the Brazilian National Ministry of Health intended to achieve, the change to FDC tablets did not result in reduced treatment abandonment rates. This finding is similar to that of a systematic review and meta-analysis performed in 2013, which showed that FDC tablets did not result in increased treatment adherence in any of the five clinical trials in which that variable was analyzed.(22) There was a significant increase in the number of MDR-TB cases during the study period. The increase in the number of cultures for M. tuberculosis (from 19% in 2003 to 32% in 2014) is not sufficient to explain the increase in the number of diagnosed cases of MDR-TB (from 0.2% to 1.1%) over the same period. The post-intervention outcome was independent of the intervention; that is, the changes in tuberculosis treatment in Brazil had no impact on MDR-TB rates, which increased significantly before and after the intervention. From a programmatic standpoint, resistance results from M. tuberculosis exposure to one drug only or to lower-than-required doses.(17) Treatment adherence problems (treatment abandonment, incorrect/irregular drug use, or both), as well as inadequate dosing, absorption, or both, are associated with increased acquired resistance. (17,25) In the study population, incorrect drug use is unlikely because patients received treatment with an FDC formulation, which has been shown to have no association with reduced treatment abandonment rates.(22) Therefore, the high number of cases of treatment abandonment in the study period might be one of the variables involved in the increased number of cases of MDR-TB in Brazil. However, why was the tuberculosis treatment change in Brazil unable to contain the increase in MDR-TB in the country? The addition of E to the RHZ regimen reduced the risk of further resistance in patients with initial resistance to H alone, in those with simultaneous resistance to H and Z, and in those with resistance to R alone (which is rare) but has no protective effect in cases of simultaneous resistance to H and R (i.e., MDR-TB).(20) In addition, a bioavailability study conducted in 2013 demonstrated a lack of bioequivalence between FDC and separate drug formulations of H.(26) These data, together with the aforementioned bioavailability problems affecting FDC formulations of R and the aforementioned reduction in the doses of H and Z, underscore the importance of conducting bioequivalence and bioavailability studies of FDC formulations of tuberculosis therapy.(19-21) The increase in resistance appears to be associated with malfunctioning tuberculosis control programs.(25) In this sense, the increase in MDR-TB cases suggests

an increase in single-drug resistance and primary multidrug resistance, as demonstrated by studies conducted in different regions of the country.(27-29) These findings suggest that there is an urgent need to make M. tuberculosis culture and drug susceptibility testing available to all tuberculosis patients in Brazil. The increase in MDR-TB cases might also be due to an increase in the number of TB/HIV coinfection cases. However, despite a significant increase in the proportion of tuberculosis patients tested for HIV (from 43% in 2003 to 77% in 2014), the proportion of cases of coinfection decreased (from 14% in 2003 to 12% in 2014). Despite being below the goal of 100%, the proportion of tuberculosis patients tested for HIV increased significantly (to 77%) in the study period. The increase in the number of deaths from pulmonary tuberculosis from 2007 onward is a very relevant finding because pulmonary tuberculosis is a treatable disease and antituberculosis drugs are provided free of charge by the public health care system in Brazil. Although our ITSA showed an association between tuberculosis treatment changes and increased mortality from tuberculosis (as evidenced by the slope of the trend line and the regression coefficient), other variables might also be involved. Nevertheless, this is worrisome in the context of economic crisis, decreased cure rates, increased treatment noncompliance, and increased MDR-TB cases. The present study has several limitations. This was a study of secondary data, and they might be inaccurate. Molecular testing is not routinely performed under tuberculosis control programs to confirm whether a case of “tuberculosis recurrence” is indeed a case of infection with the same mycobacterial strain that caused the first episode of tuberculosis or whether it is actually a case of reinfection. Although the previous definition of recurrence (i.e., development of a new tuberculosis case within twelve months after cure) was widely accepted, it is no longer used. The analyzed data were not stratified by state or municipality. Therefore, our findings might not be representative of all Brazilian states and municipalities. Although all methodological designs can lead to erroneous conclusions, ITSA appears to be the least likely to in studies evaluating public health interventions.(6) In summary, during the study period, there were decreases in the number of reported new cases of pulmonary tuberculosis, the total number of cases, and cure rates, as well as increases in MDR-TB and mortality from pulmonary tuberculosis, together with a high rate of treatment abandonment. Our ITSA showed that the changes in tuberculosis treatment in Brazil did not result in reduced treatment abandonment or MDR-TB rates; they were associated with increased mortality from pulmonary tuberculosis and showed a trend toward a further decline in cure rates. ACKNOWLEDGMENTS The authors thank Professor Ronir Raggio Luiz at the Federal University of Rio de Janeiro for the suggestion of statistical analysis. J Bras Pneumol. 2017;43(6):437-444

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Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country

REFERENCES 1. World Health Organization [homepage on the Internet]. Geneva: WHO; c2016 [cited 2016 Oct 18]. Global Tuberculosis Report 2016 [about 2 screens]. Available from: http://www.who.int/tb/ publications/global_report/en/ 2. Conde MB, Melo FA, Marques AM, Cardoso NC, Pinheiro VG, Dalcin Pde T, et al. III Brazilian Thoracic Association Guidelines on tuberculosis. J Bras Pneumol. 2009;35(10):1018-48. https://doi. org/10.1590/S1806-37132009001000011 3. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Programa Nacional de Controle da Tuberculose [monograph on the Internet]. Brasília: Ministério da Saúde [cited 2016 Oct 18]. Nota técnica sobre as mudanças no tratamento da tuberculose no Brasil para adultos e adolescentes – Versão 2 [Adobe Acrobat document, 5p.]. Available from: http://www1.saude.rs.gov.br/dados/1293729099101Nota%20 T%E9cnica%20-%202%AA%20vers%E3o%20%28corrigida%20 em%2022-10%29.pdf 4. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância Epidemiológica. Manual de recomendações para o controle da tuberculose no Brasil. Brasília: Ministério da Saúde; 2011. 284 p. 5. Santos LA, Galesi VM. Mudança no esquema de tratamento da tuberculose. Bepa. 2010;7(73):28-32. 6. Soumerai SB, Starr D, Majumdar SR. How Do You Know Which Health Care Effectiveness Research You Can Trust? A Guide to Study Design for the Perplexed. Prev Chronic Dis. 2015;12:E101. https://doi.org/10.5888/pcd12.150187 7. Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27(4):299-309. https://doi. org/10.1046/j.1365-2710.2002.00430.x 8. Brasil. Ministério da Saúde. Portal da Saúde. Sistema de Informações de Agravos de Notificações [homepage on the Internet]. Brasília: Ministério da Saúde [cited 2016 Oct 18]. Informações de Saúde (TABNET) – Epidemiológicas e Mortalidade [about 2 screens]. Available from: http://www2.datasus.gov.br/DATASUS/index.php? area=0203&id=31009407&VObj=http://tabnet.datasus.gov.br/cgi/ tabcgi.exe?sinannet/cnv/tuberc 9. Linden A. Conducting interrupted time series analysis for single-and multiple-group comparisons. Stata J. 2015;15(2):480-500. 10. Ruffino-Netto A. Tuberculosis in Brazil: general information and new perspectives [Article in Portuguese]. Inf Epidemiol Sus. 2001;10(3):129-38. http://dx.doi.org/10.5123/S010416732001000300004 11. Hijar MA, Oliveira MJ, Teixeira GM. A tuberculose no Brasil e no mundo. Bol Pneumol Sanit. 2001;9(2):9-16. 12. Brasil. Ministério da Saúde. Coordenação de Pneumologia Sanitária. Manual de normas para o controle da tuberculose. Brasília: Ministério da Saúde; 1995. 13. Ploubidis GB, Palmer MJ, Blackmore C, Lim TA, Manissero D, Sandgren A, et al. Social determinants of tuberculosis in Europe: a prospective ecological study. Eur Respir J. 2012;40(4):925-30. https://doi.org/10.1183/09031936.00184011 14. Myers WP, Westenhouse JL, Flood J, Riley LW. An ecological study of tuberculosis transmission in California. Am J Public Health. 2006;96(4):685-90. https://doi.org/10.2105/AJPH.2004.048132

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15. Janssens JP, Rieder HL. An ecologic analysis of incidence of tuberculosis and per capita gross domestic product. Eur Respir J. 2008;32(5):1415-6. https://doi.org/10.1183/09031936.00078708 16. Guimarães RM, Lobo Ade P, Siqueira EA, Borges TF, Melo SC. Tuberculosis, HIV, and poverty: temporal trends in Brazil, the Americas, and worldwide. J Bras Pneumol. 2012;38(4):511-7. https:// doi.org/10.1590/S1806-37132012000400014 17. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis. 1998;2(1):10-5. 18. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet. 2004,364(9441):1244-51. https://doi.org/10.1016/S01406736(04)17141-9 19. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ. 2001;79(1):61-8. 20. Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med. 2005; 71(7):699-706. https://doi.org/10.1164/rccm.200411-1603OE 21. Peloquin CA, Berning SE, Huitt GA, Iseman MD. AIDS and TB drug absorption. Int J Tuberc Lung Dis. 1999;3(12):1143-4. 22. Albanna AS, Smith BM, Cowan D, Menzies D. Fixed-dose combination antituberculosis therapy: a systematic review and meta-analysis. Eur Respir J. 2013;42(3): 721-32. https://doi. org/10.1183/09031936.00180612 23. Gallardo CR, Rigau Comas D, Valderrama Rodríguez A, Roqué i Figuls M, Parker LA, Caylà J, et al. Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis. Cochrane Database Syst Rev. 2016;(5):CD009913. https://doi. org/10.1002/14651858.CD009913.pub2 24. Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet. 1972;1(7760):1079-85. 25. Vareldzis BP, Grosset J, de Kantor I, Crofton J, Laszlo A, Felten M, et al. Drug-resistant tuberculosis: laboratory issues. World Health Organization recommendations. Tuber Lung Dis. 1994;75(1):1-7. https://doi.org/10.1016/0962-8479(94)90096-5 26. Xu J, Jin H, Zhu H, Zheng M, Wang B, Liu C, et al. Oral bioavailability of rifampicin, isoniazid, ethambutol, and pyrazinamide in a 4-drug fixed-dose combination compared with the separate formulations in healthy Chinese male volunteers. Clin Ther. 2013;35(2):161-8. https://doi.org/10.1016/j.clinthera.2013.01.003 27. Bastos GM, Cezar MC, Mello FC, Conde MB. Prevalence of primary drug resistance in pulmonary tuberculosis patients with no known risk factors for such. J Bras Pneumol. 2012;38(6):733-9. https://doi. org/10.1590/S1806-37132012000600008 28. Marques M, Cunha EA, Ruffino-Netto A, Andrade SM. Drug resistance profile of Mycobacterium tuberculosis in the state of Mato Grosso do Sul, Brazil, 2000-2006. J Bras Pneumol. 2010;36(2):22431. https://doi.org/10.1590/S1806-37132010000200011 29. Baliza M, Bach AH, Queiroz GL, Melo IC, Carneiro MM, Albuquerque Mde F, et al. High frequency of resistance to the drugs isoniazid and rifampicin among tuberculosis cases in the city of Cabo de Santo Agostinho, an urban area in Northeastern Brazil. Rev Soc Bras Med Trop. 2008;41(1):11-6. https://doi.org/10.1590/S003786822008000100003

J Bras Pneumol. 2017;43(6):445-450 http://dx.doi.org/10.1590/S1806-37562017000000035

ORIGINAL ARTICLE

Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014 Eduardo Algranti1, Cézar Akiyoshi Saito2, Diego Rodrigues Mendonça e Silva3, Ana Paula Scalia Carneiro4, Marco Antonio Bussacos2 1. Serviço de Medicina, Fundação Jorge Duprat Figueiredo de Segurança e Medicina do Trabalho – FUNDACENTRO – São Paulo (SP) Brasil. 2. Serviço de Epidemiologia e Estatística, Fundação Jorge Duprat Figueiredo de Segurança e Medicina do Trabalho – FUNDACENTRO – São Paulo (SP) Brasil. 3. Departamento de Epidemiologia, Centro Internacional de Pesquisa, A.C. Camargo Cancer Center, São Paulo (SP) Brasil. 4. Serviço Especializado em Saúde do Trabalhador, Hospital das Clínicas, Universidade Federal de Minas Gerais – UFMG – Belo Horizonte (MG) Brasil. Submitted: 3 February 2017. Accepted: 16 July 2017. Study carried out at the Serviço de Medicina, Fundação Jorge Duprat Figueiredo de Segurança e Medicina do Trabalho – FUNDACENTRO – São Paulo (SP) Brasil.

ABSTRACT Objective: To analyze mortality from idiopathic pulmonary fibrosis (IPF) in Brazil over the period 1979-2014. Methods: Microdata were extracted from the Brazilian National Ministry of Health Mortality Database. Only deaths for which the underlying cause was coded as International Classification of Diseases version 9 (ICD-9) 515 or 516.3 (until 1995) or as ICD version 10 (ICD-10) J84.1 (from 1996 onward) were included in our analysis. Standardized mortality rates were calculated for the 2010 Brazilian population. The annual trend in mortality rates was analyzed by joinpoint regression. We calculated risk ratios (RRs) by age group, time period of death, and gender, using a person-years denominator. Results: A total of 32,092 deaths were recorded in the study period. Standardized mortality rates trended upward, rising from 0.24/100,000 population in 1979 to 1.10/100,000 population in 2014. The annual upward trend in mortality rates had two inflection points, in 1992 and 2008, separating three distinct time segments with an annual growth of 2.2%, 6.8%, and 2.4%, respectively. The comparison of RRs for the age groups, using the 50- to 54-year age group as a reference, and for the study period, using 1979-1984 as a reference, were 16.14 (14.44-16.36) and 6.71 (6.34-7.12), respectively. Men compared with women had higher standardized mortality rates (per 100,000 person-years) in all age groups. Conclusion: Brazilian IPF mortality rates are lower than those of other countries, suggesting underdiagnosis or underreporting. The temporal trend is similar to those reported in the literature and is not explained solely by population aging. Keywords: Idiopathic pulmonary fibrosis/epidemiology; Idiopathic pulmonary fibrosis/ mortality; Population dynamics.

INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a disease of unknown cause, predominantly occurring in individuals over 60 years of age and usually exhibiting rapid clinical progression and high lethality, with a median survival of less than 5 years.(1) Estimates of prevalence and incidence vary according to the data sources used and to the broadness or narrowness of the criteria for disease definition.(2-4) It is known that mortality from IPF has been increasing worldwide, ranging from 4 to 10 deaths per 100,000 population in ten countries in Europe, North America, Asia, and Oceania.(5) Studying the rates of occurrence of IPF is an aiding tool in developing appropriate health policies and in planning IPF management.(4) Recently, the availability of antifibrotic drugs with the potential to slow down the functional decline associated with IPF has sharpened the need for precision, on the part of specialists, in identifying the disease, given the possibility of a change in the clinical approach.(6,7) Because the symptoms and imaging findings of IPF have similarities with those of

other interstitial lung diseases, added weight has been given to the differential diagnosis, since other diseases of similar presentation progress differently, require different approaches, and differ in prognosis.(8) National data reveal that, in the Brazilian state of Rio Grande do Sul, mortality from IPF increased significantly between 1970 and 2000, rising from 0.22/100,000 population to 0.48/100,000 population during that period. (9) In Brazil, another analysis of mortality showed that there was an increase from 0.65/100,000 deaths in 1996 to 1.21/100,000 deaths in 2010.(10) The objective of the present study was to investigate mortality from IPF as the underlying cause and examine its temporal trend, on the basis of deaths occurring between 1979 and 2014 in Brazil. METHODS

Study design This was an ecological study of temporal trends in mortality from IPF as the underlying cause, involving

Correspondence to:

Eduardo Algranti. Serviço de Medicina, FUNDACENTRO, Rua Capote Valente, 710, CEP 05409-002, São Paulo, SP, Brasil. Tel.: 55 11 3066-6190. E-mail: eduardo@fundacentro.gov.br Financial support: Diego Rodrigues Mendonça e Silva is a research assistant working on the “Projeto interdisciplinar sobre a exposição ocupacional ao asbesto e seus efeitos sobre a saúde no Brasil” (Interdisciplinary Project on occupational asbestos exposure and its effects on health in Brazil), which is coordinated by FUNDACENTRO/SP and by the Instituto de Saúde Coletiva /UFBA, and is funded by the Brazilian Public Ministry of Labor (15th region). © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

445

Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014

analysis of aggregate data from the Brazilian National Ministry of Health Sistema de Informações de Mortalidade (SIM, Mortality Database), for the period 1979 to 2014. Because of possible inclusion of inaccurate data in the SIM (deaths from other interstitial lung diseases, here referred to as “similars”), cases were defined as deaths for which the underlying cause was attributed to IPF + similars (IPF-S).(11) Microdata were extracted from the SIM, in an anonymized fashion, for the period January 1, 1979 to December 31, 2014. During that period, two versions of the International Classification of Diseases (ICD) were used: ICD version 9 (ICD-9), from 1979 to 1995; and ICD version 10 (ICD-10), from 1996 onward. Deaths occurring until December 31, 1995 for which the underlying cause was coded as ICD-9 515 (post-inflammatory pulmonary fibrosis) or 516.3 (idiopathic pulmonary fibrosis) in the SIM were included in our analysis. For deaths occurring from January 1, 1996 onward, code J84.1 (other interstitial lung diseases with fibrosis) was used, assuming that the diseases were equivalent to IPF.(12) For each unit of observation, information on year of death, age, and gender was collected.

Data analysis Annual crude mortality rates were calculated using the population of each year, obtained through census data for years 1980, 1991, 2000, and 2010 or from estimates for intercensal years provided by the Brazilian Institute of Geography and Statistics. The annual crude mortality rates were adjusted to the 2010 census in order to obtain standardized mortality rates per 100,000 population. The annual percent change (APC) in the rates was calculated using joinpoint regression(13) (Joinpoint Regression Program; Statistical Methodology and Applications Branch and Data Modeling Branch, Surveillance Research Program, National Cancer Institute, Rockville, MD, USA). The inflection points indicate statistically significant changes in the curve. Mortality was also analyzed by obtaining standardized mortality rates per 100,000 person-years, which were calculated for three variables: a) age—first age group: 0-49 years, followed by groups covering a 5-year age range; b) time—˜5-year time periods of death, with no combination of the period preceding and that following the ICD change; and c) gender. For calculating personyears, the 2010 Brazilian population was used as a reference. For age, the number of person-years was estimated by multiplying the population within each age group by the midpoint of that range. Confidence intervals were calculated assuming a Poisson distribution and using Byar approximation. Risk ratios (RRs) were calculated using the 50- to 54-year age group, the first time period studied (1979-1984), and the male gender as a reference. The corresponding confidence intervals were calculated using Taylor series. These calculations were performed using OpenEpi, version 3.01. 446

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Ethical aspects Because the present study used anonymized secondary public domain data, available, with unrestricted access, in government digital databases, it did not require approval from an ethics committee. RESULTS Between 1979 and 2014, there were 32,092 deaths for which the underlying cause was IPF-S. Of those, 3,169 (9.9%) were deaths of individuals up to 49 years of age. Regarding gender, there were 15,782 and 16,302 deaths of men and women, respectively. In 8 cases, there was no information about gender. Among individuals 75 years of age or older, the absolute number of deaths of women was greater than that of men. Crude and standardized mortality rates trended upward, with the latter rising from 0.24/100,000 population in 1979 to 1.10/100,000 population in 2014. Figure 1 shows the temporal variation over the study period. There were no differences in the pattern of increase in mortality rates when women and men were analyzed separately. The temporal trend in standardized mortality rates had two inflection points separating three distinct time segments: 1979-1992; 1992-2008; and 20082014. Figure 2 shows the time segments and their corresponding APCs. There was a significant increase in mortality throughout the time period analyzed; however, in the years 1992 to 2008, there was an average annual growth of 6.8%. The annual increase in APCs differed slightly between genders, and the trends for both genders had two inflection points (Table 1). The greatest increase in the rates occurred between 1992 and 2008 in men and between 1992 and 2007 in women. Analysis of census population changes occurring between 1980 and 2010, during which time there were four demographic censuses, revealed a 68% increase in the population 50 years of age or older, which increased by 61% among men and by 74% among women. In that same period, the increase in standardized mortality rates from IPF-S among individuals 50 years of age or older was 317%. The RRs, calculated from mortality rates per personyears, are shown in Table 2. There was a strong upward trend in mortality as the age group increased and by time period of death. The rates, adjusted by person-years, showed that mortality increased by a factor of more than 16 when comparing the age groups, using the 50- to 54-year age group as a reference, and by a factor of more than 6, when comparing the time periods of death, using the first time period studied as a reference. There were no gender-related differences in overall standardized mortality rates (95% CI: 0.99-1.04). Analysis by gender and age group showed that the standardized mortality rates per 100,000 person-years were higher in men, with the differences in RR between

Algranti E, Saito CA, Silva DRM, Carneiro APS, Bussacos MA

men and women being statistically significant in all age groups, except in the 85-year or older age group (Figure 3). DISCUSSION The data obtained from the Brazilian National Ministry of Health SIM showed a consistent increase in mortality from IPF-S as the underlying cause over the period 1979-2014. During that period, the standardized mortality rates increased 4.6 times, rising from 0.24 to 1.10 per 100,000 population. The upward trend in mortality from IPF had been described in the Brazilian state of Rio Grande do Sul for the period 1970-2000(9) and in Brazil for the period 1996-2010.(10) Possibly, the small difference between the study by Rufino et al.(10) and ours is due to the reference population used for standardization of rates. In the present study, we

Mortality rate per 100,000 pop.

1.2

Standardized Crude

0.9

0.6

0.3

0 1979

1986

1993

2000

2007

2017

Year Figure 1. Crude and standardized mortality rates from idiopathic pulmonary fibrosis + similars, 1979-2014, Brazil. pop.: population.

Standardized mortality rate per 100,000 pop.

1.2

1979-1992, APC = 2.2^ 1992-2008, APC = 6.8^ 2008 - 2014, APC = 2.4^

0.9

0.6

0.3

0 1979

1986

1993

2000

2007

2017

Year Figure 2. Annual trend in standardized mortality rates from idiopathic pulmonary fibrosis + similars, as determined by joinpoint regression, 1979-2014, Brazil. pop.: population; APC: annual percent change. The APC was significantly different from zero at α = 0.05 in all periods.

did not include any mention of IPF on other lines of the death certificate because this information was unavailable in the SIM until 1999. In our study, analysis of the annual trend in mortality revealed a marked annual increase, with the average annual growth being strongest between 1992 and 2008 (6.8%). In comparison, an analysis of mortality in ten countries revealed an average annual growth of 2-3% between 1999 and 2012.(5) The change from ICD-9 to ICD-10 in 1996 was not accompanied by a change in curve inflection, which demonstrates that there was no detectable impact on the reporting of deaths. The increase in mortality rates, as well as the existence of a period when growth was most marked (1992-2008), is possibly due to a combination of factors. Technical issues that are hard to “measure”, such as the increased availability and use of HRCT after the 1990s, as well as the advances in CT scanner technology, have made it possible to define, with increasing precision, the imaging aspects associated with IPF.(14,15) Additionally, the practice of multidisciplinary discussions among medical specialties involved in the investigation of interstitial lung diseases has been adopted, which has facilitated the differential diagnosis of this group of diseases, possibly preventing misclassifications.(16) Demographic factors have also contributed to explaining the increase in mortality rates. According to census counts, between 1980 and 2010, the Brazilian population over 50 years of age increased by 68%. The standardized mortality rates per person-years ranged from 0.69/100,000 population in the first period (1979-1984) to 4.60/100,000 population in the last period (2011-2014); therefore, there was an almost sevenfold increase between the first and last observation periods. In comparison, in England and Wales, an analysis of mortality from IPF-S as the underlying cause revealed a sixfold increase between the first and last observation periods (total observation period: 1968 to 2008).(11) Although the period analyzed in that study does not exactly correspond to that of the present study, the greater increase observed here could be partially explained by the marked change in Brazil’s population pyramid relative to that of those countries. The standardized mortality rates per person-years were higher in men in all age groups. However, the male-to-female death ratio was 0.97, in comparison with 1.57 in the study of mortality in England and Wales(11) and with 1.29 in the study of the incidence of IPF in Canada.(4) A likely explanation for this finding is the marked difference in life expectancy between

Table 1. Trends in standardized mortality rates from idiopathic pulmonary fibrosis + similars, by gender, as determined by joinpoint regression, 1979-2014, Brazil.

Gender Male Female

Period 1979-1992 1979-1992

Trend 1 Trend 2 Trend 3 APC (95% CI) Period APC (95% CI) Period APC (95% CI) 2.0 (1.6-2.4) 1992-2008 6.4 (6.1-6.8) 2008-2014 1.6 (0.5-2.9) 2.1 (1.8-2.4) 1992-2007 7.3 (7.0-7.6) 2007-2014 3.6 (2.7-4.5)

APC: annual percent change. J Bras Pneumol. 2017;43(6):445-450

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Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014

Table 2. Mortality risk ratio from idiopathic pulmonary fibrosis + similars, by age group, time period of death, and gender, 1979-2014, Brazil.

Variable Age group, years < 50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85 or older Time period of death 1979-1984 1985-1990 1991-1995 1996-2000 2001-2005 2006-2010 2011-2014 Gendera Male Female

Deaths

Person-years

SMR per 100,000 personyears (95% CI)*

RR (95% CI)**

3,169 1,370 2,056 2,880 3,644 4,688 5,142 4,356 4,787

3.793.719.975 527.300.904 471.744.483 403.565.378 324.334.270 269.397.864 197.385.496 136.691.704 114.175.170

0.08 (0.06-0.09) 0.26 (0.24-0.27) 0.44 (0.41-0.45) 0.71 (0.68-0.74) 1.12 (1.09-1.16) 1.74 (1.69-1.79) 2.61 (2.54-2.68) 3.19 (3.09-3.28) 4.19 (4.07-4.31)

0.32 (0.29-0.37) 1.00 1.68 (1.55-1.79) 2.75 (2.53-2.89) 4.32 (4.01-4.55) 6.70 (6.18-7.00) 10.03 (9.32-10.54) 12.27 (11.3-12.81) 16.14 (14.44-16.36)

1,308 1,904 2,147 3,605 5,641 8,704 8,783

190.755.799 190.755.799 190.755.799 190.755.799 190.755.799 190.755.799 190.755.799

0.69 (0.64-0.71) 1.00 (0.95-1.03) 1.13 (1.09-1.16) 1.89 (1.87-1.91) 2.96 (2.95-3.00) 4.56 (4.48-4.61) 4.60 (4.58-4.63)

1.00 1.46 (1.36-1.56) 1.64 (1.53-1.75) 2.76 (2.58-2.94) 4.31 (4.07-4.58) 6.65 (6.28-7.05) 6.71 (6.34-7.12)

15,782 16,302

1.112.062.549 1.128.472.320

1.42 (1.38-1.45) 1.44 (1.40-1.46)

1.00 1.02 (0.99-1.04)

Men Women

4 3 2 1

-5 9 60 -6 4 65 -6 9 70 -7 4 75 -7 9 80 -8 85 4 or ol de r

-5 4

Standardized mortality rate per 100,000 person-years

SMR: standardized mortality rate; and RR: risk ratio. aEight cases lacked information on gender. *95% CIs were calculated assuming a Poisson distribution and using Byar approximation. &95% CIs were calculated using Taylor series.

Age group

Figure 3. Standardized mortality rates per 100,000 personyears, by gender and age group, 1979-2014, Brazil.

men and women in Brazil compared with industrialized countries: over the period 2005-2010, the difference in life expectancy between men and women was close to 4 years in Great Britain and in Canada, whereas it was 8 years in Brazil.(17) The numerical excess of deaths from IPF-S in women is essentially due to greater female survival and to the greater number of females in the general population. Except in the 85-year or older age group, all RRs were significantly higher in men. It should be noted that, in three referral centers in Brazil, the extent to which the proportion of individuals with IPF was higher among men than women was more pronounced than that found in the present study.(18) 448

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Problems in comparing statistics on IPF lie in the data extraction source and in the criteria for defining the disease.(2-4) However, there is a consensus that the incidence of IPF has been gradually rising, approaching that of diseases such as stomach and liver cancer, as well as cervical cancer.(5,19) The nationwide study in Canada revealed a higher incidence of IPF in the more industrialized areas of the country.(4) In the literature, there are reports of significantly increased risk of IPF for the following occupational and environmental factors: working in agriculture; raising livestock; working with wood; being exposed to metal dusts; being exposed to dusts containing silica; and smoking.(20) This indicates the need to explore possible occupational and environmental exposures. Recently, it has been demonstrated that deaths from IPF-S and from mesothelioma show a significant linear relationship with historical data on asbestos imports in Great Britain.(21) It should be pointed out that, because of its clinical presentation and, especially, its imaging presentation, asbestosis is one of the main differential diagnoses of IPF.(22) A review of 1,718 cases of lobectomy for lung tumors demonstrated that, among patients with asbestos exposure markers, the proportion of histology results consistent with usual interstitial pneumonia was significantly higher than it was among patients without these markers, it being concluded that there is evidence that asbestos exposure leads to the development of IPF.(23) Given the long-term, historically high consumption of asbestos

Algranti E, Saito CA, Silva DRM, Carneiro APS, Bussacos MA

in Brazil, this merits attention, because the legal and clinical management implications of asbestosis are very different from those of IPF. Population-based mortality data have the advantages of the strength of large numbers, of not requiring extrapolations, and of making it possible to analyze long historical series. Because of the high lethality of IPF, mortality and incidence rates are close. However, an important limitation associated with the use of mortality data lies in the reliability of the diagnosis. In the present analysis, it was not possible to review the clinical data on the recorded deaths. It is likely that other interstitial lung diseases have been erroneously coded as ICD-9 515, ICD-9 516.3, or as ICD-10 J84.1, which is why we adopted the term IPF-S, similarly to the study by Navaratnam et al.(11) Differences in utilization of ICD codes by physicians who certify deaths and the lack of a specific ICD code for IPF preclude the determination of the actual mortality rate.(2) Another important limitation concerns the completeness of mortality data in the SIM. From 2000 onward, the estimated coverage of the SIM was 100% for the southern region and nearly 100% for the southeastern region. However, for the northern region, in 2000 and 2010, the estimated coverage was 75.3% and 85.4%, respectively.(12) Given the heterogeneity in the

completeness of mortality data in Brazil, it is likely that there are regional differences in mortality from IPF-S. Although IPF is highly lethal, underlying cause-ofdeath data alone could mask the actual incidence of the disease. In England and Wales, it was estimated that approximately 60% of patients with known IPF had this disease recorded as the underlying cause of death on the death certificate.(24) Despite its limitations, the use of underlying cause-of-death data revealed an upward temporal trend similar to that obtained when analyzing IPF cases derived from outpatient clinical records of chronic disease patients, which are records that have higher diagnostic accuracy.(11) We conclude that mortality from IPF-S in Brazil shows an upward trend, similar to that reported in other countries, but with low mortality rates, suggesting that the disease is underdiagnosed and/or underreported. The change in Brazil’s population pyramid does not alone explain the observed increase. Other studies with appropriate designs should be conducted to provide a better understanding of the findings. ACKNOWLEDGMENTS We are grateful to Dr. Maria Paula Curado and the JBP reviewers for their critical reading of the manuscript and their suggestions.

REFERENCES 1. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-40. https://doi.org/10.1164/rccm.201006-0894CI 2. Samet JM, Coultas D, Raghu G. Idiopathic pulmonary fibrosis: tracking the true occurrence is challenging. Eur Respir J. 2015;46(3):604-6. https://doi.org/10.1183/13993003.00958-2015 3. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-6. https://doi.org/10.1164/rccm.200602163OC 4. Hopkins RB, Burke N, Fell C, Dion G, Kolb M. Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. Eur Respir J. 2016;48(1):187-95. https://doi. org/10.1183/13993003.01504-2015 5. Hutchinson JP, McKeever TM, Fogarty AW, Navaratnam V, Hubbard RB. Increasing global mortality from idiopathic pulmonary fibrosis in the twenty-first century. Ann Am Thorac Soc. 2014;11(8):1176-85. https://doi.org/10.1513/AnnalsATS.201404-145OC 6. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82. https://doi.org/10.1056/ NEJMoa1402584 7. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92. https://doi.org/10.1056/NEJMoa1402582 8. Martinez FJ, Chisholm A, Collard HR, Flaherty KR, Myers J, Raghu G, et al. The diagnosis of idiopathic pulmonary fibrosis: current and future approaches. Lancet Respir Med. 2017;5(1):61-71. https://doi. org/10.1016/S2213-2600(16)30325-3 9. Fortuna FP, Perin C, Cunha L, Rubin AS. Mortality due to idiopathic pulmonary fibrosis in the State of Rio Grande do Sul (Brazil). J Pneumol. 2003;29(3):1-4. https://doi.org/10.1590/S010235862003000300002 10. Rufino RL, Costa CH, Accar J, Torres GR, Silva VL, Barros NP, et al. Incidence and mortality of interstitial pulmonary fibrosis in Brazil. Am J Respir Crit Care Med. 2013;187:A1458 11. Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, Fogarty A,

et al. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 2011;66(6):462-7. https://doi.org/10.1136/thx.2010.148031 12. Brasil. Ministério da Saúde. Rede Interagencial de Informações para a Saúde [homepage on the Internet]. Brasília: o Ministério; [updated 2013 Dec 20; cited 2016 Jul 20]. Indicadores e Dados Básicos – Brasil – 2012. Available from: http://tabnet.datasus.gov.br/cgi/idb2012/ matriz.htm#cobe 13. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19(3):335-51. https://doi.org/10.1002/(SICI)10970258(20000215)19:3<335::AID-SIM336>3.0.CO;2-Z 14. Mathieson JR, Mayo JR, Staples CA, Müller NL. Chronic diffuse infiltrative lung disease: comparison of diagnostic accuracy of CT and chest radiography. Radiology. 1989;171(1):111-6. https://doi. org/10.1148/radiology.171.1.2928513 15. Swensen SJ, Aughenbaugh GL, Myers JL. Diffuse lung disease: diagnostic accuracy of CT in patients undergoing surgical biopsy of the lung. Radiology. 1997;205(1):229-34. https://doi.org/10.1148/ radiology.205.1.9314990 16. Hunninghake GW, Zimmerman MB, Schwartz DA, King TE Jr, Lynch J, Hegele R, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001;164(2):193-6. https://doi.org/10.1164/ajrccm.164.2.2101090 17. United Nations. Department of Economic and Social Affairs. Population Division (2015). World Population Prospects. The 2015 Revision. Volume I: Comprehensive Tables. ST/ESA/SER.A/379 18. Soares MR, Pereira C, Ferreira R, Nei Aparecida Martins Coletta E, Silva Lima M, Muller Storrer K. A score for estimating survival in idiopathic pulmonary fibrosis with rest SpO2>88. Sarcoidosis Vasc Diffuse Lung Dis. 2015;32(2):121-8 19. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795-806. https://doi. org/10.1183/09031936.00185114 20. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3(4):293-8. https://doi.org/10.1513/pats.200512-131TK 21. Barber CM, Wiggans RE, Young C, Fishwick D. UK asbestos imports J Bras Pneumol. 2017;43(6):445-450

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and mortality due to idiopathic pulmonary fibrosis. Occup Med (Lond). 2016;66(2):106-11. https://doi.org/10.1093/occmed/kqv142 22. Valeyre D, Jeny F, Freynet O, Nunes H. Key diagnostic issues. In: Idiopathic Pulmonary Fibrosis 2016. ERS Monogr. 2016;71:50-56. https://doi.org/10.1183/2312508X.10004915 23. Kawabata Y, Shimizu Y, Hoshi E, Murai K, Kanauchi T, Kurashima

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K, et al. Asbestos exposure increases the incidence of histologically confirmed usual interstitial pneumonia. Histopathology. 2016;68(3):339-46. https://doi.org/10.1111/his.12751 24. Johnston I, Britton J, Kinnear W, Logan R. Rising mortality from cryptogenic fibrosing alveolitis. BMJ. 1990;301(6759):1017-21. https://doi.org/10.1136/bmj.301.6759.1017

J Bras Pneumol. 2017;43(6):451-455 http://dx.doi.org/10.1590/S1806-37562017000000062

ORIGINAL ARTICLE

Niemann-Pick disease type B: HRCT assessment of pulmonary involvement Heloisa Maria Pereira Freitas1, Alexandre Dias Mançano2, Rosana Souza Rodrigues1,3, Bruno Hochhegger4, Pedro Paulo Teixeira e Silva Torres5, Dante Escuissato6, Cesar Augusto Araujo Neto7, Edson Marchiori1 1. Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 2. Departamento de Radiologia, Radiologia Anchieta – Hospital Anchieta, Taguatinga (DF) Brasil. 3. Departamento de Radiologia, Instituto D’Or de Pesquisa e Educação, Rio de Janeiro (RJ) Brasil. 4. Departamento de Radiologia, Santa Casa de Porto Alegre, Porto Alegre (RS) Brasil. 5. Multimagem Diagnósticos, Goiânia (GO) Brasil. 6. Departamento de Radiologia, Universidade Federal do Paraná, Curitiba (PR) Brasil. 7. Universidade Federal da Bahia, Salvador (BA) Brasil. Submitted: 1 March 2017. Accepted: 18 June 2017. Study carried out at the Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil.

ABSTRACT Objective: To analyze HRCT findings in patients with Niemann-Pick disease (NPD) type B, in order to determine the frequency of HRCT patterns and their distribution in the lung parenchyma, as well as the most common clinical characteristics. Methods: We studied 13 patients (3 males and 10 females) aged 5 to 56 years. HRCT images were independently evaluated by two observers, and disagreements were resolved by consensus. The inclusion criteria were presence of abnormal HRCT findings and diagnosis of NPD type B confirmed by histopathological examination of a bone marrow, lung, or liver biopsy specimen. Results: The most common clinical findings were hepatosplenomegaly and mild to moderate dyspnea. The most common HRCT patterns were smooth interlobular septal thickening and ground-glass opacities, which were both present in all patients. Intralobular lines were present in 12 patients (92.3%). A crazy-paving pattern was observed in 5 patients (38.4%), and areas of air trapping were identified in only 1 case (7.6%). Pulmonary involvement was bilateral in all cases, with the most affected area being the lower lung zone. Conclusions: Smooth interlobular septal thickening, with or without associated ground-glass opacities, in patients with hepatosplenomegaly is the most common finding in NPD type B. Keywords: Niemann-Pick diseases; Tomography, X-ray computed; Lung diseases.

INTRODUCTION Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by acid sphingomyelinase deficiency, which causes accumulation of sphingomyelin, especially in the tissues of the reticuloendothelial system.(1-4) Symptoms are due to accumulation of vacuolated lipid-filled macrophages, known as Niemann-Pick cells, in several organs, such as the liver, spleen, bone marrow, lung, and central nervous system.(2,4-6) NPD is divided into six subtypes, from A to F, depending on the organs affected and the severity of the clinical course.(2) In subtype B, an enzymatic deficiency causes chronic visceral involvement, characterized by hepatosplenomegaly and lung and bone marrow involvement, without significant neurological deficit, with pulmonary involvement being one of the leading causes of morbidity and mortality.(2-4) The presence of hepatosplenomegaly associated with specific HRCT findings, such as interlobular septal thickening, groundglass opacities, intralobular lines, and a crazy-paving pattern, constitutes important information that indicates NPD as a likely diagnosis.(3,4,7) Although a presumptive diagnosis can be made on the basis of clinical history and radiological findings, laboratory studies—measurement of sphingomyelinase activity in peripheral leukocytes

together with fibroblast cell culture or analysis of bone marrow biopsy specimens revealing accumulation of lipid-filled macrophages (sea-blue histiocytes)—are definitive for the diagnosis.(8) In the present study, we analyzed HRCT scans from 13 patients with NPD type B, all of whom had histopathological confirmation. The objectives of the present study were to describe the most common HRCT findings and the major clinical and epidemiological characteristics observed in these patients. METHODS This was a descriptive, retrospective, observational study of chest HRCT scans from 13 patients with NPD type B. These scans were randomly gathered from personal contact with radiologists and pulmonologists from eight different institutions, located in six Brazilian states. The diagnoses were suspected on the basis of a clinical history of hepatosplenomegaly associated with chest HRCT findings. All diagnoses were confirmed by biopsy. Pulmonary changes were assessed using HRCT. There was no standardization of HRCT assessment because multiple institutions were involved, with HRCT scans being performed according to the protocol used at each facility. However, all HRCT scans were performed at end-inspiration, using 1- to 2-mm-thick slices, at 5- to

Correspondence to:

Edson Marchiori. Rua Thomaz Cameron, 438, Valparaiso, CEP 25685-120, Petrópolis, RJ, Brasil. Tel.: 55 24 2249-2777. Fax: 55 21 2629-9017. E-mail: edmarchiori@gmail.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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10-mm intervals, from the apex to the hemidiaphragm, with patients in the supine position. Images were reconstructed on a 512 Ă&#x2014; 512 pixel matrix, digitized, and photographed, for assessment of the lung fields, at window widths of 1,000-1,500 HU and window levels of â&#x2C6;&#x2019;650 to â&#x2C6;&#x2019;750 HU. For assessment of the mediastinum, window width was set to 350-500 HU, and the window center level was set to 40-60 HU. There was no administration of intravenous iodinated contrast medium. All HRCT scans were independently evaluated by two observers, and disagreements were resolved by consensus. The scans were analyzed for the following characteristics: lesion distribution relative to their predominance in the upper or lower halves of the lungs; and pattern of changes (interlobular septal thickening, intralobular lines, ground-glass opacities, a crazy-paving pattern, and other pulmonary or extrapulmonary changes). Interlobular septal thickening was defined as the presence of linear opacities delimiting secondary pulmonary lobules. Intralobular lines were defined as thin linear images within the secondary pulmonary lobule. When numerous, they have a fine, lacy appearance. Ground-glass opacity was defined as increased pulmonary attenuation, with preserved bronchial and vascular margins. A crazy-paving pattern was defined as ground-glass opacities superimposed on interlobular septal thickening. Air trapping was defined as decreased lung parenchymal attenuation, apparent mainly as lower-than-usual density, and absence of volume reduction, both of which result from excessive accumulation of gas in the parenchyma due to partial or total airway obstruction. The criteria for defining these findings are those provided by the glossary of terms for thoracic imaging from the Fleischner Society,(9) and the terminology used is that presented in the consensus statement on terminology developed by the Imaging Department of the Brazilian Thoracic Association.(10)

At the time of HRCT, 6 patients were 16 years of age or younger (ranging in age from 5 to 16 years, with a mean of 11.7 years) and 7 were 22 years of age or older (ranging in age from 22 to 56 years, with a mean of 40.3 years). Extensive ground-glass opacities were identified in 4 of the 6 patients who were 16 years of age or younger, but in only 1 of the 7 patients who were 22 years of age or older. In addition, of the 5 patients who had a crazy-paving pattern, 4 were 16 years of age or younger. Hepatosplenomegaly was an important clinical finding in our series of patients with NPD type B. Splenomegaly was more marked than hepatomegaly. Three patients also underwent abdominal CT. Curiously, the 3 patients had hypodense splenic nodules. These nodules were not biopsied. DISCUSSION In our sample, 10 patients (76.9%) were female and 3 (23.1%) were male. McGovern et al.(11) reviewed 59 patients with a diagnosis of NPD type B. Gender prevalence was 53% male (31 patients) and 47% female (28 patients). This disagreement is probably due to the limited number of patients studied by us. In our study, ages ranged from 5 to 56 years, with a mean age of 27 years. Six patients were less than 20 years of age. Our findings were relatively similar

RESULTS We evaluated 13 patients with NPD type B with pulmonary involvement, 10 (76.9%) of whom were female and 3 (23.1%) of whom were male. The patients ranged in age from 5 to 56 years, with a mean age of 27 years. In the sample, there were four pairs of siblings. All patients had hepatosplenomegaly, which was painless in 6 (46.1%). Eight (61.5%) had had hepatosplenomegaly since childhood. From a respiratory standpoint, 8 patients (61.5%) were asymptomatic, and 5 (38.4%) had dyspnea. The HRCT findings in descending order of frequency were smooth interlobular septal thickening (n = 13; 100.0%; Figure 1); ground-glass opacities (n = 13; 100.0%); intralobular lines (n = 12; 92.3%); a crazypaving pattern (n = 5; 38.4%; Figure 2); and areas of air trapping (n = 1; 7.6%; Figure 3). The ground-glass opacities were focal in 10 patients (76.9%) and diffuse in 3 (23.1%). The pulmonary involvement was bilateral in all of the 13 cases studied, predominantly affecting the lower lobes, with no laterality predominance. 452

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Figure 1. Twenty-eight-year-old female patient. Chest HRCT slices (lung window) from the lower lung zones. Note smooth interlobular septal thickening in both lungs (predominantly in the lower lobes), intralobular lines, and small foci of ground-glass opacity.

Freitas HMP, Manรงano AD, Rodrigues RS, Hochhegger B, Torres PPTS, Escuissato D, Araujo Neto CA, Marchiori E

onset is 5-7 years, and diagnostic suspicion is generally raised also in childhood, around age 10 years, with the detection of hepatosplenomegaly.(12) Most patients initially present with hepatosplenomegaly (with the volume of the spleen being more marked than that of the liver), interstitial lung disease, and dyslipidemia. The absence of neurological involvement is one of the characteristics of NPD type B.(11) Laboratory and biochemical tests may reveal thrombocytopenia; abnormal liver function tests; high levels of lowdensity lipoprotein, very low-density lipoprotein, and triglycerides; and low levels of high-density lipoprotein and sphingomyelinase.(11,13)

Figure 2. Sixteen-year-old male patient. Chest HRCT slices (lung window) from the lower lung zones. Note smooth interlobular septal thickening in both lungs (predominantly in the lower lobes), intralobular lines, and ground-glass opacities with a crazy-paving pattern.

In our sample, all patients had hepatosplenomegaly. The predominant respiratory symptom was mild to moderate dyspnea, in 5 patients (38.4%). Eight patients (61.5%) were asymptomatic from a respiratory standpoint. In the literature, the most commonly reported clinical finding is hepatosplenomegaly, present in approximately 75% of patients, followed by bleeding, dyspnea, pulmonary infections, and joint pain. There have also been reports of growth retardation in adolescence.(11) Survival to adulthood occurs frequently, since the disease runs a chronic course, developing slowly and exhibiting a wide range of severity of symptoms and clinical findings.(11,12,14) The disease rarely progresses to liver failure.(11,15) NPD type B is familial in approximately one third of cases, given that it is an autosomal recessive hereditary disease.(16,17) In our sample, we studied four pairs of siblings. However, the incidence of hereditary association may be greater, since the families of the remaining patients were not adequately investigated to exclude other familial cases. The diagnosis can be confirmed by bone marrow, lung, or liver biopsy findings of accumulation of finely vacuolated, foamy, lipid-filled macrophages.(11,13) In the lung, these macrophages accumulate in the alveolar septa, bronchial walls, and pleura.(6,13) In our sample, the diagnosis was confirmed by biopsy in all patients. The patients, because of their different institutions of origin, were not followed according to a pre-established protocol. Therefore, biopsies of various sites were performed at the discretion of the attending physician. Of the 13 patients, 5 underwent lung biopsy, 4 underwent liver biopsy, and 4 underwent bone marrow biopsy.

Figure 3. Fourteen-year-old female patient. HRCT scan of the chest. Note ground-glass opacities predominantly in the lower lobes, interspersed with areas of air trapping in the left lower lobe.

to data found in the literature. With regard to age at diagnosis, studies have shown that NPD type B has been reported in patients in different age groups, although it is most commonly observed in those less than 20 years of age.(12) It is difficult to determine with precision the age group predominantly affected by NPD type B; however, the mean age at symptom

The most common HRCT patterns in our sample were interlobular septal thickening and ground-glass opacities, which were both present in the 13 cases (100.0%). The ground-glass opacities were focal (in 76.9%) and diffuse (in 23.1%). The second most common pattern was intralobular lines, present in 12 of our patients (92.3%). A crazy-paving pattern was found in 5 patients (38.4%). It should be noted that, as was the case in our study, interlobular septal thickening and ground-glass opacities can coexist in the same patient without, however, causing a crazypaving pattern. Crazy-paving refers exclusively to the J Bras Pneumol. 2017;43(6):451-455

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pattern of interlobular septal thickening superimposed on ground-glass opacities. These findings corroborate those reported in the literature.(1,3,11,16) Areas of air trapping were observed in only 1 patient (7.6%). We found no previous reports of air trapping associated with NPD. Although it is not possible to state that there is a direct relationship between air trapping and NPD, Baldi et al.,(2) reporting the finding of lung cysts in NPD, suggested that a possible mechanism would be macrophage migration into the bronchiolar lumen, leading to a check-valve mechanism and resulting in air trapping. With regard to possible differences in HRCT findings between children and adults, 6 patients in our sample were 16 years of age or younger at the time of HRCT and 7 were 22 years of age or older. Extensive groundglass opacities were identified in 4 of the 6 patients who were 16 years of age or younger, but in only 1 of the 7 patients who were 22 years of age or older. In addition, of the 5 patients who had a crazy-paving pattern, 4 were 16 years of age or younger. We found no explanation in the literature for these differences observed in our sample. NPD is a rare disease, and literature data on imaging tests are mostly found in case reports, there being very few studies focusing on the assessment of HRCT findings from series of patients. The most commonly reported HRCT findings in the literature are smooth interlobular septal thickening and intralobular lines, predominantly in the lower lobes of the lungs, and focal or diffuse ground-glass opacities, also predominantly in the lower lung zones.(2,4,8,13,16) A crazy-paving pattern has also been reported.(3,4) In the literature, the changes seen on CT most commonly affect the lower lobes, bilaterally. The same distribution was observed in our sample. Smooth interlobular septal thickening can be observed in a large number of venous, lymphatic, or infiltrative diseases, the most common of which is pulmonary edema. Knowledge of the different causes of this pattern can be useful in preventing diagnostic errors. In addition, although the causes of this pattern are often indistinguishable by radiological assessment, differences in the distribution of lesions in the lungs, associated radiological findings, patient history, and clinical presentation can often be useful in suggesting the appropriate diagnosis.(18,19) The major differential diagnoses of crazy-paving are due to acute or chronic causes. The major acute conditions that cause crazy-paving are pulmonary edema; ARDS; acute infections, such as pneumocystosis, leptospirosis, and H1N1 pneumonia; and diffuse alveolar hemorrhage. The major chronic conditions that cause crazy-paving are invasive adenocarcinoma, lipoid pneumonia, lymphangitic carcinomatosis, and alveolar proteinosis.(20-23) The changes histopathologically correspond to the presence of foamy macrophages in the interlobular 454

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septa and some degree of interstitial fibrosis, resulting in an appearance of septal thickening. The same cells involving the alveoli are associated with ground-glass opacities.(2,13,15,24) Hepatosplenomegaly is the most important clinical finding in NPD type B,(11,25) with splenomegaly being more marked than hepatomegaly.(6,11) Splenomegaly may be associated with the presence of intraparenchymal nodules or masses, which have an echogenic appearance on ultrasonography and low attenuation values on CT, as well as varied signal intensity on magnetic resonance imaging. Splenic nodules in NPD type B histologically consist of dilated sinuses containing lipid-filled macrophages (Niemann-Pick cells), demonstrated by Giemsa stain.(16) However, the nodules can also be associated with the presence of hemangiomas,(16,26) areas of infarction, and lymphomas.(14,27) In our sample, all patients had hepatosplenomegaly, 3 of whom (23.7%) had hypodense splenic nodular lesions, which were revealed on HRCT. These lesions were not biopsied. The association of diffuse pulmonary infiltration and hepatosplenomegaly can be observed in a number of diseases of varying etiologies, such as infectious diseases (tuberculosis, fungal diseases, malaria, and schistosomiasis), neoplastic diseases (lymphoma and leukemia), metabolic diseases (amyloidosis and Gaucher’s disease), autoimmune diseases (rheumatoid arthritis and systemic lupus erythematosus), and others (sarcoidosis, histiocytosis, hemosiderosis, etc.).(28,29) However, marked interlobular septal thickening associated with a history of hepatosplenomegaly since childhood is highly suggestive of storage disease. Therefore, the major differential diagnosis is Gaucher’s disease. Although pulmonary involvement is uncommon in Gaucher’s disease, clinical and imaging findings may be very similar, and, frequently, differential diagnosis is possible only on the basis of biopsies or enzymatic studies.(16,30) Our study had some limitations. The study was retrospective and observational. The analysis of some cases was cross-sectional, with the progression and possible complications of NPD not being assessed. The HRCT scans were performed according to the protocol used at each institution involved in the study. However, we do not believe that this variation had an impact on the results. Despite these limitations, we did not find in the literature any case series focusing on the study of CT findings from NPD type B patients and including as many cases as our study (the PubMed database was searched using the term “Niemann-Pick type B” in combination with “computed tomography”). In conclusion, the predominant HRCT patterns found in the patients with NPD type B were, in descending order of frequency, smooth interlobular septal thickening, ground-glass opacities, intralobular lines, and a crazy-paving pattern. A finding of smooth septal thickening in the lower lobes, associated with hepatosplenomegaly, especially in young patients, should raise the suspicion of NPD type B.

Freitas HMP, Mançano AD, Rodrigues RS, Hochhegger B, Torres PPTS, Escuissato D, Araujo Neto CA, Marchiori E

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type-B Niemann-Pick disease. Eur Radiol. 1997;7(3):361-4. https:// doi.org/10.1007/s003300050167 16. von Ranke FM, Pereira Freitas HM, Mançano AD, Rodrigues RS, Hochhegger B, Escuissato D, et al. Pulmonary Involvement in Niemann-Pick Disease: A State-of-the-Art Review. Lung. 2016;194(4):511-8. https://doi.org/10.1007/s00408-016-9893-0 17. Harzer K, Beck-Wödl S, Bauer P. Niemann-Pick disease type C: new aspects in a long published family - partial manifestations in heterozygotes. JIMD Rep. 2014;12:25-9. https://doi. org/10.1007/8904_2013_240 18. Griese M, Brasch F, Aldana VR, Cabrera MM, Goelnitz U, Ikonen E, et al. Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis. Clin Genet. 2010;77(2):119-30. https://doi.org/10.1111/j.1399-0004.2009.01325.x 19. Rossi SE, Erasmus JJ, Volpacchio M, Franquet T, Castiglioni T, McAdams HP. “Crazy-paving” pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics. 2003;23(6):1509-19. https://doi.org/10.1148/rg.236035101 20. Marchiori E, Zanetti G, Hochhegger B. Interlobular septal thickening. J Bras Pneumol. 2016;42(2):161. https://doi.org/10.1590/S180637562015000000294 21. Hochhegger B, Schumacher Neto R, Marchiori E. Crazy-paving pattern. J Bras Pneumol. 2016;42(1):76. https://doi.org/10.1590/ S1806-37562016000000275 22. De Wever W, Meersschaert J, Coolen J, Verbeken E, Verschakelen JA. The crazy-paving pattern: a radiological-pathological correlation. Insights Imaging. 2011;2(2):117-132. https://doi.org/10.1007/s13244010-0060-5 23. Johkoh T, Itoh H, Müller NL, Ichikado K, Nakamura H, Ikezoe J, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. 1999;211(1):155-60. https://doi. org/10.1148/radiology.211.1.r99ap10155 24. von Ranke F, Zanetti G, Hochhegger B, Marchiori E. Infectious diseases causing diffuse alveolar hemorrhage in immunocompetent patients: a state-of-the-art review. Lung. 2013;191(1):9-18. https:// doi.org/10.1007/s00408-012-9431-7 25. Wasserstein MP, Desnick RJ, Schuchman EH, Hossain S, Wallenstein S, Lamm C, et al. The natural history of type B NiemannPick disease: results from a 10-year longitudinal study. Pediatrics. 2004;114(6):e672-7. https://doi.org/10.1542/peds.2004-0887 26. Benedetti E, Proietti A, Miccoli P, Basolo F, Ciancia E, Erba PA, et al. Contrast-enhanced ultrasonography in nodular splenomegaly associated with type B Niemann-Pick disease: an atypical hemangioma enhancement pattern. J Ultrasound. 2009;12(3):85-92. 27. Omarini LP, Frank-Burkhardt SE, Seemayer TA, Mentha G, Terrier F. Niemann-Pick disease type C: nodular splenomegaly. Abdom Imaging. 1995;20(2):157-60. https://doi.org/10.1007/BF00201528 28. vom Dahl S, Mengel E. Lysosomal storage diseases as differential diagnosis of hepatosplenomegaly. Best Pract Res Clin Gastroenterol. 2010;24(5):619-28. https://doi.org/10.1016/j.bpg.2010.09.001 29. Elsayes KM, Narra VR, Mukundan G, Lewis JS Jr, Menias CO, Heiken JP. MR imaging of the spleen: spectrum of abnormalities. Radiographics. 2005;25(4):967-82. https://doi.org/10.1148/ rg.254045154 30. Gülhan B, Ozçelik U, Gürakan F, Güçer S, Orhan D, Cinel G, et al. Different features of lung involvement in Niemann-Pick disease and Gaucher disease. Respir Med. 2012;106(9):1278-85. https://doi. org/10.1016/j.rmed.2012.06.014

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ORIGINAL ARTICLE

Validation of the STOP-Bang questionnaire as a means of screening for obstructive sleep apnea in adults in Brazil Ricardo Luiz de Menezes Duarte1,2, Lorena Barbosa de Moraes Fonseca3,4,5, Flavio José Magalhães-da-Silveira1, Erika Aparecida da Silveira3, Marcelo Fouad Rabahi3,4,5 1. Sleep – Laboratório de Estudo dos Distúrbios do Sono, Centro Médico BarraShopping, Rio de Janeiro (RJ) Brasil. 2. Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 3. Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Goiás, Goiânia (GO) Brasil. 4. Hospital Geral de Goiânia Dr. Alberto Rassi, Goiânia (GO) Brasil. 5. Clínica do Aparelho Respiratório, Goiânia (GO) Brasil. Submitted: 25 May 2017. Accepted: 3 September 2017. Study carried out at Sleep – Laboratório de Estudo dos Distúrbios do Sono, Centro Médico BarraShopping, Rio de Janeiro (RJ) Brasil and at the Clínica do Aparelho Respiratório, Goiânia (GO) Brasil.

ABSTRACT Objective: To validate the Portuguese-language version of the STOP-Bang (acronym for Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender) questionnaire, culturally adapted for use in Brazil, as a means of screening for obstructive sleep apnea (OSA) in adults. Methods: In this validation study, we enrolled patients ≥ 18 years of age, recruited between May of 2015 and November of 2016. All patients completed the STOP-Bang questionnaire and underwent overnight polysomnography. To evaluate the performance of the questionnaire, we used contingency tables and areas under the (receiver operating characteristic) curve (AUCs). Results: We included 456 patients. The mean age was 43.7 ± 12.5 years, and 291 (63.8%) of the patients were male. On the basis of the apnea-hypopnea index (AHI), we categorized OSA as mild/moderate/severe (any OSA; AHI ≥ 5 events/h), moderate/ severe (AHI ≥ 15 events/h), or severe (AHI ≥ 30 events/h). The overall prevalence of OSA was 78.3%, compared with 52.0%, and 28.5% for moderate/severe and severe OSA, respectively. The most common score on the STOP-Bang questionnaire was 4 points (n = 106), followed by 3 points (n = 85) and 5 points (n = 82). An increase in the score was paralleled by a reduction in sensitivity with a corresponding increase in specificity for all AHI cut-off points. The AUCs obtained for the identification of any, moderate/severe, and severe OSA were: 0.743, 0.731, and 0.779, respectively. For any OSA, the score on the questionnaire (cut-off, ≥ 3 points) presented sensitivity, specificity, and accuracy of 83.5%, 45.5%, and 75.2%, respectively. Conclusions: The STOP-Bang questionnaire performed adequately for OSA screening, indicating that it could be used as an effective screening tool for the disorder. Keywords: Sleep apnea, obstructive/diagnosis; Polysomnography; Diagnostic techniques and procedures; Surveys and questionnaires.

INTRODUCTION Obstructive sleep apnea (OSA) is the most common sleep disorder and a major public health problem, affecting 2-4% of the adult population.(1,2) However, due to the aging of the population(3) and the obesity epidemic,(4) the actual prevalence of OSA might be higher than previously reported.(5-7) The signs, symptoms, and consequences of OSA are a direct result of the disturbances associated with repetitive upper airway collapse(8): sleep fragmentation, hypoxemia, hypercapnia, marked oscillations in intrathoracic pressure, and increased sympathetic activity. Left untreated, OSA limits the ability to perform activities of daily living, worsens quality of life, compromises personal safety, and decreases labor productivity, as well as increasing health care expenditures.(3,4) The current gold standard for the diagnosis of OSA is overnight polysomnography in a laboratory. However, OSA has become so prevalent that the available sleep laboratories have been overwhelmed. Sleep laboratories around the world have long waiting lists of patients

suspected of having OSA.(9) To address this issue, several screening questionnaires and clinical screening models have been developed to help identify patients with suspected OSA.(10-16) The great majority of these models were developed in other countries, and their reproducibility in Brazil remains unclear. The use of practical screening tools will probably translate to a higher rate of diagnosis and a reduction in costs. That is especially true for portable diagnostic methods in areas with limited resources. The STOP-Bang (acronym for Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender) questionnaire and its predecessor, the STOP questionnaire, were first developed and validated for use in surgical patients.(14) The STOP and STOP-Bang are both self-report questionnaires and consist of 4 and 8 yes/no questions, respectively. When a cut-off score of ≥ 3 points was used in a sample of surgical patients, the STOP-Bang questionnaire showed the following conditional probabilities for the diagnosis

Correspondence to:

Ricardo Luiz de Menezes Duarte. Sleep – Laboratório de Estudo dos Distúrbios do Sono, Centro Médico BarraShopping, Avenida das Américas, 4666, sala 309, Barra da Tijuca, CEP 22649-900, Rio de Janeiro, RJ, Brasil. Tel.: 55 21 2430-9222. Fax: 55 21 2430-9220. E-mail: rlmduarte@gmail.com Financial support: None.

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Duarte RLM, Fonseca LBM, Magalhães-da-Silveira J, Silveira EA, Rabahi MF

of OSA(14): sensitivity of 83.6%, specificity of 56.4%, a positive predictive value (PPV) of 81.0%, and a negative predictive value (NPV) of 60.8%. The population of Brazil includes individuals from diverse ethnic, racial, and social groups. Given that the Brazilian population is racially and ethnically diverse, it could be useful to determine the validity and performance of the STOP-Bang questionnaire in this setting. To our knowledge, there have been no studies determining the reproducibility of this questionnaire in Brazil. The objective of the present study was to validate the Portuguese-language version of the STOP-Bang questionnaire that has been culturally adapted for use in Brazil(17) in patients with suspected OSA who were submitted to overnight polysomnography. METHODS

Patient selection Consecutive outpatients were recruited from among those referred for overnight polysomnography at two sleep laboratories in Brazil: one in the city of Goiânia (enrollment from May 2015 to August 2015, n = 229) and one in the city of Rio de Janeiro (enrollment from October 2016 to November 2016, n = 227). The study protocol was approved by the Research Ethics Committees of the Alberto Rassi Hospital, in Goiânia (Protocol no. 752/14), and of the Federal University of Rio de Janeiro, in Rio de Janeiro (Protocol no. 1,764,165). All procedures were performed in accordance with the Declaration of Helsinki, and all participating patients gave written informed consent. All clinical and polysomnography data were collected prospectively. The following inclusion criteria were applied: being ≥ 18 years of age; not having previously been diagnosed with OSA; and having been referred to a sleep laboratory for polysomnography, for any reason. We excluded patients who had participated in the cultural adaptation of the STOP-Bang questionnaire,(17) as well as those who did not complete the questionnaire fully or correctly and those is whom the polysomnography was incomplete or technically inadequate.

Application of the STOP-Bang questionnaire After signing the consent form, the patients completed the STOP-Bang questionnaire. The four initial questions—those corresponding to the “STOP” portion of the questionnaire—were answered by the patients themselves. The responses to the questions corresponding to the “Bang” portion of the questionnaire were collected by the researcher on a standardized form. Body weight was measured in kilograms, and height was measured in meters. The body mass index (BMI) was then calculated as follows: weight in kilograms divided by height in meters squared (kg/ m2). Neck circumference was measured with a 150cm tape measure, whose smallest markings were at 0.01-cm intervals, and was determined at the level of the cricothyroid membrane.

Sleep studies All sleep studies were conducted either in Goiânia, on an Alice 5 diagnostic sleep system (Philips Respironics, Murrysville, PA, USA), or in Rio de Janeiro, on an EMBLA S7000 digital system (Embla Systems Inc., Broomfield, CO, USA). The following were performed: electroencephalography; left and right electro-oculography; electromyography of the submental and anterior tibialis muscles; snore detection; nasal airflow monitoring (with a nasal cannula); respiratory effort assessment (with the use of thoracic and abdominal straps); pulse oximetry; electrocardiography; body position monitoring; and digital video capture. Polysomnography records were scored manually and were interpreted in accordance with existing guidelines,(18) which define apnea as a ≥ 90% reduction in airflow for ≥ 10 s and hypopnea as a ≥ 30% reduction in airflow for ≥ 10 s, accompanied by desaturation ≥ 3% or an arousal. The apnea-hypopnea index (AHI) was calculated by determining the total number of apnea and hypopnea events per hour of sleep. The diagnosis of OSA was based on an AHI ≥ 5 events/h. The severity of OSA was classified as follows: mild/moderate/severe (any OSA; AHI ≥ 5 events/h); moderate/severe (AHI ≥ 15 events/h); or severe (AHI ≥ 30 events/h). At both sleep laboratories, the physicians who carried out the polysomnography examinations were blinded to the STOP-Bang scores.

Statistical analysis Statistical analysis was performed with the IBM SPSS Statistics software package, version 23.0 for Windows (IBM Corporation, Armonk, NY, USA). Continuous variables are expressed as mean and standard deviation, whereas categorical (dichotomous) variables are expressed as absolute and relative frequencies. Groups were compared with the chi-square-test (for dichotomous variables), Student’s t-test and one-way ANOVA (for normally distributed continuous variables), or the Mann-Whitney U test and the Kruskal-Wallis test (for non-normally distributed continuous variables). Correlations were evaluated by determining Spearman’s correlation coefficient (rs). The ROC curves and the areas under the curve (AUCs) were assessed at all three AHI thresholds (5 events/h, 15 events/h, and 30 events/h). Multivariate tests were used in order to calculate the odds ratios and their respective 95% confidence intervals. Using 2 × 2 contingency tables, we calculated the following conditional probabilities: sensitivity, specificity, PPV, NPV, accuracy, likelihood ratios, and odds ratios. The post-test probability of each STOP-Bang score was calculated by logistic regression. All statistical tests were two-sided, and values of p < 0.05 were considered statistically significant. RESULTS A total of 522 patients were referred for diagnostic polysomnography. Of those 522 patients, 66 (12.6%) were excluded, as follows: 50 patients, because the polysomnography was technically inadequate; J Bras Pneumol. 2017;43(6):456-463

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11 patients, because the STOP-Bang questionnaire was completed incorrectly; and 5 patients, because they had previously participated in the cross-cultural adaptation of the questionnaire. Therefore, the final study population comprised 456 patients, in two independent samples: one from Rio de Janeiro (n = 229) and one from Goiânia (n = 227). As can be seen in Table 1, 63.8% of the patients were male, the mean age was 43.7 ± 12.5 years, the mean BMI was 32.1 ± 7.8 kg/m2, and the mean neck circumference was 40.8 ± 4.3 cm. We observed statistically significant differences between the patients with and without OSA for all continuous variables (age, BMI, and neck circumference), those with OSA (AHI ≥ 5 events/h) being older (p < 0.001), having a higher BMI (p = 0.001), and having a larger neck circumference (p < 0.001). Six of the eight items on the STOP-Bang questionnaire presented a statistically significant difference between the patients with and without OSA, the two exceptions being tiredness (p = 0.730) and BMI > 35 kg/m2 (p = 0.705). In comparison with the patients without OSA, those with OSA were more likely to snore (p = 0.002), to present with apnea (p < 0.001), to have hypertension (p < 0.001), to be over 50 years of age (p = 0.011), to have a neck circumference > 40 cm (p < 0.001), and to be male (p < 0.001). Among the patients with severe OSA (AHI ≥ 30 events/h), the mean age was 45.9 ± 12.8 years, the mean BMI was 33.5 ± 7.9 kg/m2, and the mean neck circumference was 43.1 ± 4.2 cm. The overall prevalence of OSA was 78.3%, compared with 52.0% and 28.5% for moderate/severe OSA and severe OSA, respectively. In addition, the overall prevalence of OSA was higher in males than in females (84.5% vs. 67.3%), as was that of moderate/severe OSA (60.1% vs. 37.6%) and severe OSA (36.4% vs. 14.5%), the differences being statistically significant (p < 0.001 for all). That suggests that male gender influences the occurrence of OSA.

Table 2 shows the adjusted odds ratios for all eight STOP-Bang items in relation to OSA severity. Only three items were independent predictors at all three AHI thresholds: observed apnea, age, and neck circumference. In contrast, the tiredness item was not an independent predictor at any AHI threshold (p = 0.912 for any OSA, p = 0.397 for moderate/severe OSA, and p = 0.097 for severe OSA). The best predictor of moderate/severe OSA was neck circumference (adjusted OR: 2.347; 95% CI: 1.445-3.816), followed by age (adjusted OR: 2.132; 95% CI: 1.308-3.472) and observed apnea (adjusted OR: 1.897; 95% CI: 1.233-2.923). Table 3 shows the distribution of the parameters according to OSA severity. The most common STOP-Bang score (occurring in 106 patients) was 4 points, followed by 3 points (occurring in 85) and 5 points (occurring in 82). Using the cut-off STOP-Bang score of 3 points, we classified 34.1% of the patients as having no OSA (AHI < 5 events/h) and 9.4% as having severe OSA (AHI ≥ 30 events/h). The mean STOP-Bang score was 3.8 ± 1.6 points in the study population as a whole and was significantly lower in females than in males (2.8 ± 1.3 points vs. 4.4 ± 1.4 points; p < 0.001). In addition, the mean STOP-Bang score increased significantly in parallel with increasing severity of OSA—from 2.8 ± 1.4 points for the patients without OSA to 4.1 ± 1.5 points for those with any OSA, 4.5 ± 1.5 points for those with moderate/severe OSA, and 5.0 ± 1.3 points for those with severe OSA—the p-value for trend being < 0.001. The performance of the STOP-Bang questionnaire is shown in Table 4. As can be seen in the table, the cut-off STOP-Bang score (≥ 3 points) showed the following conditional probabilities for the identification of any OSA: sensitivity of 83.5%, specificity of 45.5%, PPV of 84.7%, NPV of 43.3%, and accuracy of 75.2%. For the identification of moderate/severe OSA, the same STOP-Bang cut-off score had a sensitivity of 88.6%, a

Table 1. Baseline characteristics of the patients screened for obstructive sleep apnea.a

Characteristic

Age (years), mean ± SD BMI (kg/m2), mean ± SD NC (cm), mean ± SD AHI (events/h), mean ± SD STOP-Bang items Snoring (loud) Tiredness Observed apnea Pressure (hypertension) BMI (> 35 kg/m2) Age (> 50 years) NC (> 40 cm) Gender (male)

All patients (n = 456)

Without OSA AHI < 5 events/h (n = 99)

AHI ≥ 5 events/h (n = 357)

With OSA

p-value

43.7 ± 12.5 32.1 ± 7.8 40.8 ± 4.3 24.6 ± 25.2

36.4 ± 12.4 29.6 ± 7.0 38.1 ± 3.8 2.1 ± 1.4

44.9 ± 12.2 32.7 ± 7.9 41.6 ± 4.2 30.9 ± 25.1

< 0.001 0.001 < 0.001 < 0.001

313 (68.6) 270 (59.2) 216 (47.4) 160 (35.1) 129 (28.3) 151 (33.1) 236 (51.8) 291 (63.8)

55 (55.6) 57 (57.6) 29 (29.3) 20 (20.2) 26 (26.3) 22 (22.2) 24 (24.2) 45 (45.5)

258 (72.3) 213 (59.7) 187 (52.4) 140 (39.2) 103 (28.9) 129 (36.1) 212 (59.4) 246 (68.9)

0.002 0.730 < 0.001 < 0.001 0.705 0.011 < 0.001 < 0.001

OSA: obstructive sleep apnea; BMI: body mass index; NC: neck circumference; and AHI: apnea-hypopnea index. a Data are presented as n (%), except where otherwise indicated.

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Table 2. Adjusted odds ratios obtained by multivariate analysis for each item of the Portuguese-language version of the STOP-Bang questionnaire.a

STOP-Bang item Any AHI ≥ 5 events/h

Snoring (loud) Tiredness Observed apnea Pressure (hypertension) BMI (> 35 kg/m2) Age (> 50 years) NC (> 40 cm) Gender (male)

(n = 357) 1.420 (0.851-2.369) 0.971 (0.585-1.612) 2.044 (1.182-3.546) 1.680 (0.911-3.095) 1.364 (0.711-2.617) 2.227 (1.193-4.166) 3.134 (1.712-5.747) 1.663 (0.934-2.958)

OSA severity Moderate/severe p AHI ≥ 15 events/h (n = 237) 0.179 1.666 (1.063-2.610) 0.026 0.912 1.199 (0.787-1.828) 0.397 0.010 1.897 (1.233-2.923) 0.004 0.096 1.650 (1.039-2.617) 0.034 0.350 1.222 (0.718-2.079) 0.458 0.012 2.132 (1.308-3.472) 0.002 < 0.001 2.347 (1.445-3.816) 0.001 0.083 1.644 (0.993-2.724) 0.053 p

Severe AHI ≥ 30 events/h (n = 130) 1.706 (0.964-3.021) 1.515 (0.926-2.475) 4.016 (2.415-6.622) 1.745 (1.047-2.915) 2.008 (1.103-3.649) 2.016 (1.184-3.436) 1.869 (1.055-3.311) 2.392 (1.265-4.524)

0.066 0.097 < 0.001 0.033 0.023 0.010 0.032 0.007

OSA: obstructive sleep apnea; AHI: apnea-hypopnea index; BMI: body mass index; and NC: neck circumference. a Values are presented as adjusted OR (95% CI). Table 3. Distribution of scores by apnea-hypopnea index (n = 456).a

STOP-Bang score

Without OSA

OSA severity Any Moderate/severe Severe AHI < 5 events/h AHI ≥ 5 events/h AHI ≥ 15 events/h AHI ≥ 30 events/h (n = 99) (n = 357) (n = 237) (n = 130) 0 (n = 2) 1 (50.0) 1 (50.0) 0 (0.0) 0 (0.0) 1 (n = 31) 17 (54.8) 14 (45.2) 7 (22.6) 0 (0.0) 2 (n = 71) 27 (38.0) 44 (62.0) 20 (28.2) 6 (8.5) 3 (n = 85) 29 (34.1) 56 (65.9) 28 (32.9) 8 (9.4) 4 (n = 106) 14 (13.2) 92 (86.8) 62 (58.5) 32 (30.2) 5 (n = 82) 5 (6.1) 77 (93.9) 57 (69.5) 37 (45.1) 6 (n = 53) 4 (7.5) 49 (92.5) 41 (77.4) 28 (52.8) 7 (n = 22) 1 (4.5) 21 (95.5) 19 (86.4) 16 (72.7) 8 (n = 4) 1 (25.0) 3 (75.0) 3 (75.0) 3 (75.0) OSA: obstructive sleep apnea; and AHI: apnea-hypopnea index. aValues are presented as n (%). specificity of 35.2%, a PPV of 59.7%, an NPV of 74.0%, and an accuracy of 62.9%; for the identification of severe OSA, it had a sensitivity of 95.4%, a specificity of 30.1%, a PPV of 35.2%, an NPV of 94.2%, and an accuracy of 48.7%. The STOP-Bang score correlated positively with the AHI (rs = 0.516; p < 0.001). According to the ROC curves (Figure 1), the STOP-Bang questionnaire showed the following AUCs: 0.743 (95% CI: 0.689-0.798) for the diagnosis of any OSA; 0.731 (95% CI: 0.685-0.777) for the diagnosis of moderate/ severe OSA; and 0.779 (95% CI: 0.735-0.824) for the diagnosis of severe OSA. Table 5 summarizes the prediction of any OSA, moderate/severe OSA, and severe OSA in relation to the various possible scores obtained on the STOP-Bang questionnaire. For a score ≥ 3 points, the post-test probability of any OSA, moderate/severe OSA, and severe OSA was 84.7%, 59.6%, and 35.2%, respectively. DISCUSSION In this prospective study, we determined that the STOP-Bang questionnaire shows promise as a screening tool for OSA in patients referred to sleep laboratories in Brazil. The use of the STOP-Bang questionnaire could provide various benefits: reducing the risk of

peri- and post-operative complications, which often go undiagnosed in surgical patients with OSA(19); reducing the occurrence of comorbidities, thus minimizing the health care costs associated with the disorder; and providing a portable diagnostic method, which could be critical in areas with limited resources, where polysomnography is not widely available. In addition, the performance of the STOP-Bang questionnaire was quite similar to that reported in previous studies for the STOP and STOP-Bang questionnaires(14,20-25); that is, high sensitivity and low-to-moderate specificity, which could be especially critical in the more severe forms of OSA, leading to a decrease in accuracy (the proportion of correctly screened individuals). This aspect of its predictive performance (low specificity) has also been reported in various studies designed to translate, adapt, or validate the STOP-Bang questionnaire.(21-25) Our study showed a high prevalence of OSA overall, as well as a high prevalence of moderate/severe OSA and severe OSA. That could be explained by the fact that it was conducted in a sleep laboratory setting. Unlike studies conducted in the community, sleep laboratory studies have reported OSA prevalence rates of 42-76%.(10) Our study, similar to previous studies, demonstrated that the prevalence of OSA J Bras Pneumol. 2017;43(6):456-463

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Table 4. Conditional probabilities of the various possible scores on the Portuguese-language version of the STOP-Bang questionnaire for the prediction of obstructive sleep apnea, by degree of severity (n = 456).a

OSA severity Sensitivity Specificity AHI ≥ 5 events/h ≥ 1 vs. < 1 99.7 (99.5-100.0) 1.0 (0.1-2.0) ≥ 2 vs. < 2 95.8 (94.2-97.3) 18.2 (12.5-23.6) ≥ 3 vs. < 3 83.5 (81.1-85.8) 45.5 (37.0-53.8) ≥ 4 vs. < 4 67.8 (65.4-69.8) 74.7 (66.0-82.2) ≥ 5 vs. < 5 42.0 (39.9-43.4) 88.9 (81.3-93.9) ≥ 6 vs. < 6 20.4 (18.7-21.4) 93.9 (87.5-97.5) ≥ 7 vs. < 7 6.7 (5.4-7.2) 98.0 (93.2-99.6) 8 vs. < 8 0.8 (0.2-1.1) 99.0 (96.9-99.9) AHI ≥ 15 events/h ≥ 1 vs. < 1 100.0 (99.3-100.0) 0.9 (0.2-0.9) ≥ 2 vs. < 2 97.0 (94.6-98.6) 11.9 (9.2-13.6) ≥ 3 vs. < 3 88.6 (84.8-91.8) 35.2 (31.1-38.6) ≥ 4 vs. < 4 76.8 (72.4-80.8) 61.2 (56.5-65.5) ≥ 5 vs. < 5 50.6 (46.4-54.4) 81.3 (76.7-85.4) ≥ 6 vs. < 6 26.6 (23.3-29.1) 92.7 (89.1-95.4) ≥ 7 vs. < 7 9.3 (7.1-10.4) 98.2 (95.8-99.4) 8 vs. < 8 1.3 (0.4-1.7) 99.5 (98.6-100.0) AHI ≥ 30 events/h ≥ 1 vs. < 1 100.0 (98.8-100.0) 0.6 (0.1-0.6) ≥ 2 vs. < 2 100.0 (96.8-100.0) 10.1 (8.8-10.1) ≥ 3 vs. < 3 95.4 (90.3-98.1) 30.1 (28.0-31.1) ≥ 4 vs. < 4 89.2 (83.0-93.6) 53.7 (51.2-55.4) ≥ 5 vs. < 5 64.6 (57.3-71.4) 76.4 (73.5-79.1) ≥ 6 vs. < 6 36.2 (29.9-42.0) 90.2 (87.7-92.5) ≥ 7 vs. < 7 14.6 (10.5-17.5) 97.9 (96.2-99.0) 8 vs. < 8 2.3 (0.7-3.0) 99.7 (99.0-100.0)

PPV

NPV

Accuracy

78.4 (78.2-78.6) 80.9 (79.5-82.1) 84.7 (82.3-87.0) 90.6 (87.4-93.4) 93.2 (88.5-96.3) 92.4 (84.3-96.8) 92.3 (74.1-98.7) 75.0 (22.1-98.7)

50.0 (2.7-97.3) 54.5 (37.4-70.8) 43.3 (35.2-51.2) 39.2 (34.6-43.0) 29.8 (27.3-31.5) 24.7 (23.0-25.6) 22.6 (21.5-22.9) 21.7 (21.2-21.9)

78.3 (77.9-78.7) 78.9 (76.5-81.3) 75.2 (71.5-78.8) 69.3 (65.5-72.5) 52.2 (48.9-54.4) 36.4 (33.6-37.9) 26.5 (24.5-27.3) 22.1 (21.2-22.6)

52.2 (51.8-52.2) 54.4 (53.0-55.3) 59.7 (57.1-61.8) 68.2 (64.3-71.7) 74.5 (68.3-80.1) 79.7 (69.8-87.4) 84.6 (64.8-94.9) 75.0 (22.0-98.7)

100.0 (19.8-100.0) 78.8 (61.2-90.3) 74.0 (65.5-81.4) 70.9 (65.4-75.9) 60.3 (56.9-63.4) 53.8 (51.8-55.4) 50.0 (48.8-50.6) 48.2 (47.8-48.4)

52.4 (51.7-52.4) 56.1 (53.6-57.8) 62.9 (59.0-66.3) 69.3 (64.8-73.5) 65.4 (61.0-69.3) 58.3 (54.9-61.0) 52.0 (49.7-53.1) 48.5 (47.5-48.9)

28.6 (28.3-28.6) 30.7 (29.7-30.7) 35.2 (33.4-36.2) 43.4 (40.4-45.6) 52.2 (46.3-57.6) 59.5 (49.1-69.1) 73.1 (52.7-87.5) 75.0 (22.0-98.7)

100.0 (19.8-100.0) 100.0 (87.4-100.0) 94.2 (87.9-97.6) 92.6 (88.3-95.6) 84.4 (81.2-87.4) 78.0 (75.8-80.0) 74.2 (73.0-75.1) 71.9 (71.4-72.1)

28.9 (28.2-28.9) 35.7 (33.9-35.7) 48.7 (45.8-50.2) 63.8 (60.3-66.3) 73.0 (68.8-76.9) 74.8 (71.2-78.1) 74.1 (71.8-75.8) 71.9 (71.0-72.3)

OSA: obstructive sleep apnea; PPV: positive predictive value; NPV: negative predictive value; and AHI: apneahypopnea index. aData are presented as estimated value (95% CI). Any OSA

1.0

0.4 0.2 0.0 0.0

0.8 Sensitivity

0.6

0.6 0.4 0.2

0.2

0.4 0.6 0.8 1 − specificity

1.0

0.0 0.0

Severe OSA

1.0

0.8 Sensitivity

Sensitivity

0.8

Moderate/severe OSA

0.6 0.4 0.2

0.2

0.4 0.6 0.8 1 − specificity

1.0

0.0

0.2

0.4 0.6 0.8 1 − specificity

1.0

Figure 1. Graphic representation of all areas under the curve obtained for the Portuguese-language version of the STOP-Bang questionnaire, culturally adapted for use in Brazil (n = 456). Obstructive sleep apnea (OSA) was classified, based on the apnea-hypopnea index, as follows: ≥ 5 events/h = OSA (any degree); ≥ 15 events/h = moderate/severe OSA; and ≥ 30 events/h = severe OSA.

is higher in men than in women.(3,8,26-30) In addition, men generally present with typical symptoms, such as snoring and observed apnea, whereas women are more likely to present with atypical symptoms, such as depression, fatigue, and insomnia.(26-29) Anthropometric and demographic data also differ between genders: men generally have larger neck circumferences than do women,(31) whereas women with OSA are generally 460

J Bras Pneumol. 2017;43(6):456-463

older than their male counterparts.(3) Furthermore, the performance of a questionnaire for OSA can vary widely depending on the population studied and the AHI cut-off point used for OSA diagnosis.(10,11) The Berlin questionnaire, for example, was initially developed in a primary care setting,(13) and its performance might therefore be better in that setting than in the sleep laboratory.(32) In contrast, the STOP-Bang questionnaire

Duarte RLM, Fonseca LBM, Magalhães-da-Silveira J, Silveira EA, Rabahi MF

Table 5. Predicting obstructive sleep apnea with the various possible scores on the Portuguese-language version of the STOP-Bang questionnaire (n = 456), by degree of severity.a

OSA severity AHI ≥ 5 events/h ≥ 1 vs. < 1 ≥ 2 vs. < 2 ≥ 3 vs. < 3 ≥ 4 vs. < 4 ≥ 5 vs. < 5 ≥ 6 vs. < 6 ≥ 7 vs. < 7 8 vs. < 8 AHI ≥ 15 events/h ≥ 1 vs. < 1 ≥ 2 vs. < 2 ≥ 3 vs. < 3 ≥ 4 vs. < 4 ≥ 5 vs. < 5 ≥ 6 vs. < 6 ≥ 7 vs. < 7 8 vs. < 8 AHI ≥ 30 events/h ≥ 1 vs. < 1 ≥ 2 vs. < 2 ≥ 3 vs. < 3 ≥ 4 vs. < 4 ≥ 5 vs. < 5 ≥ 6 vs. < 6 ≥ 7 vs. < 7 8 vs. < 8

High-risk patientsb

Low-risk patientsb

454 (99.6) 423 (92.8) 352 (77.2) 267 (58.6) 161 (35.3) 79 (17.3) 26 (5.7) 4 (0.9)

2 (0.4) 33 (7.2) 104 (22.8) 189 (41.4) 295 (64.7) 377 (82.7) 430 (94.3) 452 (99.1)

454 (99.6) 423 (92.8) 352 (77.2) 267 (58.6) 161 (35.3) 79 (17.3) 26 (5.7) 4 (0.9) 454 (99.6) 423 (92.8) 352 (77.2) 267 (58.6) 161 (35.3) 79 (17.3) 26 (5.7) 4 (0.9)

LR+

LR−

Post-test probability

3.63 (0.09-134.11) 1.00 (0.99-1.02) 5.06 (2.31-11.12) 1.17 (1.07-1.27) 4.20 (2.52-7.03) 1.53 (1.28-1.85) 6.22 (3.65-10.66) 2.68 (1.92-3.91) 5.79 (2.88-11.91) 3.78 (2.13-7.17) 3.98 (1.60-10.52) 3.37 (1.49-8.48) 3.49 (0.78-21.79) 3.32 (0.79-20.30) 0.83 (0.07-20.95) 0.83 (0.07-20.73)

0.27 (0.00-10.11) 0.23 (0.11-0.46) 0.36 (0.26-0.51) 0.43 (0.36-0.52) 0.65 (0.60-0.73) 0.84 (0.80-0.93) 0.95 (0.93-1.01) 1.00 (0.98-1.03)

78.3 80.8 84.7 90.6 93.2 92.4 92.3 75.0

2 (0.4) 33 (7.2) 104 (22.8) 189 (41.4) 295 (64.7) 377 (82.7) 430 (94.3) 452 (99.1)

∞ (0.26-∞) 4.42 (1.78-11.47) 4.21 (2.52-7.07) 5.21 (3.40-8.00) 4.45 (2.85-6.96) 4.59 (2.47-8.61) 5.50 (1.75-19.18) 2.79 (0.25-70.25)

0.00 (0.00-3.73) 0.24 (0.10-0.58) 0.32 (0.21-0.48) 0.37 (0.29-0.48) 0.60 (0.53-0.69) 0.79 (0.74-0.86) 0.92 (0.90-0.96) 0.99 (0.98-1.01)

52.0 54.4 59.6 68.1 74.5 79.7 84.6 75.0

2 (0.4) 33 (7.2) 104 (22.8) 189 (41.4) 295 (64.7) 377 (82.7) 430 (94.3) 452 (99.1)

∞ (0.09-∞) 1.00 (0.98-1.00) 0.00 (0.00-10.13) ∞ (2.93-∞) 1.11 (1.06-1.11) 0.00 (0.00-0.36) 8.88 (3.62-23.16) 1.36 (1.25-1.42) 0.15 (0.06-0.34) 9.60 (5.12-18.27) 1.92 (1.70-2.10) 0.20 (0.11-0.33) 5.90 (3.71-9.41) 2.73 (2.15-3.41) 0.46 (0.36-0.58) 5.20 (3.02-8.96) 3.68 (2.42-5.61) 0.70 (0.62-0.80) 7.80 (3.00-21.05) 6.80 (2.78-17.54) 0.87 (0.83-0.93) 7.67 (0.70-193.35) 7.52 (0.70-187.51) 0.98 (0.97-1.00)

28.5 30.7 35.2 43.4 52.1 59.5 73.0 75.0

1.00 (0.99-1.00) 1.10 (1.04-1.14) 1.36 (1.23-1.49) 1.97 (1.66-2.34) 2.70 (1.99-3.72) 3.63 (2.13-6.39) 5.08 (1.70-17.28) 2.77 (0.26-69.10)

OSA: obstructive sleep apnea; LR: likelihood ratio; and AHI: apnea-hypopnea index. aData are presented as n (%) or as estimated value (95% CI). bPatients were classified as being at high- or low-risk of OSA according to whether their score on STOP-Bang questionnaire was above or below the cut-off of 3 points, respectively.

was initially developed for use in surgical patients. (14) Although the STOP-Bang questionnaire has been widely validated as a screening tool,(20) it was found to be inadequate and inappropriate as a means of confirming the presence of significant OSA among patients at a Veterans Administration facility in the United States, possibly because of the low (4.9%) specificity obtained in that study.(33) The STOP-Bang is a screening instrument with high sensitivity, that sensitivity increasing in proportion to increases in the AHI threshold used (from 5 events/h to 30 events/h).(14) Conversely, it exhibits low-to-moderate specificity, which reduces its accuracy. Because it prioritizes sensitivity over specificity, the STOP-Bang questionnaire classifies a large number of patients as high-risk, thus increasing the rate of false-positive results. Consequently, the STOP-Bang questionnaire alone is insufficient to rule out the need for a sleep study in all patients. Another important feature of the instrument is that an increase in its score (maximum, 8 points) has been shown to result in an increase in post-test probability.(34-36) Unfortunately, our study failed to show a linear increase in the post-test probability with increasing STOP-Bang scores, except in the patients

with severe OSA, among whom such an increase was observed for all scores. One previous study evaluated four tools for OSA screening(37): the four-variable screening tool, the STOP questionnaire, the STOP-Bang questionnaire, and the Epworth Sleepiness Scale. To predict moderate/severe OSA, the STOP-Bang questionnaire had the highest sensitivity (87.0%), with an AUC of 0.64, whereas the four-variable screening tool presented the highest specificity (93.2%) and accuracy (79.4%). Similar findings were reported in another study comparing five different questionnaires (the STOP questionnaire, the STOP-Bang questionnaire, the Berlin questionnaire, the Epworth Sleepiness Scale, and the four-variable screening tool).(38) In that study, the STOP-Bang questionnaire had the highest sensitivity (97.6%), as well as the lowest specificity (12.7%), for the identification of moderate/severe OSA. The present study has some limitations that need to be emphasized. It involved patients referred to the sleep laboratory, who are typically pre-selected patients, which could represent a selection bias. In addition, we did not compare the performance of the STOP-Bang J Bras Pneumol. 2017;43(6):456-463

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questionnaire with that of other validated screening instruments, and there is therefore a need for further studies comparing it with such tools. Nevertheless, our study was performed with a considerable sample of adults, all of whom underwent overnight polysomnography, which is the gold standard for the diagnosis of OSA. Additional strengths were the fact that it was a prospective study, with manual analysis of the polysomnography results, and the fact that the physicians involved in the polysomnography examinations had no prior knowledge of the STOP-Bang results. In conclusion, the STOP-Bang questionnaire showed good performance in screening for OSA and can predict

the severity of the disorder. The validation of the STOP-Bang questionnaire will promote its use as an important screening tool for OSA in sleep laboratories in Brazil. Because our study was conducted in a sleep laboratory setting, further studies are needed in order to validate the STOP-Bang questionnaire for use in other contexts, such as primary care. ACKNOWLEDGMENTS The authors would like to thank Dr. Frances Chung for her kindness in authorizing the validation of the STOP-Bang questionnaire for use in Brazil.

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Duarte RLM, Fonseca LBM, MagalhĂŁes-da-Silveira J, Silveira EA, Rabahi MF

29. Shah N, Hanna DB, Teng Y, Sotres-Alvarez D, Hall M, Loredo JS, et al. Sex-specific prediction models for sleep apnea from the Hispanic Community Health Study/Study of Latinos. Chest. 2016;149(6):140918. https://doi.org/10.1016/j.chest.2016.01.013 30. Duarte RL, MagalhĂŁes-da-Silveira FJ. Factors predictive of obstructive sleep apnea in patients undergoing pre-operative evaluation for bariatric surgery and referred to a sleep laboratory for polysomnography. J Bras Pneumol. 2015;41(5):440-8. https://doi. org/10.1590/S1806-37132015000000027 31. Dancey DR, Hanly PJ, Soong C, Lee B, Shepard J Jr, Hoffstein V. Gender differences in sleep apnea: the role of neck circumference. Chest 2003;123(5):1544-50. https://doi.org/10.1378/ chest.123.5.1544 32. Ahmadi N, Chung SA, Gibbs A, Shapiro CM. The Berlin questionnaire for sleep apnea in a sleep clinic population: relationship to polysomnographic measurement of respiratory disturbance. Sleep Breath. 2008;12(1):39-45. https://doi.org/10.1007/s11325-007-0125-y 33. Kunisaki KM, Brown KE, Fabbrini AE, Wetherbee EE, Rector TS. STOP-BANG questionnaire performance in a Veterans Affairs unattended sleep study program. Ann Am Thorac Soc. 2014;11(2):192-7. https://doi.org/10.1513/AnnalsATS.201305-134OC

34. Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. High STOP-Bang score indicates a high probability of obstructive sleep apnoea. Br J Anaesth. 2012;108(5):768-75. https://doi.org/10.1093/ bja/aes022 35. Chung F, Yang Y, Liao P. Predictive performance of the STOP-Bang score for identifying obstructive sleep apnea in obese patients. Obes Surg. 2013;23(12):2050-7. https://doi.org/10.1007/s11695-0131006-z 36. Farney RJ, Walker BS, Farney RM, Snow GL, Walker JM. The STOPBang equivalent model and prediction of severity of obstructive sleep apnea: relation to polysomnographic measurements of the apnea/ hypopnea index. J Clin Sleep Med. 2011;7(5):459-65B. https://doi. org/10.5664/jcsm.1306 37. Silva GE, Vana KD, Goodwin JL, Sherrill DL, Quan SF. Identification of patients with sleep disordered breathing: comparing the four-variable screening tool, STOP, STOP-Bang, and Epworth Sleepiness Scales. J Clin Sleep Med. 2011;7(5):467-72. https://doi.org/10.5664/jcsm.1308 38. Pataka A, Daskalopoulou E, Kalamaras G, Fekete Passa K, Argyropoulou P. Evaluation of five different questionnaires for assessing sleep apnea syndrome in a sleep clinic. Sleep Med. 2014;15(7):776-81. https://doi.org/10.1016/j.sleep.2014.03.012

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J Bras Pneumol. 2017;43(6):464-471 http://dx.doi.org/10.1590/S1806-37562017000000103

ORIGINAL ARTICLE

Effects of simple long-term respiratory care strategies in older men with COPD Fabrício Zambom-Ferraresi1, Pilar Cebollero2,Javier Hueto2, María Hernández2, José Cascante2, María Milagros Antón1

1. Facultad de Ciencias de la Salud, Universidad Pública de Navarra, Navarra, España. 2. Servicio de Neumología, Complejo Hospitalario de Navarra, Navarra, España. Submitted: 29 March 2017. Accepted: 3 September 2017. Study carried out at the Facultad de Ciencias de la Salud, Universidad Pública de Navarra, and in the Servicio de Neumología, Complejo Hospitalario de Navarra, Navarra, España.

ABSTRACT Objective: To evaluate a 24-month supervised, community-based maintenance exercise program after 3 months of pulmonary rehabilitation (PR) in comparison with a 27-month physical activity counseling program, in terms of the effects on maximal muscle strength, muscle power output, and exercise capacity, in individuals with COPD. Methods: Sixtythree men with moderate-to-severe COPD were recruited from two previous studies. Of those 63 participants, 31 were offered 3 months of PR followed by a 24-month supervised maintenance exercise program (24MME group) and 32 were offered a 27-month physical activity counseling program (27MPAC group). Measurements at 3 months and at the end of the study period included maximal strength of the upper and lower limbs, power output of the lower limbs, six-minute walk distance (6MWD), and quality of life. Results: At 27 months, the improvements in maximal strength of the upper and lower limbs were greater in the 24MME group than in the 27MPAC group (37.6 ± 28.3% and 28.4 ± 13.3%, respectively, vs. 8.8 ± 16% and 13.6 ± 16.4%, respectively; p < 0.05), as was the improvement in power output of the lower limbs (24.6 ± 18.4% vs. −2.3 ± 28.5%; p < 0.01). The increase in the 6MWD after 3 months was also greater in the 24MME group than in the 27MPAC group (33.2 ± 36.6 m vs. 2.9 ± 34.7 m; p < 0.05), although there were no differences between the two groups in terms of the Δ6MWD at 27 months (vs. baseline). Conclusions: A supervised, community-based maintenance program is a successful long-term strategy to preserve the benefits of PR on peripheral muscle function and exercise capacity in individuals with COPD. However, physical activity counseling can maintain maximal muscle strength and exercise capacity in such individuals. Keywords: Pulmonary disease, chronic obstructive; Muscle strength; Leg/physiology, Muscle, skeletal/physiology; Physical fitness; Exercise therapy/methods.

INTRODUCTION One strategy to promote long-term health-enhancing behavioral changes, resulting in improvements in dyspnea, exercise capacity, and health-related quality of life, as well as to maximize skeletal muscle function, in older adults with COPD is the use of a maintenance exercise program after pulmonary rehabilitation (PR). However, the effectiveness of such programs is not well established, because of their heterogeneity in terms of duration, components, exercise intensity, and level of supervision.(1-5) Another short- and long-term strategy, which might be a more economical and feasible approach to improving exercise capacity and quality of life in COPD patients, is the use of a physical activity counseling program.(6) A few studies have examined the benefits of long-term PR maintenance programs,(1,2,4,5,7) and one study(6) examined the longterm effects of a physical activity program. However, to our knowledge, there have been no studies comparing a long-term supervised maintenance exercise program and a long-term physical activity counseling program in terms of their effects on exercise capacity and quality of life in older individuals with COPD.

The peripheral muscle dysfunction of the lower limbs observed in patients with COPD is characterized by a reduction in maximal muscle strength and a loss of muscle mass, which also occur during the milder stages of the disease.(8) Aging is known to be associated with decreases in muscle mass, maximal strength, and muscle power.(9) Maximal strength peaks in the third decade of life,(10) remains unchanged or decreases slightly from approximately 40 years of age(11) into the fifth decade, declining more rapidly (at a rate of 12-15% per decade) thereafter.(10,12) This muscle weakness and muscle atrophy result in functional limitations and are associated with increased mortality.(13) Recently, muscle power has emerged as a discriminative variable for understanding the reduction in mobility and in the ability to perform activities of daily living.(14) In older adults, physical inactivity might be one of the mechanisms of this peripheral muscle dysfunction.(15) Nevertheless, few studies have examined the effects that long-term strategies of maintenance exercise or physical activity counseling have on muscle strength and muscle power output in individuals with COPD.(7) Therefore, the primary aim of the present study was to compare a community-based maintenance exercise

Correspondence to:

María M. Antón. Facultad de Ciencias de la Salud, Universidad Pública de Navarra, Campus de Tudela, Avenida de Tarazona, s/n, 31500, Tudela, Navarra, España. Tel.: 34 948417877. Fax: 34 948417892. E-mail: milagros.anton@unavarra.es Financial support: This study received financial support from the Spanish Ministry of Education and Science (Plan Nacional I+D+i 2008-20011; Strategic action: “Sport and physical education” Ref: DEP2011-30042).

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Zambom-Ferraresi F, Cebollero P, Hueto J, Hernández M, Cascante J, Antón MM

program, applied for 24 months after 3 months of PR, and a physical activity counseling program, applied for 27 months, in terms of their effects on maximal dynamic strength, muscle power output, exercise capacity, and quality of life in older adults with COPD. We hypothesized that, in older adults with moderateto-severe COPD, a supervised maintenance exercise program after PR would maintain the improvements in functional capacity, muscle function, and health-related quality of life better than would the physical activity counseling program. METHODS This was a retrospective, non-randomized study designed to compare the impact that two different treatments have on exercise capacity, muscle function, and health-related quality of life in older adults with COPD. The sample consisted of 63 men with stable, moderate-to-severe COPD who were recruited from pulmonology consultations. The participants were enrolled in one of two programs: a 3-month PR program, followed by a 24-month community-based maintenance exercise program (24MME group, n = 31); and a 27-month physical activity counseling program (27MPAC group, n = 32). The inclusion criteria were as follows: being male; having been diagnosed with moderate-to-severe COPD, characterized by an FEV1/FVC ratio < 0.70 and a postbronchodilator FEV1 value 30-80% of the predicted value, corresponding to stage II or III according to the Global Initiative for Chronic Obstructive Lung Disease criteria(16); showing grade 2 or 3 (symptomatic) dyspnea, as defined by the Modified Medical Research Council scale score; and being over 50 years of age. Current smokers were excluded, as were individuals who had experienced an exacerbation of COPD in the last 3 months, those who suffered from uncontrolled heart disease, and those who had been diagnosed with neoplasia in the last 5 years, as well as those with any neuromuscular, musculoskeletal, or joint disorders that might limit their exercise capacity. The research was conducted in accordance with the World Medical Association Declaration of Helsinki for medical research involving human subjects, and the study was approved by the Committee on Ethics, Animal Experimentation, and Biosafety of the Public University of Navarre, in Navarra, Spain (Protocol no. PI-002-112). All participants gave written informed consent. Participants were tested at baseline, at 3 months, and at the end of the study period. All underwent spirometry, with determination of lung volumes by body plethysmography and of the DLCO.(16) In addition, anthropometric variables were assessed, as was the distance walked on the six-minute walk test, or six-minute walk distance (6MWD),(17) which was used in order to evaluate functional and exercise capacity. The Chronic Respiratory Questionnaire (CRQ) was used in order to assess the health-related quality

of life.(18) The CRQ is a disease-specific instrument evaluating four domains (on a scale of 1 to 7), and the Spanish-language version has been validated for use in Spain.(19) The minimal clinically significant difference is defined as a mean improvement of 0.5 per domain.(19) The production of muscle force by the upper and lower limbs was examined. The participants were familiarized with the strength tests. Maximal dynamic strength, based on the one-repetition maximum (1RM), was assessed on a commercial machine (Technogym, Gambettola, Italy) and was defined as the load displaced in the bilateral leg press exercise, in which the knees and hips were flexed at 90° and 45°, respectively. On the day of the test, the participant warmed up during a 5-min period of walking and stretching exercises. In addition, several warm-up contractions for the leg press exercise were performed. Thereafter, four to five attempts were made in order to determine the 1RM. The maneuvers were performed separately, with a break of 2 min between each attempt. The 1RM was defined as the last extension accepted as valid, performed with the maximum load. After determination of the 1RM values, the muscle power output in the leg press exercise was measured. The muscle power of the extensor muscles of the leg and hip was measured during the concentric phase of the bilateral leg press exercise, the weight (in kg) corresponding to the load at 50% of the 1RM. The participants were instructed and encouraged to displace the weights as rapidly as possible. Two trials were performed, with 2 min of recovery between attempts. The best of the two was used for further analysis.(20) The bilateral maximum dynamic strength (1RM) of the upper limb muscles was examined via the seated chest press exercise. To avoid the influence of fatigue on the 1RM values, the maximal load was determined in four to five attempts with a 2-min recovery period between attempts. The 1RM was defined as the last extension accepted as valid, performed with the maximum load. During the initial 3-month period, participants in the 24MME group completed an outpatient PR program, as described elsewhere.(21) Upon completion of the PR program, a pulmonologist invited each 24MME group participant to receive the maintenance exercise intervention at a recreational sport facility. The maintenance exercise program consisted of two non-consecutive, multi-component, supervised training sessions per week over a 24-month period, with four-month gaps during the summer (school vacation) breaks. Each training session was 90 min long and comprised the following components: exercises of balance and proprioception; 20-30 min of walking at moderate intensity (87.5-100% of the maximum heart rate achieved during the six-minute walk test); and strength training (with free weights) that included the sit-to-stand exercise, supine chest press, biceps exercises, and the seated row at moderate intensity (3 sets, 6-12 repetitions, at 40-70% of the 1RM). J Bras Pneumol. 2017;43(6):464-471

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Heart rate and SpO2 were monitored throughout the sessions. All sessions were supervised by an exercise physiologist. During the summer breaks, the participants were encouraged to remain as physically active as possible. The participants in the 27MPAC group enrolled in the 27-month physical activity counseling program, which consisted of a recommendation of walking at least 3 times weekly for at least 30 min each time. Participants recorded the number of times that they walked per week and their walking duration (in minutes per day) in a diary. In addition, they received a structured telephone call once a month from the same nurse with whom they had interacted during the pulmonology consultations. This phone call consisted of a brief introductory conversation followed by the administration of a questionnaire to collect the diary information. Statistical analyses were performed with the SPSS Statistics software package for Windows, version 20.0 (IBM Corporation, Armonk, NY, USA). The assumption of a normal distribution of the data was evaluated with the Shapiro-Wilk test. Baseline differences between the groups were compared via unpaired Student’s t-test or via the Mann-Whitney U test for non-normally distributed data. The intervention-related effects were assessed using two-way repeated-measures ANOVA (group vs. time). For each group, the differences between variables over time (time effect: from baseline to 3 months and to the end of the study period) were evaluated by using pairwise comparisons with Bonferroni correction or the Friedman test for non-normally distributed variables. For non-normally distributed variables, the data were log10-transformed. If the data still had non-parametric characteristics, a non-parametric statistical technique was used. Selective relative changes (proportional or absolute changes) between the groups were assessed

with unpaired t-tests or with the Mann-Whitney U test for non-normally distributed variables. The values in the text, tables, and figures are reported as the mean and standard deviation. The level of statistical significance was set at p < 0.05. RESULTS Sixty-three participants were recruited for this study: 31 in the 24MME group and 32 in the 27MPAC group. In the 24MME group, 3 participants dropped out after the 3 months of the PR program, 6 participants refused to continue the maintenance program, 8 dropped out of the maintenance program due to clinical worsening, and 2 died during the 24-month intervention period. In the 27MPAC group, 2 participants dropped out after 3 months, and 6 dropped out before the end of the intervention period (Figure 1). The anthropometric and pulmonary function characteristics of the participants are shown in Table 1. No significant differences between the groups were found at baseline for any of the variables measured, except for the 6MWD and lower-limb muscle power output at 50% of the 1RM. Between the study outset (baseline) and the end of the study period, the maximal strength on the leg press exercise increased by 28.4 ± 13.3% in the 24MME group (from 203.6 ± 45.7 kg to 262.5 ± 70.3 kg; p < 0.001) and by 13.6 ± 16.4% in the 27MPAC group (from 222.3 ± 82.1 kg to 251.1 ± 88.3 kg; p < 0.01), as shown in Figure 2. The magnitude of improvement was greater in the 24MME group than in the 27MPAC group (p < 0.05). Figure 2 also shows that, between those same two time points, muscle power output increased by 24.6 ± 18.4% in the 24MME group (from 725.5 ± 163.9 W to 897.1 ± 211.6 W; p < 0.05) and decreased by 2.3 ± 28.5% in the 27MPAC group (from 659.7 ± 287.1 W to 625.4 ± 298.8 W; p = 0.77). The

Eligible COPD participants (n = 63)

3-month outpatient pulmonary rehabilitation program group (n = 31) Withdrawal (n = 1) Clinical worsening (n = 1) Surgery (n = 1)

3-month physical activity counseling program group (n = 32) Withdrawal (n = 2)

2-year community-based maintenance exercise program group (n = 28) Declined to enroll (n = 6) Clinical worsening (n = 8) Death (n = 2) 2-year community-based maintenance exercise program completion group (n = 12)

2-year physical activity counseling program group (n = 30) Withdrawal (n = 3) Clinical worsening (n = 1) Death (n = 2) 2-year physical activity counseling program completion group (n = 24)

Figure 1. Flow chart for screening, recruitment, allocation, and intervention.

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Table 1. Clinical characteristics at baseline, by group.a

Characteristic Age (yr) Weight (kg) BMI (kg/m2) FEV1 (%) FVC (%) FEV1/FVC (%) TLC (%) 6MWD (m)

24MME (n = 12) 64 ± 6 88.5 ± 22.9 30.8 ± 6.6 51.5 ± 10.6 78.8 ± 16.7 47.2 ± 7.0 118.2 ± 20.1 553.3 ± 63.4

27MPAC (n = 24) 68.7 ± 7.8 80.5 ± 14.3 28.6 ± 4.8 46.8 ± 15.5 76.7 ± 14.2 43.6 ± 12.1 117.2 ± 22.0 475.7 ± 69.7

p 0.14 0.20 0.25 0.86 0.68 0.85 0.95 0.01

24MME: 24-month community-based maintenance exercise program preceded by 3 months of outpatient pulmonary rehabilitation; 27MPAC: 27-month physical activity counseling program; BMI: body mass index; and 6MWD: sixminute walk distance.aResults expressed as mean ± SD.

magnitude of improvement was greater in the 24MME group than in the 27MPAC group (p < 0.01).

Over the course of the study period (from baseline to 3 months to the end of the study period), the 6MWD showed a significant time-dependent effect in the 24MME group (from 553.3 ± 63.4 m to 586.6 ± 67.4 m to 570.5 ± 97.9 m; p < 0.04), although not in the 27MPAC group (from 475.7 ± 69.7 m to 478.7 ± 77.6 m to 470.2 ± 107.9 m; p = 0.68). From baseline to 3 months, the mean increase in the 6MWD was greater in the 24MME group than in the 27MPAC group (33.2 ± 36.6 m vs. 2.9 ± 34.7 m; p < 0.05), as shown in Figure 4. As can be seen in Table 2, from baseline to 3 months, the changes in the CRQ scores for the dyspnea and mastery domains, as well as in the total score, were greater in the 24MME group than in the 27MPAC group (p < 0.05 for all). At the end of the study period, there were no differences between the two groups in terms of the changes in the CRQ domain scores. From baseline to the end of the study period, all CRQ domain scores showed time-dependent effects in the 24MME group (p < 0.05), statistically significant improvements in the domain scores also being observed at 3 months (p < 0.05). DISCUSSION The major findings of the present study were that the supervised, community-based maintenance exercise program preserved the benefits in maximal strength, muscle power, 6MWD, and quality of life obtained with PR, and that the physical activity counseling program achieved greater gains in maximal strength at the end of the study period in comparison with the 3-month time point and improved the CRQ dyspnea domain score over the 24-month intervention period,

1RM Leg press (kg)

330

24MME 27MPAC

300 270 240 210 180 150 120

† || Baseline

3 months

27 months

Muscle power output (w)

At the end of the study period, the maximal strength in the chest press exercise was greater than the baseline value by 37.6 ± 28.3% in the 24MME group (from 57.5 ± 16.7 kg to 76.2 ± 15.2 kg; p < 0.001) and by 8.8 ± 16% in the 27MPAC group (from 59.7 ± 13.2 kg to 63.9 ± 12.9 kg; p = 0.26), as can be seen in Figure 3. The magnitude of improvement was greater in the 24MME group than in the 27MPAC group (p < 0.01).

A 360

1200 1100 1000 900 800 700 600 500 400 300 200

§ §

‡ || Baseline

3 months

27 months

Figure 2. Maximal dynamic strength, defined as onerepetition maximum (1RM), in the leg press exercise (A) and muscle power output at 50% of the 1RM in the leg press exercise (B), at the three time points evaluated, in the 24-month community-based maintenance exercise program preceded by 3 months of outpatient pulmonary rehabilitation (24MME) group and in the 27-month physical activity counseling program (27MPAC) group. *p < 0.001 vs. baseline in the 24MME group. †p < 0.01 vs. baseline in the 27MPAC group. ‡p < 0.05 vs. baseline in the 27MPAC group. §p < 0.05 vs. baseline in the 24MME group. ||p < 0.05 for 3 months vs. 27 months in the 27MPAC group.

as well as attenuating the decline in the 6MWD over that same period. Skeletal muscle dysfunction has been postulated to be one of the extrapulmonary effects of COPD, resulting in reduced peripheral muscle strength,(22,23) increased mortality risk, and decreased quality of life. (13,24) Few studies have evaluated the maximal strength of the upper and lower limbs after two different long-term simple strategies have been applied in patients with COPD. In contrast with the findings J Bras Pneumol. 2017;43(6):464-471

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100 1RM Chest press (kg)

24MME 27MPAC

80 70 60 50 40 30

Baseline

3 months

27 months

Figure 3. Maximal dynamic strength, defined as onerepetition maximum (1RM), on the chest press exercises, at the three time points evaluated, in the 24-month community-based maintenance exercise program preceded by 3 months of outpatient pulmonary rehabilitation (24MME) group and in the 27-month physical activity counseling program (27MPAC) group. *p < 0.001 vs. baseline in the 24MME group.

24MME 27MPAC

Î&#x201D; 6MWD (m)

100 80 60 40 20 0 -20 -40 -60 -80 -100

Baseline

3 months

27 months

Figure 4. Changes in the six-minute walk distance (Î&#x201D;6MWD, in m), in relation to the baseline measurement, in the 24-month community-based maintenance exercise program preceded by 3 months of outpatient pulmonary rehabilitation (24MME) group and in the 27-month physical activity counseling program (27MPAC) group. *Significant difference between the two groups (p < 0.05).

of a previous study,(7) which demonstrated no effects on maximal muscle strength after 20 months of an active maintenance phase, our results indicate that a supervised community-based maintenance exercise program preserved the PR-induced increases achieved in maximal strength of the upper and lower limbs over the 24-month intervention period. One unique finding was that, in the 27MPAC group, the maximal strength of the lower limbs was 13.6% higher at the end of the study period than at baseline. Our findings have important clinical implications. Waschki et al.(25) reported that a sustained low level of physical activity is related to the progressive muscle depletion that occurs in all patients with COPD. Our findings suggest that a physical activity counseling program is an effective, simple strategy to attenuate the deconditioning of the peripheral muscles in the lower limbs in older men with COPD. On the basis of our findings, it was not possible to identify the physiological mechanisms responsible for the difference between the maintenance exercise program and the physical activity counseling program 468

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in terms of the increase in the maximal strength of the lower limbs, which was greater after the former program. One possible explanation for our finding that the observed gains in the muscle strength of the lower limbs were lesser in the 27MPAC group than in the 24MME group is that the relative training intensity (40-70% of the 1RM) was greater in the 24MME group than in the 27MPAC group. Another possible explanation is that, in older men with COPD, the 6MWD is positively associated with leg muscle power output, although not with maximal strength.(26) Taken together, our results suggest that a practicable, supervised, communitybased maintenance program is a satisfactory means of maintaining the benefits that PR provides in terms of maximal muscle strength in the upper and lower limbs; that a physical activity counseling program is a simple, effective strategy to attenuate peripheral muscle deconditioning in the lower limbs of older adult men with COPD; and that such individuals might require a specific strength training program. The age-related decrease in maximal strength and explosive force production has been attributed to a loss of muscle mass mediated by a loss and a decrease in the size of individual muscle fibers.(27,28) In the lower limbs of older adults, impaired muscle power output has recently emerged as a more important predictor of limitations to mobility in tasks, such as rising from a chair and climbing stairs, than is maximal muscle strength, lower-limb muscle power output also constituting a determinant of habitual walking speed and the risk of falls.(9,29-34) To our knowledge, this is the first article to report the effects that long-term strategies have on the muscle power output of the lower limbs in older men with COPD. The results of the present study indicate that a community-based maintenance exercise program can maintain muscle power output for at least 24 months after PR. However, we found that muscle power output decreased by 15% after 3 months in the 27MPAC group. Our results suggest that a physical activity program for older men with COPD should include high-velocity muscle power training for the lower limbs, to attenuate the loss of muscle mass. Our results are in agreement with those of previous studies reporting that the observed benefits of PR on exercise capacity and quality of life are maintained over a 24-month period with a supervised, communitybased exercise program.(4,5) In the present study, we expanded our investigation by determining the effects that a physical activity counseling program had on exercise capacity and quality of life over a 27-month period. We found that the 24-month community-based maintenance exercise program maintained the benefits of PR in all CRQ domains, and that the 27-month physical activity counseling program resulted in improvement in the CRQ dyspnea domain. Two possible explanations for the difference between the two programs are the supervision and the intensity of the exercise in the 24-month community-based maintenance exercise program. One important and clinically relevant finding of the present study is that there was no decline in the

Zambom-Ferraresi F, Cebollero P, Hueto J, Hernández M, Cascante J, Antón MM

Table 2. Changes in Chronic Respiratory Questionnaire scores over time.a

CRQ score Dyspnea domain Baseline Month 3 Month 27 Change from baseline to 3 months Change from baseline to 27 months Time-dependent effect (baseline vs. 27 months) Fatigue (points) Baseline Month 3 Month 27 Change from baseline to 3 months Change from baseline to 27 months Time-dependent effect (baseline vs. 27 months) Emotional (points) Baseline Month 3 Month 27 Change from baseline to 3 months Change from baseline to 27 months Time-dependent effect (baseline vs. 27 months) Mastery (points) Baseline Month 3 Month 27 Change from baseline to 3 months Change from baseline to 27 months Time-dependent effect (baseline vs. 27 months) CRQ Total Score (points) Baseline Month 3 Month 27 Change from baseline to 3 months Change from baseline to 27 months Time-dependent effect (baseline vs. 27 months)

24MME group

27MPAC group

3.8 ± 1.1 4.9 ± 1.3 5.1 ± 1.2 1.2 ± 0.7 1.3 ± 0.7 < 0.001

4.0 ± 1.1 4.6 ± 1.5 4.8 ± 1.8 0.6 ± 1.0 0.8 ± 1.8 0.07

0.59

5.1 ± 1.1 5.7 ± 1.5 5.7 ± 0.9 0.6 ± 0.9 0.7 ± 0.8 0.03

5.1 ± 0.8 5.3 ± 1.0 5.4 ± 1.1 0.2 ± 0.7 0.3 ± 1.1 0.14

0.83

4.9 ± 1.4 5.7 ± 1.3 5.9 ± 0.8 0.8 ± 0.8 0.9 ± 1.0 0.02

5.4 ± 1.0 5.7 ± 1.1 5.7 ± 1.2 0.4 ± 0.7 0.4 ± 0.8 0.18

5.5 ± 1.5 6.2 ± 1.4 6.4 ± 0.8 0.7 ± 1.0 0.4 ± 1.3 < 0.01

6.4 ± 0.5 6.4 ± 0.8 6.4 ± 0.8 0.0 ± 0.5 −0.02 ± 0.6 0.83

19.3 ± 4.6 22.6 ± 5.1 22.6 ± 4.0 3.3 ± 2.9 3.3 ± 1.5 0.001

20.5 ± 2.7 21.6 ± 3.5 21.8 ± 3.8 1.1 ± 2.1 1.3 ± 3.1 0.055

0.04 0.23

0.14 0.43

0.33

0.16 0.10

0.09

0.02 0.09

0.34

0.01 0.047

CRQ: Chronic Respiratory Questionnaire; 24MME: 24-month community-based maintenance exercise program preceded by 3 months of outpatient pulmonary rehabilitation; and 27MPAC: 27-month physical activity counseling program. aResults expressed as mean ± SD.

6MWD during the study period in the 27MPAC group. In addition, there were no significant differences between the two groups in terms of the changes in the 6MWD at the end of the study period. In the present study, no gains in the 6MWD were observed in the 27MPAC group. That differs from what has been found in previous studies,(6,35,36) in which improvements in the 6MWD were observed after 3 months of physical activity counseling. These discrepancies could be explained by the fact that some previous studies have used a pedometer during the intervention and have set goals for their participants,(6,35,36) some even using a semiautomated telecoaching program.(35) Taken together, these results suggest that a physical activity counseling program could prevent the predicted decline in the 6MWD (35 m/year) for patients who are physically inactive.(25)

Our experimental approach has several methodological limitations. First, ours was a prospective study involving two independent, single-arm trials without randomization. In addition, the sample size was small. Furthermore, all of the participants were male, and the results therefore cannot be extrapolated to females. In Spain, the prevalence of COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease criteria, is higher in men than in women (15.1% vs. 5.6%).(37) Moreover, the dropout rate was greater in the 24MME group than in the 27MPAC group (57% vs. 20%). Six of the 24MME group participants declined to continue the maintenance exercise program, and most of the 24MME group participants who dropped out of the program did so because of clinical worsening during J Bras Pneumol. 2017;43(6):464-471

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the intervention period. In each of the two groups, there were 2 participants who died during the study period (Figure 1). However, in comparison with that reported in previous studies,(4) the dropout rate in the present study was not unusual, especially considering the duration of the intervention period. Finally, the 24-month community-based maintenance exercise program was preceded by outpatient PR program, whereas the 27-month physical activity counseling program was not, and there were no measurements taken at one year in.

In conclusion, the results of the present study indicate that a 24-month, supervised community-based maintenance exercise program provides a significant training stimulus to preserve the gains in maximal strength, muscle power, 6MWD, and quality of life observed after 3 months of PR in older men with COPD. A 27-month physical activity counseling program results in improvements in maximal muscle strength of the lower limbs and may be an effective, simple strategy to attenuate peripheral muscle dysfunction and maintain exercise capacity in older men with COPD.

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12. https://doi.org/10.1097/JES.0b013e31823b5f13 15. Abizanda Soler P, López-Torres Hidalgo J, Romero Rizos L, López Jiménez M, Sánchez Jurado PM, Atienzar Núñez P, et al. Frailty and dependence in Albacete (FRADEA study): reasoning, design and methodology [Article in Spanish]. Rev Espanola Geriatr Gerontol. 2011;46(2):81-8. https://doi.org/10.1016/j.regg.2010.10.004 16. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347-65. https:// doi.org/10.1164/rccm.201204-0596PP 17. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-7. https://doi. org/10.1164/ajrccm.166.1.at1102 18. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease. Thorax. 1987;42(10):773-8. http://dx.doi.org/10.1136/thx.42.10.773 19. Güell R, Casan P, Sangenís M, Morante F, Belda J, Guyatt GH. Quality of life in patients with chronic respiratory disease: the Spanish version of the Chronic Respiratory Questionnaire (CRQ). Eur Respir J. 1998;11(1):55-60. 20. Izquierdo M, Ibañez J, HAkkinen K, Kraemer WJ, Larrión JL, Gorostiaga EM. Once weekly combined resistance and cardiovascular training in healthy older men. Med Sci Sports Exerc. 2004;36(3):43543. http://dx.doi.org/10.1249/01.MSS.0000117897.55226.9A 21. Zambom-Ferraresi F, Cebollero P, Gorostiaga EM, Hernández M, Hueto J, Cascante J, et al. Effects of Combined Resistance and Endurance Training Versus Resistance Training Alone on Strength, Exercise Capacity, and Quality of Life in Patients With COPD. J Cardiopulm Rehabil Prev. 2015;35(6):446-53. https://doi.org/10.1097/ HCR.0000000000000132 22. Bernard S, LeBlanc P, Whittom F, Carrier G, Jobin J, Belleau R, et al. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;158(2):629-34. https://doi.org/10.1164/ajrccm.158.2.9711023 23. Gosker HR, Kubat B, Schaart G, van der Vusse GJ, Wouters EF, Schols AM. Myopathological features in skeletal muscle of patients with chronic obstructive pulmonary disease. Eur Respir J. 2003;22(2):280-5. https://doi.org/110.1183/09031936.03.00012803 24. Decramer M, Gosselink R, Troosters T, Verschueren M, Evers G. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J. 1997;10(2):417-23. 25. Waschki B, Kirsten AM, Holz O, Mueller KC, Schaper M, Sack AL, et al. Disease Progression and Changes in Physical Activity in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2015;192(3):295-306. https://doi.org/10.1164/rccm.2015010081OC 26. Hernández M, Zambom-Ferraresi F, Cebollero P, Hueto J, Cascante JA, Antón MM. The Relationships between Muscle Power and Physical Activity in Older Men with Chronic Obstructive Pulmonary Disease. J Aging Phys Act. 2017;25(3):360-366. https://doi. org/10.1123/japa.2016-0144 27. Larsson L. Morphological and functional characteristics of the ageing skeletal muscle in man. A cross-sectional study. Acta Physiol Scand Suppl. 1978;457:1-36. 28. Lexell J. Ageing and human muscle: observations from Sweden. Can J Appl Physiol. 1993;18(1):2-18. https://doi.org/10.1139/h93-002

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29. Izquierdo M, Aguado X, Gonzalez R, López JL, Häkkinen K. Maximal and explosive force production capacity and balance performance in men of different ages. Eur J Appl Physiol Occup Physiol. 1999;79(3):260-7. https://doi.org/10.1007/s004210050504 30. Bassey EJ, Fiatarone MA, O’Neill EF, Kelly M, Evans WJ, Lipsitz LA. Leg extensor power and functional performance in very old men and women. Clin Sci (Lond). 1992;82(3):321-7. https://doi.org/10.1042/ cs0820321 31. Bean JF, Leveille SG, Kiely DK, Bandinelli S, Guralnik JM, Ferrucci L. A comparison of leg power and leg strength within the InCHIANTI study: which influences mobility more? J Gerontol A Biol Sci Med Sci. 2003;58(8):728-33. https://doi.org/10.1093/gerona/58.8.M728 32. Bean JF, Kiely DK, Herman S, Leveille SG, Mizer K, Frontera WR, et al. The relationship between leg power and physical performance in mobility-limited older people. J Am Geriatr Soc. 2002;50(3):461-7. https://doi.org/10.1046/j.1532-5415.2002.50111.x 33. Cadore EL, Casas-Herrero A, Zambom-Ferraresi F, Idoate F, Millor N, Gómez M, et al. Multicomponent exercises including muscle power training enhance muscle mass, power output, and functional outcomes in institutionalized frail nonagenarians. Age (Dordr).

2014;36(2):773-85. https://doi.org/10.1007/s11357-013-9586-z 34. Casas-Herrero A, Cadore EL, Zambom-Ferraresi F, Idoate F, Millor N, Martínez-Ramirez A, et al. Functional capacity, muscle fat infiltration, power output, and cognitive impairment in institutionalized frail oldest old. Rejuvenation Res. 2013;16(5):396-403. https://doi. org/10.1089/rej.2013.1438 35. Demeyer H, Louvaris Z, Frei A, Rabinovich RA, de Jong C, Gimeno-Santos E, et al. Physical activity is increased by a 12-week semiautomated telecoaching programme in patients with COPD: a multicentre randomised controlled trial. Thorax. 2017;72(5):415-23. http://dx.doi.org/10.1136/thoraxjnl-2016-209026 36. Mendoza L, Horta P, Espinoza J, Aguilera M, Balmaceda N, Castro A, et al. Pedometers to enhance physical activity in COPD: a randomised controlled trial. Eur Respir J. 2015;45(2):347-54. https:// doi.org/10.1183/09031936.00084514 37. Miravitlles M, Soriano JB, García-Río F, Muñoz L, Duran-Tauleria E, Sanchez G, et al. Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities. Thorax. 2009;64(10):863-8. https://doi.org/10.1136/thx.2009.115725

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REVIEW ARTICLE

Tuberculosis treatment Marcelo Fouad Rabahi1,2, José Laerte Rodrigues da Silva Júnior2, Anna Carolina Galvão Ferreira1,3, Daniela Graner Schuwartz Tannus-Silva1, Marcus Barreto Conde4,5

1. Faculdade de Medicina, Universidade Federal de Goiás, Goiânia (GO) Brasil. 2. Centro Universitário de Anápolis, Anápolis (GO) Brasil. 3. Pontifícia Universidade Católica de Goiás, Goiânia (GO) Brasil. 4. Faculdade de Medicina de Petrópolis, Petrópolis (RJ) Brasil. 5. Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. Submitted: 21 December 2016. Accepted: 4 May 2017.

ABSTRACT Tuberculosis treatment remains a challenge due to the need to consider, when approaching it, the context of individual and collective health. In addition, social and economic issues have been shown to be variables that need to be considered when it comes to treatment effectiveness. We conducted a critical review of the national and international literature on the treatment of tuberculosis in recent years with the aims of presenting health care workers with recommendations based on the situation in Brazil and better informing decision-making regarding tuberculosis patients so as to minimize morbidity and interrupt disease transmission. Keywords: Tuberculosis/drug therapy; Tuberculosis/prevention & control; Tuberculosis/ surgery; Tuberculosis/classification.

Study carried out at the Faculdade de Medicina, Universidade Federal de Goiás, Goiânia (GO) Brasil.

INTRODUCTION Tuberculosis treatment is aimed at curing and rapidly reducing disease transmission. For this to occur, the drugs used should be able to reduce the bacillary population rapidly (interrupting transmission); prevent selection of naturally resistant strains (avoiding the emergence of drug resistance during therapy); and sterilize the lesion (preventing disease relapse).(1) Although antituberculosis regimens have an efficacy of up to 95%, treatment effectiveness (patients who are cured at the end of treatment under routine conditions) varies greatly with location, with the national average being around 70% (50-90%). One of the causes of low effectiveness is nonadherence, which can occur at three levels(2,3): • treatment default (patients stop using all medications) or • incorrect medication use (patients use some of the prescribed medications) and/or • irregular medication use (patients take the medications some days of the week but not every day of the week) Treatment adherence problems are responsible both for treatment failure and for selection of resistant organisms and disease relapse. In order to improve adherence to tuberculosis treatment and restructure health care facilities, the World Health Organization (WHO) has, since the early 1990s, recommended the adoption of the directly observed treatment, short course (DOTS) strategy. The DOTS strategy includes five elements(4,5): 1. Political commitment and financial support to maintain tuberculosis control activities

2. Identification of tuberculosis cases on the basis of sputum smear microscopy among patients with respiratory symptoms 3. A standardized antituberculosis drug regimen administered as directly observed treatment (DOT) for at least the first 2 months of treatment 4. Guarantee of a regular supply of antituberculosis drugs 5 A system for reporting and assessment of treatment results for each patient and for the tuberculosis control program as a whole Although supervised medication-taking through DOT allows frequent contact between patients and the health care system and favors treatment adherence, systematic reviews have failed to demonstrate greater effectiveness of DOT compared with self-administered treatment.(6-8) This probably occurs because treatment effectiveness is in fact related to several factors (Chart 1) and not only to medication-taking, which is a variable related to patient care. Nevertheless, DOT remains the standard practice of most tuberculosis control programs in the USA and Europe, since it appears to be significantly associated with sputum smear conversion (from positive to negative) during treatment. As a result, DOT is recommended in both Europe and the USA for all forms of tuberculosis. In 1998, the Programa Nacional de Controle da Tuberculose (PNCT, Brazilian National Tuberculosis Control Program) implemented DOT in Brazil, and, since 2000, measures of decentralization have been taken, including integration of tuberculosis control into primary health care and the proposal to provide DOT at 100% of the health care clinics in the priority cities and for at least 80% of patients with active tuberculosis in those cities; however, this has not

Correspondence to:

Marcelo Rabahi. Avenida B, 483, CEP 74605-220, Goiânia, GO, Brasil. Tel.: 55 62 3521-3333. E-mail: mfrabahi@gmail.com Financial support: None.

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Rabahi MF, Silva Júnior JLR, Ferreira ACG, Tannus-Silva DGS, Conde MB

Chart 1. Factors that influence the effectiveness of tuberculosis treatment.

PATIENT-RELATED FACTORS Age, comorbidities, immune status, nutritional status, abusive alcohol intake, adherence to treatment, and drug tolerance Genetic characteristics affecting drug absorption and metabolism, and individual vulnerability to toxicities FACTORS RELATED TO THE ORGANISM/DISEASE PRESENTATION Virulence of the organism Susceptibility of the strain Radiological extent of the disease and presence of cavities CARE-RELATED FACTORS Motivational capacity of the staff, access of patients to the health care system, and monitoring and supervision of patients regarding treatment TREATMENT-RELATED FACTORS Amount of each drug administered, plasma concentrations of administered drugs; relationship between administered drugs and proteins, clearance, metabolism, and absorption Drug bioavailability of the presentations (single-drug tablets, fixed-dose combination tablets), and drug interactions with other drugs Treatment regimen used (daily or intermittent), which influences duration and frequency of drug administration; bactericidal and sterilizing potency; and drug synergy or antagonism

occurred. It should be borne in mind that most of the countries that use DOT offer intermittent (non-daily) treatment, as is the case in Brazil.(1,2,9,10) There are situations in which self-administered treatment cannot be used, however, and, in such cases, all efforts should be made toward DOT. Such cases include patients with drug-resistant tuberculosis or at high risk of developing drug resistance (individuals without a fixed home; drinkers; users of illicit drugs; individuals who cannot take medications on their own because of mental, emotional, or physical impairment; children and adolescents; individuals deprived of their liberty; and individuals with a history of nonadherence to treatment).(11,12) TUBERCULOSIS AND THE BRAZILIAN NATIONAL HEALTH CARE SYSTEM Reporting of tuberculosis is mandatory in Brazil. The report form should record patient identification data, place of origin of the case, clinical form of the disease, and comorbidities. In addition, tuberculosis case type should be indicated on the form (field 32: type of admission). Below are the definitions of the types of admission for tuberculosis cases used in the Brazilian Case Registry Database. A new case is defined as one in which the individual has never received antituberculosis treatment or received it for up to 30 days. A retreatment case or a case of readmission after default is defined as one in which the individual was treated for more than 30 days and requires additional treatment because of relapse after cure or return after default. A relapse case is defined in the PNCT manual (2011) as one in which the individual with active tuberculosis has been previously treated and cured, regardless of the time elapsed since the previous treatment. In tuberculosis relapse cases, it is mandatory to request sputum culture and drug susceptibility testing for Mycobacterium tuberculosis,

and the possibility of resistance to antituberculosis drugs should be ruled out. Until culture and drug susceptibility testing results are available, treatment with the basic regimen should be initiated. This working definition does not include relapse due to lack of sterilization of a lesion of exogenous reinfection, a piece of information that might be relevant in the assessment of the efficacy and effectiveness of both the treatment and the tuberculosis control program. Studies conducted in Africa, Europe, and the USA suggest that most relapse cases occurring two years after cure are due to reinfection and not to relapse. In fact, a certain diagnosis of relapse of tuberculosis would be made regardless of length of discharge as cured and would be based on the identification of the same M. tuberculosis cluster by a molecular biology technique (fingerprinting). However, in Brazil, fingerprinting is available only in research laboratories and in some private laboratories. Field 32 (type of admission) also includes the following options: “transfer”; “post-death”; and “unknown.” The term “transfer” is used to refer to the admission of patients coming from another city, and this type of admission can produce changes in tuberculosis indicators, since these data are excluded from the calculation of the rates of diagnosis and treatment outcomes, such as treatment default. The same applies to the terms “unknown” and “post-death”. Therefore, in Brazil, there is uncertainty regarding the representativeness of the tuberculosis indicators presented by the PNCT. Antituberculosis drugs are provided free of charge, this being guaranteed by the PNCT, and they are not commercially available. These drugs are widely available in the public health care system, but they are dispensed to patients only upon presentation of a completed report form. The responsibility of completing the report form lies with the health care worker who makes the diagnosis of tuberculosis and prescribes the medication.(1,10,13,14) J Bras Pneumol. 2017;43(5):472-486

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TUBERCULOSIS TREATMENT

Tuberculosis treatment in adults In the 1940s, the Brazilian National Campaign against Tuberculosis was started, and, during that period, two antituberculosis drugs were used: streptomycin and para-aminosalicylic acid. In the 1950s, Brazil chose to use a twice-weekly regimen with isoniazid and streptomycin. In the 1960s, given bacterial resistance and the increase in mortality from tuberculosis, treatment regimens began to be standardized, and the use of isoniazid (H), streptomycin (S), and pyrazinamide (Z) for 18 months (HSZ regimen) was implemented. (15,16) In the mid 1970s, short-term antituberculosis chemotherapy, with rifampin (R), isoniazid (H), and pyrazinamide (Z) for 6 months (RHZ regimen), was developed. Brazil was the first country in the world to implement the 6-month regimen in the public health care system, with all drugs being administered p.o. and being distributed free of charge. In the 1980s, combination capsules of RH were implemented already aiming to prevent acquired bacterial resistance. In 2009, Brazil introduced the use of fixed-dose combination (FDC) tablets and added ethambutol (E) to the RHZ regimen, as defined by the PNCT, on the basis of the preliminary results of the Second National Survey on Antituberculosis Drug Resistance, which showed an increase in primary resistance to isoniazid (from 4.4% to 6.0%). In addition, besides the change in presentation to FDC, the doses of isoniazid and pyrazinamide in the tablets were reduced in the treatment change (from 400 mg to 300 mg and from 2,000 mg to 1,600 mg, respectively), without bioavailability or bioequivalence studies being carried out. The basic regimen currently used in Brazil for the treatment of adults with tuberculosis and without clinical suspicion of drug resistance is presented in Chart 2. It consists of a 2-month intensive phase with the FDC RHZE regimen, followed by a 4-month maintenance phase with the FDC RH regimen, and it is used for all forms of the disease in patients over 10 years of age. The exception is patients with meningitis due to tuberculosis, who, in the maintenance phase, are treated for 7 months and with the combination of an oral corticosteroid (prednisone, at a dose of

1-2 mg/kg/day for 4 weeks) or an i.v. corticosteroid (dexamethasone, at a dose of 0.3-0.4 mg/kg/day for 4-8 weeks).(10,15,16) The medications are available in FDC tablets. Each tablet contains 150 mg of rifampin, 75 mg of isoniazid, 400 mg of pyrazinamide, and 275 mg of ethambutol. As defined in the PNCT handbook on tuberculosis,(10) the second phase of treatment can be extended for 7 months, after consultation with a referral center, in the following cases: • Patients with HIV/AIDS • Patients whose direct smears show few organisms at 5 or 6 months of treatment, alone, as long as there is clinical and radiological improvement—treatment can be extended for an additional 3 months, at which period cases should be redefined or closed • Patients with negative direct smears and an unsatisfactory clinical and radiological course • Patients with cavitary forms who remain smear-positive at the end of the second month of treatment—in such cases, culture and drug susceptibility testing are mandatory • Patients with monoresistance to rifampin or isoniazid, identified in the maintenance phase of treatment—a careful assessment of the clinical, bacteriological, and radiological course, as well as of adherence and previous tuberculosis treatment, should be performed at or under the guidance of a tertiary referral center According to the literature, individuals at the highest risk of relapse of tuberculosis (due to lack of sterilization of the lesion) include those whose weight is less than 10% of the ideal weight and whose weight gain is less than or equal to 5% in the intensive phase of treatment; smokers; and patients with insulin-dependent diabetes, HIV infection, or another immunosuppressive condition. For such individuals, extension of the maintenance phase of treatment should be considered. In addition, in patients who had cavitation (total diameter ≥ 2 cm) on the initial chest X-ray and are culture positive for M. tuberculosis at the end of the first 8 weeks of treatment (completion of the intensive phase of treatment), the maintenance phase of treatment can be extended for an additional 3 months because of the increased risk of relapse. Unfortunately, only 15-20% of the cases

Chart 2. Treatment regimen for all new cases of all forms of pulmonary and extrapulmonary tuberculosis (except meningoencephalitis), as well as for all cases of relapse and return after default.a

Regimenb 2RHZE Intensive phase

Drugs (mg/tablet)c RHZE (150/75/400/275)

4RH Maintenance phase

RH (150/75)

Body weight, kg ≤ 20 20- 35 36-50 > 50 ≤ 20 20-35 36-50 > 50

Dose 10/10/35/25 mg/kg/day 2 tablets 3 tablets 4 tablets 10/10 mg/kg/day 2 tablets 3 tablets 4 tablets

R: rifampin; H: isoniazid; Z: pyrazinamide; and E: ethambutol. aThe drugs are given as fixed-dose combination tablets. bThe number preceding the acronym indicates duration of treatment in months. cThe dose of each drug in mg in each tablet is listed below its corresponding letter in the acronym.

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of pulmonary tuberculosis in Brazil undergo sputum culture and drug susceptibility testing.(1,17-23) In cases in which it is impossible to use the basic regimen because of intolerance to two or more drugs, the use of a regimen for multidrug-resistant tuberculosis (MDR-TB) is indicated (Chart 3). In instances of treatment failure (as defined by the PNCT: individuals who remain sputum smear-positive at the end of treatment; individuals who are ++ or +++ smear positive and remain so until the fourth month of treatment; and those with initial smear-positivity followed by smear-negativity and then smear-positivity again for 2 consecutive months, from the fourth month of treatment onward), the use of the basic regimen should be extended until culture and drug susceptibility testing results are available. The possibility of nontuberculous mycobacterial infection should be considered, as should medication dosage error, irregular medication use, and inadequate drug absorption. The bioavailability of the drugs used in the treatment of tuberculosis (except rifapentine) is increased when they are taken on an empty stomach (the bioavailability of rifapentine increases by up to 86% with high-fat meals). If the medications need to be taken with foods or liquids, glucose-rich or lactose-rich foods should be avoided, since glucose and lactose reduce the absorption of isoniazid. Few drug interactions can cause substantial changes in the concentrations of medications for tuberculosis treatment; however, medications for tuberculosis treatment often cause clinically relevant changes in the concentrations of other drugs.(1,10,24,25)

Tuberculosis treatment in children In Brazil, patients under 10 years of age are treated with three medications: rifampin (10 mg/kg), isoniazid (10 mg/kg), and pyrazinamide (35 mg/kg). This decision is based on the lower risk of resistance to isoniazid in patients with a low bacterial load, as is more common in children with tuberculosis, and on the risk of ethambutol-related visual impairment, the diagnosis of which can be difficult in children.(24,26,27) On the basis of systematic reviews of the literature, the American Academy of Pediatrics(27) recommends the four-drug treatment, with the addition of ethambutol, in the intensive phase of treatment, along with monitoring of visual acuity and of the ability to discriminate between red and green colors. In cases of children whose visual acuity cannot be monitored, the risk-benefit ratio of the use of ethambutol should be considered, observing that ethambutol can be routinely used to treat active tuberculosis in infants and children unless there is some other contraindication.Â (27) The WHO recommends that HIV-negative children with pulmonary tuberculosis who live in areas with a low prevalence of HIV infection and a low prevalence of resistance to isoniazid can be treated with three drugs (RHZ regimen) in the induction phase, without the addition of ethambutol. In cases of children who live in areas with a high prevalence of HIV infection and/or a high prevalence of resistance to isoniazid,

ethambutol should be added to the regimen in the induction phase.(27,28)

Tuberculosis treatment: approaches in cases of treatment interruption Occasionally, patients interrupt drug therapy during treatment. Chart 4 presents the management of such cases in each of six circumstances.(1)

Tuberculosis treatment outcomes Reporting of treatment completion (outcome) is obligatory in the same way as reporting of tuberculosis cases for treatment initiation. Below are the definitions of treatment outcome. Cure is defined as a negative sputum smear or culture in the last month of treatment and at least once previously, in cases of tuberculosis confirmed bacteriologically at the start of treatment. Failure is defined as a positive sputum smear or culture at 5 months or later during treatment. Default is defined as tuberculosis treatment interruption of â&#x2030;Ľ 30 days after the predicted date of return (self-administered treatment) or of 30 days after the last drug intake (DOT; for management of treatment interruptions, see Chart 4). A death from tuberculosis is defined as a death caused by tuberculosis and occurring during treatment. A death from another cause is defined as a death from a cause other than tuberculosis and occurring during treatment.(10,29) DRUG-RESISTANT TUBERCULOSIS Cases of drug-resistant tuberculosis are classified according to the susceptibility of M. tuberculosis to first- and second-line drugs used in the pharmacological treatment of this disease. Below are the definitions of the main terms used in communication about cases of drug-resistant tuberculosis. Monodrug-resistant tuberculosis is defined as tuberculosis caused by organisms resistant to one first-line antituberculosis drug. Polydrug-resistant TB is defined as tuberculosis caused by organisms resistant to more than one first-line antituberculosis drug (except isoniazid and rifampin, resistance to both of which is characterized as multidrug resistance). MDR-TB is defined as tuberculosis caused by organisms resistant to both isoniazid and rifampin. Extensively drug-resistant tuberculosis is defined as tuberculosis caused by organisms resistant to rifampin, isoniazid, a fluoroquinolone, and at least one of three injectable second-line drugs (amikacin, kanamycin, or capreomycin). Rifampin-resistant tuberculosis is defined as tuberculosis caused by organisms identified as having resistance to rifampin by rapid molecular testing for tuberculosis drug resistance (with it being possible that there are other resistances still unknown, since a large proportion of cases identified as having resistance to rifampin also have resistance to isoniazid).(29,30) In addition to the classification of tuberculosis based on the susceptibility of organisms to drugs, mycobacterial resistance can be classified as primary or acquired. Primary resistance occurs in tuberculosis caused by J Bras Pneumol. 2017;43(5):472-486

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Chart 3. Treatment of multidrug-resistant and extensively drug-resistant tuberculosis.

Resistance R + H (Âą S)

Phase

Druga,b

Intensive

Cm3

Lfx

Trd

Maintenance

Lfx

Trd

Body weight, kg 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70 30 31-45 46-55 56-70 > 70

Dose 15-20 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 15-25 mg/kg/day 800 mg/day 1,200 mg/day 1,200 mg/day 1,200 mg/day 20-30 mg/kg/day 1,000 mg/day 1,500 mg/day 1,500 mg/day 2,000 mg/day 10-15 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 10-20 mg/kg/day 500 mg/day 500 mg/day 750 mg/day 750 mg/day 15-25 mg/kg/day 800 mg/day 1,200 mg/day 1,200 mg/day 1,200 mg/day 10-15 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 10-20 mg/kg/day 500 mg/day 500 mg/day 750 mg/day 750 mg/day

Treatment duration, months 8

R: rifampin; H: isoniazid; S: streptomycin; Cm: capreomycin; E: ethambutol; Z: pyrazinamide; Lfx: levofloxacin; Trd: terizidone; and Et: ethionamide. aThe subscript number after a drug abbreviation indicates the number of days per week that the drug will be used; if there is no subscript number, treatment with that drug is daily. bIn patients who have already used capreomycin, use amikacin as an alternative. In patients who do not have resistance to streptomycin as determined by drug susceptibility testing and who have not used amikacin, amikacin can also be considered for use. Doses of amikacin and streptomycin: up to 30 kg, 15-20 mg/kg/day; from 31 to 45 kg, 500 mg/day; from 46 to 55 kg, 750 mg/day; â&#x2030;Ľ 56 kg, 1,000 mg/day.

a bacillary population that is primarily resistant to an antituberculosis drug. In such cases, the individuals have never used an antituberculosis drug and are infected with an already resistant strain, presumably transmitted by a case of acquired resistance. Acquired resistance is that which occurs in a bacillary population that is initially susceptible to antituberculosis drugs and subsequently acquires resistance to some of them. Since the frequency of spontaneous mutations is low and since the use of an appropriate combination of drugs in the pharmacological treatment of tuberculosis makes the occurrence of clinically significant resistance 476

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unlikely, this type of resistance is presumably the result of irregular or inadequate treatment.(1)

Drug-resistant tuberculosis treatment Drug-resistant tuberculosis treatment depends on the type of resistance identified. The approaches in cases of monoresistance and polyresistance are described in Chart 5. The presence of multidrug resistance (resistance to RH or to RH and another first-line drug) is an indication for the use of the MDR-TB treatment regimen. The MDR-TB treatment regimen (Chart 3) has been changed by

Rabahi MF, Silva Júnior JLR, Ferreira ACG, Tannus-Silva DGS, Conde MB

Chart 3. Continued...

Resistance

Phase

Druga,b

R + H + E (± S) or R + H + E + Z (± S)

Intensive

Cm3

Lfx

Trd

Maintenance

Lfx

Trd

Dose 15-20 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 15-20 mg/kg/day 500 mg/day 750 mg/day 750 mg/day 750 mg/day 20-30 mg/kg/day 1,000 mg/day 1,500 mg/day 1,500 mg/day 2,000 mg/day 10-15 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 10-20 mg/kg/day 500 mg/day 500 mg/day 750 mg/day 750 mg/day 15-20 mg/kg/day 500 mg/day 750 mg/day 750 mg/day 750 mg/day 10-15 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 10-20 mg/kg/day 500 mg/day 500 mg/day 750 mg/day 750 mg/day

Treatment duration, months 8

including capreomycin (as the injectable drug of choice because it results in fewer side effects and less crossresistance with other injectable drugs); by replacing ethambutol with ethionamide when drug susceptibility testing shows resistance to ethambutol; and by using levofloxacin (in accordance with the recommendations of the WHO). Note that pyrazinamide should always be used in the intensive phase of treatment, even when drug susceptibility testing shows resistance, since there are limitations to interpreting such results (do not use pyrazinamide only in cases of hepatotoxicity or severe adverse effects).(30)

In cases of rifampin-resistant tuberculosis as determined by a rapid molecular test for tuberculosis drug resistance, initiate treatment with the recommended regimen (Chart 4) and wait until drug susceptibility testing results are available. If drug susceptibility testing shows susceptibility to all drugs, assess the risk of resistance on a case-by-case basis. In low-risk patients, start the basic regimen, which should be administered for 6 months, regardless of duration of MDR-TB regimen use. In high-risk patients (for example, retreatment cases, contacts of MRD-TB patients, or alcohol and drug users), maintain the MDR-TB regimen. J Bras Pneumol. 2017;43(5):472-486

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Chart 3. Continued...

Resistance R + H + Z (± S)

Phase

Druga,b

Intensive

Cm3

Lfx

Trd

Maintenance

Lfx

Trd

Dose 15-20 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 15-25 mg/kg/day 800 mg/day 1,200 mg/day 1,200 mg/day 1,200 mg/day 20-30 mg/kg/day 1,000 mg/day 1,500 mg/day 1,500 mg/day 2,000 mg/day 10-15 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 15-20 mg/kg/day 500 mg/day 750 mg/day 750 mg/day 750 mg/day 10-20 mg/kg/day 500 mg/day 500 mg/day 750 mg/day 750 mg/day 15-25 mg/kg/day 800 mg/day 1,200 mg/day 1,200 mg/day 1,200 mg/day 10-15 mg/kg/day 500 mg/day 750 mg/day 1,000 mg/day 1,000 mg/day 15-20 mg/kg/day 500 mg/day 750 mg/day 750 mg/day 750 mg/day 10-20 mg/kg/day 500 mg/day 500 mg/day 750 mg/day 750 mg/day

Treatment duration, months 8

In patients who have already used capreomycin, use amikacin as an alternative in those who do not have 478

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resistance to streptomycin as determined by drug susceptibility testing and who have not used amikacin;

Rabahi MF, Silva Júnior JLR, Ferreira ACG, Tannus-Silva DGS, Conde MB

Chart 4. Management of treatment interruptions.

Interruption time point During the intensive phase

During the maintenance phase

Details of interruption Lapse is < 14 days in duration

Lapse is ≥ 14 days in duration Received ≥ 80% of the doses and was smear-negativeb Received ≥ 80% of the doses and was smear-positive at the start of treatment Received < 80% of the doses, and accumulative lapse is < 3 months in duration

Received < 80% of the doses, and accumulative lapse is ≥ 3 months in duration

Approach Continue treatment to complete the planned total number of doses (60 doses), as long as the intensive phase lasts 3 months at most Restart treatment from the beginning Continue treatment. The patient may not need to take all doses Continue treatment until all 120 doses are completed Continue treatment until all 120 doses are completed, unless consecutive lapse is > 2 months in duration. In such cases, restart treatment. If treatment cannot be completed within 9 months (with the intensive phase lasting 3 months at most and the maintenance phase lasting 6 months at most), restart treatment from the beginning of the intensive phase. Restart treatment from the beginning (new intensive and maintenance phases)

Smear microscopy, culture, and susceptibility testing should always be performed when patients resume treatment. Smear-negative patient: a patient with at least two AFB-negative sputum samples (including one sample collected in the morning); X-ray findings consistent with tuberculosis and/or no clinical response to treatment with broadspectrum antimicrobial agents (Note: fluoroquinolones should not be used because they have activity against the Mycobacterium tuberculosis complex and can produce transient improvement in patients with tuberculosis); satisfactory response to antituberculosis treatment.

Chart 5. Treatment of monodrug-resistant and polydrug-resistant tuberculosis.

Regimena

Resistance to H R R (identified by rapid molecular testing)b H + Zc H + Ec R+Z R+E H+Z+E

Intensive phase 2RZES 6S3HZELfx 8Cm3EZLfxTrd 2RESO 2RZSO 8HCm3EZLfxTrd 8Cm3EtZLfxTrd 3RSOTd

Maintenance phase 4RE(10) 6HELfx(30) 10ELfxTrd 7REO 7RO 10HELfxTrd(30) 10HEtLfxTrd(30) 12ROT(10)

H: isoniazid; R: rifampin; Z: pyrazinamide; E: ethambutol; S: streptomycin; Lfx: levofloxacin; Cm: capreomycin; Trd: terizidone; O: ofloxacin; and Et: ethionamide. aThe number preceding the acronym indicates duration of treatment in weeks. The subscript number after a drug abbreviation indicates the number of days per week that the drug should be used; if there is no subscript number, treatment with that drug is daily. bIf there is monoresistance to R and the patient has been on the 8Cm3EZLfxTrd/10ELfxTrd regimen for more than 1 month, continue the regimen until completion; if the patient has been on that regimen for less than 1 month, discontinue it and start the 6S3HZELfx/6HELfx regimen. If susceptibility testing shows multidrug resistance (R + H or R + H + resistance to any other first-line drugs), see Chart 3. If susceptibility testing shows polyresistance (R + resistance to first-line drugs other than H), continue the regimen for R-resistant tuberculosis with the addition of H: 8HCm3EZLfxTrd/10 HLfxTrd (Chart 4).(30) cOptionally replace O with Lfx.(10) dExtend the intensive phase for 6 months in cases of extensive bilateral disease.(10)

amikacin can be considered for use in patients with a history of previous treatment. Assess each case individually on the basis of medications used and drug susceptibility testing results.(30) Treatment of extensively drug-resistant tuberculosis (Chart 3) should be carried out at a tertiary health care facility, specializing in the treatment of drug-resistant tuberculosis. Individualized regimens and salvage drugs are used.(24)

Adverse reactions to tuberculosis treatment The most frequent adverse reactions to the RHZE regimen are a change in urine color (it occurs universally), gastric intolerance (in 40% of patients), skin changes (in 20%), jaundice (in 15%), and joint pain (in 4%). The major associated factors are age (from the fourth decade of life onward), alcohol dependence (daily alcohol intake > 80 g), malnutrition (loss of more than 15% of body weight), history of liver disease, J Bras Pneumol. 2017;43(5):472-486

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Chart 6. Adverse reactions and approach.a

Adverse reactions Minor Anorexia, vomiting, nausea, abdominal pain

Orange- or red-colored sweat/urine Pruritus Joint pain Paresthesia Asymptomatic hyperuricemia Hyperuricemia and arthralgia Arthritis/arthralgia Headache, anxiety, euphoria, insomnia Major Exanthema/pruritus

Probable causative drug

Approach

R, H, Z

Advise patients to take the antituberculosis drugs at the appropriate time, prescribe symptomatic treatment, and reassess the need for requesting the determination of hepatic enzyme levels. R Instruct patients. S, R Prescribe antihistamines. Z Prescribe aspirin. H (common) or E (uncommon) Prescribe pyridoxine (50 mg/day). Z Prescribe follow-up/diet. E Prescribe follow-up/diet/symptomatic treatment. H, Z Prescribe symptomatic treatment. H Instruct patients. S, R

Discontinue the drugs and reintroduce one drug at a time. Discontinue Z. Use the 2RHE/7RH regimen.

Fever, oliguria, exanthema (interstitial nephritis, rhabdomyolysis) Hypoacusis

Vertigo/nystagmus

Convulsive seizures, encephalopathy Vomiting and mental confusion (prehepatic jaundice?)

H Any drug (H, R, Z, E, S, Et)

Jaundice (if other causes have been ruled out)

Any drug (H, R, Z, E, S, Et)

Optic neuritis (loss of side vision, change E (common) and H in color vision) (uncommon) Shock, purpura R

Replace S with E (maintain the planned duration of the regimen). Replace S with E (maintain the planned duration of the regimen). Use the 2RZES5/7RE regimen. Discontinue the regimen and request the determination of hepatic enzyme levels. If ALT is abnormal, follow a regimen for managing hepatotocixity.b Discontinue the regimen and request the determination of hepatic enzyme levels. If ALT is abnormal, follow a regimen for managing hepatotoxicity.b Use the 2RHZ/4RH or 2RZES5/7RE regimen. Use the 2HZES5/10HE regimen.

Adapted from Conde et al.,(24) Maciel et al.,(32) and Ferreira et al.(33) R: rifampin; H: isoniazid; Z: pyrazinamide; E: ethambutol; S: streptomycin; Et: ethionamide; and ALT: alanine aminotransferase. aThe number preceding the acronym indicates duration of treatment in weeks. The subscript number after a drug abbreviation indicates the number of days per week that the drug should be used; if there is no subscript number, treatment with that drug is daily. bSee “Tuberculosis and liver disease.”

and HIV coinfection. Chart 6 presents the suggested approaches to major adverse reactions; it is important to note that, when an adverse reaction results from a hypersensitivity reaction (thrombocytopenia, hemolytic anemia, or renal failure), the suspected drug should not be restarted after discontinuation, since the adverse reaction upon reintroduction is even more intense and severe.(10,24,31,32) In two observational studies conducted in Brazil,(32,33) the frequency of adverse reactions to the use of the RHZE regimen was found to be 47.5% and 83.4%, respectively, which is higher than that historically seen in the medical literature; however, there were no severe reactions or the need for treatment discontinuation. The most common adverse reactions were joint pain and gastric reactions, followed by skin reactions.(32,33) 480

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TUBERCULOSIS AND LIVER DISEASE The risk of hepatitis induced by drugs used in tuberculosis treatment is increased in patients with liver disease, especially in those with advanced liver disease, those undergoing liver transplantation, and those with hepatitis C, and therefore it is necessary to monitor transaminases—alanine aminotransferase (ALT) and aspartate aminotransferase (AST)—and bilirubin every 1-4 weeks in the first 2-3 months.(1) In patients with chronic, stable liver disease who are asymptomatic, do not have cirrhosis, and have ALT levels ≤ 3 times the upper limit of normal (ULN), the basic regimen can be used unchanged; in those with ALT levels > 3 times the ULN, the RHE regimen should be used for 2 months in the intensive phase and RH should be used for 7 months in the maintenance phase.(34,35) In symptomatic chronic liver disease with

Rabahi MF, Silva JĂşnior JLR, Ferreira ACG, Tannus-Silva DGS, Conde MB

ALT levels > 3 times the ULN, the following regimens can be used: HRES for 2 months followed by HE for 6 months; HRE for 2 months followed by HE for 6 months; HSE for 2 months followed by HE for 10 months; or SE + ofloxacin (O) for 3 months followed by EO for 9 months. In patients with cirrhosis, the regimen with the least hepatotoxic potential is used: RE + a fluoroquinolone or ofloxacin or cycloserine, for 12-18 months. In cases of acute hepatitis, an attempt should be made to defer tuberculosis treatment initiation until hepatitis resolves. If this is not possible, prescribe the SE regimen for 3 months followed by RH for 6 months or the SEO regimen for 3 months followed by RH for 6 months (in extensive tuberculosis) and ofloxacin (400 mg/day) once daily in the morning, regardless of body weight.(1,10,11,24,27,34-40) A transient increase in ALT/AST may occur during the first weeks of treatment, being of no clinical significance. Treatment should be discontinued only if there is anorexia, malaise, and vomiting and the ALT level is > 3 times the ULN or when the ALT level is > 3 times the ULN, even in the absence of symptoms, if jaundice is present. In cases of hepatotoxicity induced by tuberculosis treatment and ALT > 5 times the ULN, even in the absence of symptoms, treatment should also be discontinued.(1,10,24) After discontinuation of tuberculosis treatment, investigate alcohol abuse and use of other hepatotoxic medications. Every patient with a history of alcoholism and being treated for tuberculosis should receive pyridoxine (50 mg/day) to prevent peripheral neuritis. In severe cases, until the cause of the abnormality is identified, or in cases in which transaminase and/or bilirubin levels do not return to normal after 4 weeks off treatment, use the SEO regimen for 3 months followed by EO for 9 months, with or without the addition of isoniazid. Given the efficacy of isoniazid and, especially, of rifampin, their use should always be attempted, even in the presence of preexisting liver injury.(1,10,24) In cases of hepatotoxicity caused by tuberculosis treatment, the medication can be restarted when the ALT level is < 2 times the ULN. Reintroduction should occur gradually, with one drug at a time. First rifampin, with or without ethambutol; after 3-7 days, reassess the ALT level: if there is no increase, restart the use of isoniazid 1 week after the introduction of rifampin and restart the use of pyrazinamide 1 week after the introduction of isoniazid. If ALT levels increase or if symptoms recur, discontinue the last medication added. In patients experiencing prolonged or severe hepatotoxicity (ALT > 10 times the ULN), do not use pyrazinamide; use the RHE regimen for 2 months followed by RH for 7 months.(1,10,24) TUBERCULOSIS AND DIABETES In insulin-dependent patients, it is suggested that the RHZE regimen be extended for 9 months. In non-insulindependent patients, the regimen remains unchanged,

with attention being given to the prophylactic use of pyridoxine and the possible need for the use of insulin during tuberculosis treatment.(1,10,21,24) TUBERCULOSIS AND IMMUNOSUPPRESSION In cases of tuberculosis/HIV coinfection, initiation of antiretroviral therapy (ART) should be based on the degree of immunosuppression; in cases of patients whose CD4 counts are below 50 cells/mm3, ART should be initiated 2 weeks after initiation of antituberculosis treatment, and, in other cases, ART should be initiated only after the eighth week of treatment. When tuberculosis is diagnosed in patients already receiving ART, it may be necessary to change ART to allow the addition of rifampin to therapy, and, in such cases, efavirenz is the antiretroviral of choice. Replacing rifampin with rifabutin is recommended when it is necessary to combine a protease inhibitor with ritonavir in the ART regimen. The recommended dose of rifabutin is 150 mg/day in such cases. The most frequent adverse reactions to rifabutin are exanthema (in 4%), gastrointestinal intolerance (in 3%), and neutropenia (in 2%).(1,23) Immune reconstitution inflammatory syndrome is not an indication for discontinuation of any treatment. Its management includes the use of medications for treating symptoms and corticosteroids in cases that are more severe. Transplant recipients should be treated at referral centers, with the RHZE regimen for 2 months followed by RH for 4 months, and treatment can be extended for up to 9 months. Attention should be given to possible drug interactions with corticosteroids, cyclosporine, and azathioprine.(1,23,35) TUBERCULOSIS AND PREGNANCY During pregnancy, the RHZE regimen can be administered at the usual doses, and concurrent use of pyridoxine (50 mg/day) is recommended because of the risk of newborns having convulsive seizures. Although the medications in the RHZE regimen cross the placental barrier, they do not appear to be teratogens. Regarding breastfeeding, although the medications are present in breast milk in small amounts, there is no risk of toxicity to newborns nor is there any prophylactic effect.(10,24,40) TUBERCULOSIS AND RENAL FAILURE Tuberculosis patients with renal failure have poorer outcomes than do those with normal renal function and should be assessed more often. Rifampin and isoniazid are metabolized in the liver and do not require dose adjustment. Pyrazinamide is also metabolized in the liver, but its metabolite may accumulate in patients with renal failure, as may ethambutol, since its metabolism occurs mainly (80%) in the kidneys; therefore, for J Bras Pneumol. 2017;43(5):472-486

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these two medications, the recommended use is 3 times a week.(41,42) Another recommendation is that the medications be administered after a hemodialysis session, since, although the hemodialysis session cannot eliminate rifampin, it efficiently removes pyrazinamide metabolites and partially removes isoniazid and ethambutol. The influence of peritoneal dialysis on the concentrations of antituberculosis drugs is unknown, and the recommendations for hemodialysis patients should not be applied to peritoneal dialysis patients; however, attention should be given to possible toxicity.(1) The safest regimen in renal failure is RHZ for 2 months followed by RH for 4 months (creatinine clearance between 30-50 mL/min). The treatment is changed in renal failure patients with creatinine clearance < 30 mL/ min or undergoing dialysis (administer after dialysis). In such patients, use isoniazid at a dose of 300 mg/ day or 900 mg 3 times a week; rifampin at a dose of 600 mg/day or 600 mg per administration 3 times a week; pyrazinamide at a dose of 25-35 mg/kg per administration 3 times a week (do not administer daily); ethambutol at a dose of 20-25 mg/kg per administration 3 times a week (do not administer daily); levofloxacin at a dose of 750-1,000 mg/kg per administration 3 times a week (do not administer daily); moxifloxacin at a dose of 400 mg daily; ethionamide at a dose of 250-500 mg/kg per administration daily; streptomycin at a dose of 15 mg/kg per administration 2-3 times a week (do not administer daily); and amikacin at dose of 15 mg/kg per administration 2-3 times a week (do not administer daily).(1) SURGICAL TREATMENT OF TUBERCULOSIS Although tuberculosis is treated by using medications, occasionally, it may even be treated surgically in specific cases, especially in cases of drug resistance and in some pulmonary tuberculosis complications. Surgical lung biopsy has application in the differential diagnosis of pulmonary tuberculosis and lung cancer. The indications for surgical treatment include mainly endobronchial tuberculosis, as well as severe adverse reactions, severe hemoptysis, empyema, pneumothorax, and bronchopleural fistula. In tuberculosis sequelae, surgical interventions may be required in cases of symptomatic pulmonary residue, fungus ball, and hemoptysis.(24) LATENT TUBERCULOSIS INFECTION (LTBI) LTBI is defined as the presence of a specific immune response to M. tuberculosis in the absence of clinical signs of disease. The number of viable organisms in such cases is unknown, but it is believed to be low. The lifetime risk of reactivation tuberculosis in individuals with documented LTBI is 5-10%, and most develop the disease in the first 5 years after the initial infection. However, this risk depends on several factors, the most 482

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important of which is the immune status of the individual. In Brazil, the estimated number of individuals infected with M. tuberculosis is 50 million, which represents a challenge for tuberculosis control in the country. One of the tuberculosis control strategies is the reduction of this large reservoir of individuals infected with M. tuberculosis who are at risk of progression to active disease.(3,43-45)

Assessment of patients on anti-TNF-α therapy and immunosuppressive therapy TNF-α plays a central role in granuloma formation, and, since anti-TNF-α agents began to be used, the reported incidence rate of tuberculosis has increased, many of such cases being cases of extrapulmonary tuberculosis and usually occurring during the first six infusions. Therefore, every patient who is a candidate for TNF-α blocker therapy should be assessed for LTBI (epidemiology, chest imaging, and specific immunity to M. tuberculosis). Tuberculin skin testing (TST) and IFN-γ release assays are adversely affected by several immunosuppressive drugs commonly used by this group of patients, and uncertainty persists as to the screening test of choice. Until better evidence is available, both seem feasible for the diagnosis. TST results ≥ 5 mm(10) or positive IFN-γ release assays indicate the need for LTBI treatment, which should be instituted for at least 30 days before the initiation of anti-TNF-α therapy. When it is not possible to carry out TST, take epidemiological risk and imaging tests into special account and assess each case individually in terms of risk/benefit. Chest CT can bring additional information because it is more sensitive than chest X-ray in detecting lesions suggestive of LTBI.(20,46-51) Corticosteroid therapy with doses equivalent to 15 mg/day of prednisone for more than 1 month is an indication for LTBI treatment if TST results are ≥ 5 mm in individuals under 65 years of age. In individuals aged 65 years or older, the increased risk of hepatotoxicity would be a limitation for this indication. In dialysis patients, the risk of reactivation tuberculosis is at least 10 times higher than in the general population. A TST result ≥ 10 mm appears to identify patients at increased risk of developing the disease and is an indication for LTBI treatment. It is estimated that 25-30% of patients with silicosis will develop tuberculosis. LTBI treatment is recommended if TST results are ≥ 10 mm.(10,52,53)

LTBI treatment LTBI is treated with isoniazid at a dose of 5-10 mg/kg of body weight up to a maximum of 300 mg/day for 6 months or with isoniazid (900 mg) plus rifapentine (900 mg) once a week for 3 months, and LTBI cases should be reported using a specific form. The risk of hepatitis with either regimen is very low, and monitoring of hepatic aminotransferase levels during LTBI treatment is recommended only in individuals with liver disease or with risk factors for liver disease. In individuals who do not tolerate isoniazid, an alternative treatment is the use of rifampin for 4 months.(10,43,54)

Rabahi MF, Silva JĂşnior JLR, Ferreira ACG, Tannus-Silva DGS, Conde MB

Chart 7. Infectious Diseases Society of America/Centers for Disease Control and Prevention/American Thoracic Society joint recommendations, based on PICO (an acronym based on questions regarding the Patients of interest, Intervention being studied, Comparison of the intervention, and Outcome of interest) questions and on the Grading of Recommendations Assessment, Development, and Evaluation approach and endorsed by the European Respiratory Society.

Question 1. Does adding case management interventions to curative therapy improve outcomes compared with curative therapy alone among patients with tuberculosis? (Case management is defined as patient education/counseling, home visits, integration/coordination of care with specialists and general practitioners, patient reminders, and use of incentives/enablers) 2. Does self-administered therapy have similar results compared with directly observed therapy in patients with various forms of tuberculosis? 3. Does intermittent dosing in the intensive phase have similar outcomes compared with daily dosing in the intensive phase for treatment of drug-susceptible pulmonary tuberculosis?

Recommendation 1. We suggest using case management interventions during treatment of patients with tuberculosis. (Conditional recommendation; very low certainty in the evidence)

2. We suggest using directly observed therapy rather than self-administered therapy for routine treatment of all forms of tuberculosis. (Conditional recommendation; low certainty in the evidence)

3a. We recommend the use of daily rather than intermittent dosing in the intensive phase of therapy for drug susceptible pulmonary tuberculosis. (Strong recommendation; moderate certainty in the evidence)) 3b. Use of thrice-weekly directly observed therapy in the intensive phase (with or without an initial 2 weeks of daily therapy) may be considered in patients who are not HIV-infected and are at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, which at the start of treatment is non-cavitary and/or smear negative). (Conditional recommendation; low certainty in the evidence) 3c. In situations in which daily or thrice-weekly directly observed therapy is difficult to achieve, use of twice-weekly therapy after an initial 2 weeks of daily therapy may be considered for patients who are not HIV-infected and are at low risk of relapse (pulmonary tuberculosis caused by drug-susceptible organisms, which at the start of treatment is non-cavitary and/or smear negative). (Conditional recommendation; very low certainty in the evidence) Note: If doses are missed in a regimen using twice-weekly dosing, then therapy is equivalent to once weekly, which is inferior (See Question 4). 4. Does intermittent dosing in the 4a. We recommend the use of daily or thrice-weekly dosing in the maintenance phase have similar maintenance phase of therapy for drug-susceptible pulmonary tuberculosis. outcomes compared with daily dosing (Strong recommendation; moderate certainty in the evidence) in the maintenance phase in patients 4b. If intermittent therapy is to be administered in the maintenance phase, with drug-susceptible pulmonary we suggest use of thrice-weekly instead of twice-weekly therapy. (Conditional tuberculosis? recommendation; low certainty in the evidence) This recommendation allows for the possibility that if some doses are missed, treatment is still adequate. In contrast, with twice-weekly therapy, if doses are missed, then therapy is equivalent to once weekly, which is inferior. 4c. We recommend against use of once-weekly therapy with isoniazid 900 mg and rifapentine 600 mg in the maintenance phase. (Strong recommendation; high certainty in the evidence) In uncommon situations in which more than once-weekly directly observed therapy is difficult to achieve, once-weekly maintenance phase therapy with isoniazid 900 mg and rifapentine 600 mg may be considered for use only in HIV-uninfected individuals without cavitation on chest X-ray. 5. Does extending treatment 5a. For HIV-infected individuals receiving antiretroviral therapy, we beyond 6 months improve outcomes recommend using the standard 6-month daily regimen consisting of an compared with the standard 6-month intensive phase of 2 months of isoniazid, rifampin, pyrazinamide, and treatment regimen among pulmonary ethambutol followed by a maintenance phase of 4 months of rifampin and tuberculosis patients coinfected with isoniazid for the treatment of drug-susceptible pulmonary tuberculosis. HIV? (Conditional recommendation; very low certainty in the evidence) 5b. In uncommon situations in which HIV-infected individuals do not receive antiretroviral therapy during tuberculosis treatment, we recommend extending the maintenance phase with isoniazid and rifampin for an additional 3 months (i.e., a maintenance phase corresponding to a total of 9 months of treatment) for the treatment of drug-susceptible pulmonary tuberculosis. (Conditional recommendation; very low certainty in the evidence) Adapted from Sotgiu et al.(1) and Nahid et al.(2) J Bras Pneumol. 2017;43(5):472-486

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Chart 7. Continued...

Question 6. Does initiation of antiretroviral therapy during tuberculosis treatment compared with at the end of tuberculosis treatment improve outcomes among tuberculosis patients coinfected with HIV?

7. Does the use of adjuvant corticosteroids in tuberculous pericarditis provide mortality and morbidity benefits? 8. Does the use of adjuvant corticosteroids in tuberculous meningitis provide mortality and morbidity benefits? 9. Does a shorter duration of treatment have similar outcomes compared with the standard 6-month treatment duration among HIV-uninfected individuals with paucibacillary tuberculosis (i.e., sputum smear negative, culture negative)?

Recommendation 6. We recommend initiating antiretroviral therapy during tuberculosis treatment. Antiretroviral therapy should ideally be initiated within the first 2 weeks of tuberculosis treatment for individuals with CD4 counts < 50 cells/ µL and by 8-12 weeks of tuberculosis treatment initiation for individuals with CD4 counts ≥ 50 cells/µL. (Strong recommendation; high certainty in the evidence) Note: An exception is individuals with HIV infection and tuberculous meningitis, in whom antiretroviral therapy is not initiated in the first 8 weeks of tuberculosis treatment. 7. We recommend that adjunctive corticosteroid therapy not be routinely used in individuals with tuberculous pericarditis. (Conditional recommendation; very low certainly in the evidence) 8. We recommend adjunctive corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks for individuals with tuberculous meningitis. (Strong recommendation; moderate certainty in the evidence) 9. We suggest that a 4-month treatment regimen is adequate for treatment of HIV-uninfected adults with sputum smear-negative, culture-negative pulmonary tuberculosis. (Conditional recommendation; very low certainly in the evidence)

Adapted from Sotgiu et al.(1) and Nahid et al.(2)

There is as yet no clear evidence to guide the choice of drugs for LTBI treatment in contacts of index cases that are known to be drug-resistant. Logic indicates that contacts of MDR-TB cases should be treated with drugs to which the organisms are susceptible. The decision regarding optimal treatment should be made at the referral center where the index case is followed. The WHO suggests that contacts should be carefully monitored for the development of active tuberculosis for 2 years instead of being treated for LTBI.(10,44) A recent study demonstrated that 3-month administration, once a week, of a combination of isoniazid and rifapentine for LTBI treatment is safe and has efficacy similar to that of monotherapy with isoniazid in children aged 2-17 years. However, the small number of children under 5 years of age and of children infected with HIV limits the generalization of the study results in these important risk groups.(55,56) NEW TREATMENTS FOR DRUGSUSCEPTIBLE TUBERCULOSIS AND DRUGRESISTANT TUBERCULOSIS New drugs and new combinations of already known drugs have been tested in tuberculosis treatment with the aims of reducing treatment duration and increasing treatment effectiveness in cases of drugsusceptible tuberculosis and in cases of MDR-TB. After five decades without new drugs for tuberculosis treatment, bedaquiline (TMC-207) and delamanid (OPC-67683) have been approved by the US Food and Drug Administration for use in clinical practice. These two drugs are basically indicated for MDR-TB. 484

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Since 2009, clinical studies have demonstrated that the use of fluoroquinolones, especially moxifloxacin, in combination with other antituberculosis drugs, RHZ and rifapentine, significantly increases the rate of M. tuberculosis culture conversion in the eighth week of treatment, suggesting the possibility of treatment shortening. In a systematic review of clinical trials of fluoroquinolones versus ethambutol, which was published in 2016, the results showed that it was possible to reduce treatment to 4 months, while maintaining the same effectiveness in patients with noncavitary pulmonary tuberculosis and a positive culture; however, the results in clinical practice remain controversial.(57-59)

New scientific evidence A recent joint publication by the Infectious Diseases Society of America, the Centers for Disease Control and Prevention, and the American Thoracic Society(2) presented tuberculosis treatment recommendations based on scientific evidence obtained by using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE; Chart 7) approach,(60) all of which have been endorsed by the European Respiratory Society.(1) GRADE is a systematic approach that assesses quality of evidence and strength of scientific recommendations. The GRADE approach has been developed by the GRADE working group and is seen as the most effective method of assessing quality of evidence and clinical recommendations. In comparing the PNCT recommendations with the new scientific evidence, we can see that some

Rabahi MF, Silva Júnior JLR, Ferreira ACG, Tannus-Silva DGS, Conde MB

points can be assessed with a view to future revised PNCT recommendations, such as adopting supervised

intermittent treatment in the second phase of treatment and not using corticosteroids in tuberculous pericarditis.(1)

REFERENCES 1. Sotgiu G, Nahid P, Loddenkemper R, Abubakar I, Miravitlles M, Migliori GB. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis. Eur Respir J. 2016;48(4):963-71. https://doi.org/10.1183/13993003.01356-2016 2. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Executive Summary: Official American Thoracic Society/ Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of DrugSusceptible Tuberculosis. Clin Infect Dis. 2016;63(7):853-67. https:// doi.org/10.1093/cid/ciw566 3. TB CARE I. International Standards for Tuberculosis Care Edition 3. The Hague: TB CARE I; 2014. 4. Parida A, Bairy KL, Chogtu B, Magazine R, Vidyasagar S. Comparison of Comparison of Directly Observed Treatment Short Course (DOTS) with Self-Administered Therapy in Pulmonary Tuberculosis in Udupi District of Southern India. J Clin Diagn Res. 2014;8(8):HC29-31. 5. Lienhardt C, Ogden JA. Tuberculosis control in resource-poor countries: have we reached the limits of the universal paradigm? Trop Med Int Health. 2004;9(7):833-41. https://doi.org/10.1111/ j.1365-3156.2004.01273.x 6. Seaworth BJ, Armitige LY, Griffith DE. First do no harm--adverse events, drug intolerance, and hepatotoxicity: how can we not justify directly observed therapy for treating tuberculosis? Clin Infect Dis. 2013;57(7):1063-4. https://doi.org/10.1093/cid/cit432 7. Pasipanodya JG, Gumbo T. A meta-analysis of self-administered vs directly observed therapy effect on microbiologic failure, relapse, and acquired drug resistance in tuberculosis patients. Clin Infect Dis. 2013;57(1):21-31. https://doi.org/10.1093/cid/cit167 8. Karumbi J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database Syst Rev. 2015;(5):CD003343. https://doi.org/10.1002/14651858.CD003343.pub4 9. Cruz MM, Cardoso GC, Abreu DM, Decotelli PV, Chrispim PP, Borenstein JS, et al. Adesão ao tratamento diretamente observado da tuberculose – o sentido atribuído pelos usuários e profissionais de saúde em duas regiões administrativas do município do Rio de Janeiro. Cad Saude Colet. 2012;20(2),217-24. 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. Munro SA, Lewin SA, Smith HJ, Engel ME, Fretheim A, Volmink J. Patient adherence to tuberculosis treatment: a systematic review of qualitative research. PLoS Med. 2007;4(7):e238. https://doi. org/10.1371/journal.pmed.0040238 12. Centers for Disease Control and Prevention. Managing tuberculosis patients and improving adherence. Atlanta, GA: CDC; 2014. 13. Verver S, Warren RM, Beyers N, Richardson M, van der Spuy GD, Borgdorff MW, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med. 2005;171(12):1430-5. https://doi.org/10.1164/ rccm.200409-1200OC 14. Interrante JD, Haddad MB, Kim L, Gandhi NR. Exogenous Reinfection as a Cause of Late Recurrent Tuberculosis in the United States. Ann Am Thorac Soc. 2015;12(11):1619-26. 15. Ruffino Netto A. Impacto da reforma do setor saúde sobre os serviços de tuberculose no Brasil. Bol Pneumol Sanit. 1999;7(1):7-18. https://doi.org/10.5123/S0103-460X1999000100002 16. Hijjar MA, Gerhardt G, Teixeira GM, Procópio MJ. Retrospect of tuberculosis control in Brazil. Rev Saude Publica. 2007;41(Suppl 1):50-8. https://doi.org/10.1590/S0034-89102007000800008 17. Brasil. Ministério da Saúde. Sistema de Informação de Agravos de Notificação [homepage on the Internet]. Brasília: Ministério da Saúde [cited 2016 Oct 1]. Available from: http://www2.datasus.gov. br/DATASUS/index.php?area=0203&id=31009407&VObj=http:// tabnet.datasus.gov.br/cgi/tabcgi.exe?sinannet/cnv/tuberc 18. Jo KW, Yoo JW, Hong Y, Lee JS, Lee SD, Kim WS, et al. Risk factors for 1-year relapse of pulmonary tuberculosis treated with a 6-month daily regimen. Respir Med. 2014;108(4):654-9. https://doi. org/10.1016/j.rmed.2014.01.010 19. Chang KC, Leung CC, Yew WW, Ho SC, Tam CM. A nested case-

control study on treatment-related risk factors for early relapse of tuberculosis. Am J Respir Crit Care Med. 2004;170(10):1124-30. https://doi.org/10.1164/rccm.200407-905OC 20. Horne DJ, Royce SE, Gooze L, Narita M, Hopewell PC, Nahid P, et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis. 2010;10(6):387-94. https://doi.org/10.1016/S1473-3099(10)70071-2 21. Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lönnroth K, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 2011;9:81. https://doi. org/10.1186/1741-7015-9-81 22. Leung CC, Yew WW, Chan CK, Chang KC, Law WS, Lee SN, et al. Smoking adversely affects treatment response, outcome and relapse in tuberculosis. Eur Respir J. 2015;45(3):738-45. https://doi. org/10.1183/09031936.00114214 23. Ahmad Khan F, Minion J, Al-Motairi A, Benedetti A, Harries AD, Menzies D. An updated systematic review and meta-analysis on the treatment of active tuberculosis in patients with HIV infection. Clin Infect Dis. 2012;55(8):1154-63. https://doi.org/10.1093/cid/cis630 24. Conde MB, Melo FA, Marques AM, Cardoso NC, Pinheiro VG, Dalcin Pde T, et al. III Brazilian Thoracic Association Guidelines on tuberculosis. J Bras Pneumol. 2009;35(10):1018-48. https://doi. org/10.1590/S1806-37132009001000011 25. Zvada SP, Van Der Walt JS, Smith PJ, Fourie PB, Roscigno G, Mitchison D, et al. Effects of four different meal types on the population pharmacokinetics of single-dose rifapentine in healthy male volunteers. Antimicrob Agents Chemother. 2010;54(8):3390-4. https://doi.org/10.1128/AAC.00345-10 26. Sant’Anna CC. Childhood tuberculosis. J Pediatr (Rio J). 1998;74 Suppl 1:S69-75. https://doi.org/10.2223/JPED.488 27. American Academy of Pediatrics. Committee on Infectious Diseases. 2015 Red Book: Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: AAP; 2015. 28. World Health Organization [homepage on the Internet]. Geneva: WHO [updated 2014; cited 2016 Oct 1]. Guidance for national tuberculosis programmes on the management of tuberculosis in children. 2nd ed. [Adobe Acrobat document, 146p.]. Available from: http://apps.who.int/medicinedocs/documents/s21535en/s21535en. pdf 29. World Health Organization [homepage on the Internet]. Geneva: WHO [updated 2014 Dec; cited 2016 Oct 1]. Definitions and reporting framework for tuberculosis—2013 revision. [Adobe Acrobat document, 47p.]. Available from: http://apps.who.int/iris/ bitstream/10665/79199/1/9789241505345_eng.pdf 30. Brasil. Ministério da Saúde. Departamento de Vigilância em Doenças Transmissíveis. Novas recomendações para tratamento da tuberculose multidrogarresistente e com resistência à rifampicina diagnosticada por meio do Teste Rápido Molecular para Tuberculose no Brasil. Nota informativa 8. Brasília: Ministério da Saúde; 2016. 31. Conde MB, Souza MG. Pneumologia e tisiologia: uma abordagem prática. São Paulo: Atheneu; 2009. 32. Maciel EL, Guidoni LM, Favero JL, Hadad DJ, Molino LP, Jonhson JL, et al. Adverse effects of the new tuberculosis treatment regimen recommended by the Brazilian Ministry of Health. J Bras Pneumol. 2010;36(2):232-8. https://doi.org/10.1590/S180637132010000200012 33. Ferreira AC, Silva Júnior JL, Conde MB, Rabahi MF. Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil. J Bras Pneumol. 2013;39(1):76-83. https://doi. org/10.1590/S1806-37132013000100011 34. Sun HY, Chen YJ, Gau CS, Chang SC, Luh KT. A prospective study of hepatitis during antituberculous treatment in Taiwanese patients and a review of the literature. J Formos Med Assoc. 2009;108(2):102-11. https://doi.org/10.1016/S0929-6646(09)60040-1 35. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solidorgan transplant recipients: impact and implications for management. Clin Infect Dis. 1998;27(5):1266-77. https://doi.org/10.1086/514993 36. Chien JY, Huang RM, Wang JY, Ruan SY, Chien YJ, Yu CJ, et al. J Bras Pneumol. 2017;43(5):472-486

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Hepatitis C virus infection increases hepatitis risk during antituberculosis treatment. Int J Tuberc Lung Dis. 2010;14(5):616-21. 37. Lomtadze N, Kupreishvili L, Salakaia A, Vashakidze S, Sharvadze L, Kempker RR, et al. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis. PLoS One. 2013;8(12):e83892. https://doi. org/10.1371/journal.pone.0083892 38. Combs DL, O‘Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med; 1990;112(6):397-406. https:// doi.org/10.7326/0003-4819-76-3-112-6-397 39. A controlled trial of 6 months’ chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. British Thoracic Society. Br J Dis Chest 1984;78(4):330-6. https://doi.org/10.1016/0007-0971(84)90165-7 40. Czeizel AE, Rockenbauer M, Olsen J, Sørensen HT. A populationbased case-control study of the safety of oral anti-tuberculosis drug treatment during pregnancy. Int J Tuberc Lung Dis. 2001;5(6):564-8. 41. Baghaei P, Marjani M, Tabarsi P, Moniri A, Rashidfarrokhi F, Ahmadi F, et al. Impact of chronic renal failure on anti-tuberculosis treatment outcomes. Int J Tuberc Lung Dis. 2014;18(3):352-6. https://doi. org/10.5588/ijtld.13.0726 42. Malone RS, Fish DN, Spiegel DM, Childs JM, Peloquin CA. The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol. Am J Respir Crit Care Med. 1999;159(5 Pt 1):1580-4. https://doi.org/10.1164/ajrccm.159.5.9810034 43. Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, et al. LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J. 2009;33(5):956-73. https://doi.org/10.1183/09031936.00120908 44. Getahun H, Matteelli A, Abubakar I, Aziz MA, Baddeley A, Barreira D, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J. 2015;46(6):1563-76. https://doi.org/10.1183/13993003.01245-2015 45. Brasil. Ministério da Saúde. Departamento de Vigilância Epidemiológica. Coordenação Geral de Doenças Endêmicas. Programa Nacional de Controle da Tuberculose. Plano Estratégico para o Controle da Tuberculose, Brasil 2007-2015. Brasília: Ministério da Saúde; 2006. 46. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345(15):1098-104. https://doi.org/10.1056/NEJMoa011110 47. Mota LM, Cruz BA, Brenol CV, Pollak DF, Pinheiro Gda R, Laurindo IM, et al. Safe use of biological therapies for the treatment of rheumatoid arthritis and spondyloarthritides [Article in Portuguese]. Rev Bras Reumatol. 2015;55(3):281-309. https://doi.org/10.1016/j. rbr.2014.06.006 48. Wong SH, Gao Q, Tsoi KK, Wu WK, Tam LS, Lee N, et al. Effect of immunosuppressive therapy on interferon γ release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax. 2016;71(1):64-72.

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https://doi.org/10.1136/thoraxjnl-2015-207811 49. Sester M, Kampmann B. What defines latent infection with Mycobacterium tuberculosis in patients with autoimmune diseases? Thorax. 2016;71(1):3-4. https://doi.org/10.1136/ thoraxjnl-2015-207991 50. Brasil. Ministério da Saúde. Departamento de Vigilância em Doenças Transmissíveis. Recomendações para controle de contatos e tratamento da infecção latente da tuberculose na indisponibilidade transitória do Derivado Proteico Purificado. Nota informativa 8. Brasília: Ministério da Saúde; 2014. 51. Piccazzo R, Paparo F, Garlaschi G. Diagnostic accuracy of chest radiography for the diagnosis of tuberculosis (TB) and its role in the detection of latent TB infection: a systematic review. J Rheumatol Suppl. 2014;91:32-40. https://doi.org/10.3899/jrheum.140100 52. Campbell J, Krot J, Marra F. Latent tuberculosis diagnostic tests to predict longitudinal tuberculosis during dialysis: a meta-analysis. Int J Tuberc Lung Dis. 2016;20(6):764-70. https://doi.org/10.5588/ ijtld.15.0825 53. Ai JW, Ruan QL, Liu QH, Zhang WH. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerg Microbes Infect. 2016;5:e10. https://doi.org/10.1038/emi.2016.10 54. Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, BlivenSizemore E, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365(23):2155-66. https:// doi.org/10.1056/NEJMoa1104875 55. Villarino ME, Scott NA, Weis SE, Weiner M, Conde MB, Jones B, et al. Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA Pediatr. 2015;169(3):247-55. Erratum in: JAMA Pediatr. 2015;169(9):878. https://doi.org/10.1001/jamapediatrics.2014.3158 56. Marais BJ. Twelve-dose drug regimen now also an option for preventing tuberculosis in children and adolescents. JAMA Pediatr. 2015;169(3):208-10. https://doi.org/10.1001/ jamapediatrics.2014.3157 57. Conde MB, Efron A, Loredo C, De Souza GR, Graça NP, Cezar MC, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet. 2009;373(9670):1183-9. https://doi.org/10.1016/S01406736(09)60333-0 58. Conde MB, Mello FC, Duarte RS, Cavalcante SC, Rolla V, Dalcolmo M, et al. A Phase 2 Randomized Trial of a Rifapentine plus MoxifloxacinBased Regimen for Treatment of Pulmonary Tuberculosis. PLoS One. 2016;11(5):e0154778. https://doi.org/10.1371/journal.pone.0154778 59. Alipanah N, Cattamanchi A, Menzies R, Hopewell PC, Chaisson RE, Nahid P. Treatment of non-cavitary pulmonary tuberculosis with shortened fluoroquinolone-based regimens: a meta-analysis. Int J Tuberc Lung Dis. 2016;20(11):1522-1528. https://doi.org/10.5588/ ijtld.16.0217 60. GRADE working group [homepage on the Internet]. c2004-2017 [cited 2016 Oct 1]. Available from: http://www.gradeworkinggroup. org/

J Bras Pneumol. 2017;43(6):487-489 http://dx.doi.org/10.1590/S1806-37562017000000012

LETTER TO THE EDITOR

Omalizumab in patients with severe uncontrolled asthma: well-defined eligibility criteria to promote asthma control Regina Maria de Carvalho-Pinto1, Rosana Câmara Agondi2, Pedro Giavina-Bianchi2, Alberto Cukier1, Rafael Stelmach1 TO THE EDITOR: After more than a decade of omalizumab being widely used in the treatment of asthma, the Brazilian National Commission for the Incorporation of Technologies stated its opposition to the incorporation of omalizumab use within the scope of the Unified Health Care System of Brazil.(1) That ruling runs contrary to expert opinion that the drug should be made available to a specific group of patients with severe uncontrolled asthma, selected according to eligibility criteria that are well defined in clinical protocols. Here, we report the results of omalizumab administration in 12 patients with severe asthma, selected according to the strict eligibility criteria presented in Chart 1. Nine of those patients met the criterion of lack of asthma control with appropriate treatment, and 3 met the criterion of the need for continuous doses of oral corticosteroids to maintain asthma control. Of the 12 patients evaluated, 8 (70%) were female. The mean age at the initiation of treatment was 45.36 ± 15.19 years. The baseline FEV1 was 1.72 ± 0.53 L (56.5 ± 12.6% predicted), with no change after omalizumab administration. At enrollment in the study, the patients were using a mean inhaled corticosteroid dose of 2,318.18 ± 844.7 µg/day, and 7 patients (63%) were using oral corticosteroid chronically, at a dose of 2.5-40 mg/day. The mean monthly dose of omalizumab was 504.54 ± 316.58 mg. During the study period, omalizumab was discontinued in 1 patient, because of fainting and a rash, which were probably associated with the use of the medication. The asthma control scores of the 11 patients who completed the recommended 16 weeks of treatment are shown in Figure 1. Six of those patients had an excellent response, with evident improvements in their scores. One of those patients had ventricular tachycardia as a side effect of β2 agonist use and was dependent on the use of corticosteroids, and that patient maintained control at the end of the 16-week follow-up period without the use of the β2 agonist. Another 3 patients (of the 6 who clearly benefited from the treatment with omalizumab) were chronic corticosteroid users. Among those 3 patients, the corticosteroid was discontinued in 1, whereas the dose of corticosteroid was reduced in 1 and maintained in 1. Two patients showed no improvement after 16 weeks of treatment, at which point the omalizumab was discontinued. In 3 patients, the response was considered partial. In 2 patients, the omalizumab was discontinued after 32 weeks, because of the occurrence of exacerbations. In 1 patient, the decision was made to

continue the treatment with omalizumab. In summary, in 58% of the patients selected, we maintained the administration of omalizumab. When we used the asthma control questionnaire, defining a half-a-point variation in the score as clinically significant, the response was classified as good in 64% of the patients, compared with 73% of those when we used the asthma control test, defining a 3-point variation as clinically significant. Of the 12 patients in our sample, 8 presented a good response to omalizumab, regardless of the method employed to evaluate that response. The decision to carry out this pilot analysis was made by the Pharmacy Board of the University of São Paulo School of Medicine Hospital das Clínicas, in 2010. At that time, there was only one nationally published study demonstrating that IgE blockade was safe in patients with asthma or allergic rhinitis caused by helminth infection.(2) However, in a multicenter study conducted in Brazil and published in 2012, Rubin et al.(3) evaluated the use of omalizumab as an add-on therapy in patients with moderate allergic asthma that was not controlled despite treatment with the combination of long-acting bronchodilators and inhaled corticosteroids (fluticasone ≥ 500 µg/day or equivalent). The authors reported improvement in asthma control and in the overall perception of efficacy among those patients. We started selecting patients in 2012, when the funds were made available in the annual budget of the institution. We estimated that it would take 1 year to conclude the analysis of 12 patients. However, because we strictly adhered to the pre-established criteria, it took nearly 3 years. Our experience was similar to that recently reported by the Australian Department of Health Subcommittee on Pharmaceutical Use.(4) Contrary to the initial estimate that approximately 1,000 patients per year would be included in the first 5 years of the program, only 148 and 156 patients were treated in the first and second year, respectively.(4) Although oral corticosteroid use was not a mandatory inclusion criterion, virtually all of our patients were using oral corticosteroids (regularly or continuously), as well as high doses of inhaled corticosteroids. Our criteria correspond to those approved by the Australian Department of Health(4) and by the National Institute for Health and Care Excellence (NICE) in the United Kingdom,(5) bodies that rely on pharmacoeconomic evaluations to guide their decisions regarding the allocation of resources for new medications. The substantial improvement observed in some of our patients demonstrates that omalizumab is capable

1. Divisão de Pneumologia, Instituto do Coração – InCor – Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. 2. Disciplina de Imunologia Clínica e Alergia, Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Omalizumab in patients with severe uncontrolled asthma: well-defined eligibility criteria to promote asthma control

ACQ - 16 weeks

ACT - 16 weeks

4.5

4 3.5

3 2.5

2 1.5

1 0.5 0

5 Before

After

Before

After

2.68 ± 1.39

1.12 ± 0.77

13.0 (12.0-15.7)

23.0 (17.2-24.0)

*p < 0.01

**p - 0.01

Figure 1. Evolution of asthma control scores over 16 weeks of treatment with omalizumab.a ACQ: asthma control questionnaire; and ACT: asthma control test. aValues expressed as mean ± SD or as median (interquartile range). *Student’s t-test. **Mann-Whitney test. Chart 1. Criteria for identifying patients eligible for treatment with omalizumab.

INCLUSION CRITERIA • Severe uncontrolled asthma (ACQ score > 1.5) + treatment with a high dose of inhaled corticosteroid (> 1,500 µg of beclomethasone or equivalent) + treatment with long-acting β2 agonists or the need for continuous or intercalary maintenance with an oral corticosteroid (≥ 3 months in the last year) • Severe controlled asthma (ACQ score ≤ 1.5) treated with an oral corticosteroid, accompanied by adverse events • Adults > 18 years of age that are adherent to treatment and have been followed for ≥ 6 months • Body weight of 30-150 kg • Total serum IgE of 30-1,500 IU/mL • Allergic asthma, confirmed clinically and by skin test or by in vitro testing for specific IgE • ≥ 2 emergency room visits or ≥ 1 hospitalization for asthma in the last year • Nonsmoker or former smoker EXCLUSION CRITERIA • Pregnancy • Infectious exacerbation in the last 30 days ACQ: asthma control questionnaire.

of radically altering the quality of life and the work capacity of a select portion of severe asthmatics. Similar results were taken into account in the United Kingdom in 2007,(3) at the time of provisional approval of omalizumab, despite the unacceptable cost-effectiveness ratio, which was > £ 30,000/quality-adjusted life year (QALY) gained. Not long ago, the NICE concluded that the use of the drug had become economically viable (cost-effectiveness ratio, £ 23,200/QALY gained) and limited its indication to patients with severe uncontrolled asthma who are users of oral corticosteroids and in whom the asthma remains uncontrolled even when the patients are medicated and followed according to the NICE guidelines(5); a similar policy was adopted by the Australian Department of Health.(4) The efficiency of those guidelines was recently confirmed in real-life studies.(6,7) In our study, the decision to maintain the treatment not only in the responders but also in the partial responders was based on the overall evaluation of efficacy by the medical staff. That practice is supported by the literature, which demonstrates, as the best parameter of a response to omalizumab, the impression of the medical staff at week 16 (according 488

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to the package insert used in Europe, that must be considered in the decision as to whether or not to continue treatment). Our study has certain limitations. We did not determine exactly how many patients were evaluated and how many were offered the treatment. However, that does not interfere with the main conclusion: among an estimated total of approximately 2,500 (new and follow-up) patients with difficult-to-control asthma seen over a 3-year period, the use of omalizumab resulted in substantial clinical improvement in only a small portion. Another limitation was the lack of a control group. In a study with an n = 1 design (in which efficacy and safety are evaluated in an individual patient using a double-blind, placebo-controlled, double-blind randomized study with multiple treatment periods), Gibson et al.(8) analyzed omalizumab administration in 12 patients with characteristics similar to those of our patients. In that study, the drug was discontinued after 12 weeks of treatment, allowing comparison between the periods with and without omalizumab treatment. The results were similar to those obtained in the present study: 50% of the patients evaluated showed a total or partial response.

Carvalho-Pinto RM, Agondi RC, Giavina-Bianchi P, Cukier A, Stelmach R

In conclusion, patients with severe asthma that remains uncontrolled despite appropriate treatment according to the available guidelines constitute only a small proportion of asthma patients and, because they are in poorer health, consume the largest share of the resources allocated.(9) For asthma patients treated at referral centers, efforts are made to identify the factors that, duly scaled and treated, have a positive effect on the evolution of their asthma.(10,11) The results obtained in our study, taken

together with those reported in studies conducted at other centers, demonstrate that IgE blockade is effective for some patients. The application of a rigid protocol at asthma treatment centers would allow the identification of patients who might benefit from treatment with omalizumab, as opposed to prescription by litigation.(12) Individualized and accurate medical practice, allowing equity within the system without impeding scientific progress, is the way of the future.(13)

REFERENCES 1. Brasil. Ministério da Saúde. Secretaria de Ciência, Tecnologia e Insumos estratégicos [homepage on the internet]. Brasília: o Ministério [updated 2016 Jul, cited 2017 Jan 2] Omalizumabe para o tratamento da asma grave. [Adobe Acrobat document, 110p.]. Available from: http://conitec.gov.br/images/Relatorios/2016/ Relatorio_Omalizumabe_AsmaGrave_final.pdf 2. Cruz AA, Lima F, Sarinho E, Ayre G, Martin C, Fox H, et al. Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy. 2007;37(2):197-207. https://doi.org/10.1111/j.1365-2222.2007.02650.x 3. Rubin AS, Souza-Machado A, Andrade-Lima M, Ferreira F, Honda A, Matozo TM, et al. Effect of omalizumab as add-on therapy on asthma-related quality of life in severe allergic asthma: a Brazilian study (QUALITX). J Asthma. 2012;49(3):288-93. https://doi.org/10.3 109/02770903.2012.660297 4. The Pharmaceutical Benefits Scheme (PBS) [homepage on the Internet]. Canberra: PBS [updated 2014 Jun, cited 2017 Jan 2]. Omalizumab: 24-month predicted versus actual analysis. Drug utilisation sub-committee (DUSC) [about 2 screens]. Available from: http://www.pbs.gov.au/info/industry/listing/participants/publicrelease-docs/omalizumab 5. National Institute for Health and Care Excellence (NICE) [homepage on the Internet]. London: NICE [updated 2013 Apr 24, cited 2017 Jan 2]. Omalizumab for treating severe persistent allergic asthma [about 3 screens]. Available from: http://www.nice.org.uk/guidance/ta278 6. Niven RM, Saralaya D, Chaudhuri R, Masoli M, Clifton I, Mansur AH, et al. Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study). BMJ Open. 2016;6(8):e011857. 7. Gibson PG, Reddel H, McDonald VM, Marks G, Jenkins C, Gillman

A et al. Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry. Intern Med J. 2016;46(9):1054-62. https://doi.org/10.1111/imj.13166 8. Gibson PG, Taramarcaz P, McDonald V. Use of omalizumab in a severe asthma clinic. Respirology. 2007;12 Suppl 3:S35-44; discussion S45-7. 9. de Carvalho-Pinto R, Cukier A, Angelini L, Antonangelo L, Mauad T, Dolhnikoff M, et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respir Med. 2012;106(1):4756. https://doi.org/10.1016/j.rmed.2011.08.013 10. Dias-Júnior SA, Reis M, de Carvalho-Pinto RM, Stelmach R, Halpern A, Cukier A. Effects of weight loss on asthma control in obese patients with severe asthma. Eur Respir J. 2014;43(5):1368-77. https://doi.org/10.1183/09031936.00053413 11. Athanazio R, Carvalho-Pinto R, Fernandes FL, Rached S, Rabe K, Cukier A, et al. Can severe asthmatic patients achieve asthma control? A systematic approach in patients with difficult to control asthma followed in a specialized clinic. BMC Pulm Med. 2016;16(1):153. https://doi.org/10.1186/s12890-016-0314-1 12. Stelmach R, Cerci Neto A, Fonseca AC, Ponte EV, Alves G, AraujoCosta IN, et al. A workshop on asthma management programs and centers in Brazil: reviewing and explaining concepts. J Bras Pneumol. 2015;41(1):3-15. https://doi.org/10.1590/S180637132015000100002 13. Sumino K, Israel E. Precision Medicine. Personalizing guidelines to the provider as well as the patient: making the juice worth the squeeze. Am J Respir Crit Care Med. 2015;191(12):1345-6. https:// doi.org/10.1164/rccm.201504-0809ED

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LETTER TO THE EDITOR

Primary sclerosing epithelioid fibrosarcoma of the pleura Erlon de Ávila Carvalho1, Daniel Oliveira Bonomi1, Astunaldo Júnior Macedo Pinho1, Paulo Guilherme Oliveira Salles1, Henrique Cunha Vieira1 TO THE EDITOR: Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma that occurs primarily in the deep musculature and is often associated with the adjacent fascia or periosteum.(1-4) We searched the Medline, LILACS, SciELO, and MD Consult databases for articles on SEF published in the last 20 years. Here, we report the case of a previously healthy 31-year-old female patient who presented with dyspnea in 2012. She was a former smoker with a smoking history of 14 pack-years. She sought emergency room treatment. Physical examination revealed decreased breath sounds at the left lung base and a Karnofsky performance status of 80%. The thoracic surgery team requested a chest CT scan, which revealed a lung mass and a pleural lesion. Pleural and lung biopsies were therefore performed. Pathological findings were suggestive of sarcoma or sarcomatoid mesothelioma. Further investigation included CT scans of the chest, abdomen, and pelvis, as well as magnetic resonance imaging of the chest. Chest CT and magnetic resonance imaging findings included extensive pleural effusion with anterior septation; contrast-enhanced tissue formations in the parietal pleura, the largest of which was 8.5 cm × 2.0 cm and located posterior to the basal segments on the left; left lung volume loss; and intraparenchymal nodules scattered throughout the left lung parenchyma, the largest of which was 1.7 cm. A decision was made to perform a pneumonectomy with thoracotomy and mediastinal lymphadenectomy. Intraoperative findings included visceral and parietal pleural involvement (affecting the underlying left lung), as well as contiguous invasion of the lower third of the anterior chest wall (ribs 7 to 10), left diaphragm, and pericardium. A decision was made to perform a pleuropneumonectomy with en bloc resection of part of the left diaphragm, pericardium, and mediastinal lymph nodes (stations 5, 6, 7, 8L, and 9L), as well as thoracotomy with resection of the affected ribs, the resection margins being macroscopically free of disease (Figure 1). The left main bronchus stump was stapled with a 75-mm stapler, and the chest wall was reconstructed with polypropylene mesh (Prolene®; Ethicon, Somerville, NJ, USA). Closed pleural drainage was performed. The patient stayed in the ICU for 6 days, being discharged on postoperative day 7. Pathological findings were consistent with locally advanced SEF of the pleura. The affected lymph nodes (5 of 12 lymph nodes) were resected, the resection margins being free of disease. Histopathological examination revealed a neoplasm composed of ovoid epithelioid cells

with hyperchromatic nuclei and inconspicuous nucleoli embedded in a densely collagenized stroma (Figure 2). Immunohistochemistry was negative for S-100 protein, CD34, calretinin, Wilms tumor 1 oncogene product, and desmin but positive for mucin-4, findings that are consistent with primary SEF of the pleura. Over the course of a 3-year follow-up period, CT scans of the chest were performed every 6 months, the last follow-up CT examination having shown mild left pleural effusion and no signs of local recurrence. SEF was first described by Meis-Kindblom et al. in 1995(5) as a rare, slow-growing, deep soft tissue sarcoma that is composed of epithelial tumor cells arranged in nests embedded in a hyalinized fibrous stroma and that affects individuals in the 14- to 87-year age bracket, affecting both genders equally.(1) It is primarily located in the lower extremities, pelvic and pectoral girdles (39%), and trunk (21%).(1) One third of cases present as painful, deep-seated intramuscular masses associated with the adjacent fascia or periosteum.(3) Although SEF is histologically classified as a low-grade sarcoma, it is clinically aggressive. Local recurrence and metastases are observed in 30-50% of cases; however, systemic spread is usually delayed for 5 years or more.(4) The most common metastases (in 43-86% of cases) are to lung, bone, chest wall/pleura, pericardium, brain, scalp, breast, and liver.(4,5) With regard to 36-month prognosis, 34% die from SEF, 35% remain alive with disease, and 31% remain alive without disease. It appears that the primary site of disease is associated with prognosis, the 36-month mortality rate being 46% in patients with SEF of the head and neck, 38% in those with SEF of the upper extremities, and 26% in those with SEF of the trunk. (1) In addition, it appears that neither gender nor tumor size influence the prognosis of SEF.(2) We found no case reports of primary SEF of the pleura. Ossendorf et al.(1) reported that distant disease was independent of tumor size; however, no patient with a primary tumor of 5 cm or less initially presented with metastases. Given the lack of randomized studies, there is no consensus regarding the optimal treatment for SEF.(1-4) The major histological features of SEF include nests and cords of rounded epithelioid cells surrounded by hyalinized collagenous stroma. The cells are relatively uniform, with scanty cytoplasm; the nuclei are eccentric and pleomorphic, being ovoid, elongated, or angulated.(1) The differential diagnosis includes hyalinizing spindle cell tumor with giant rosettes, low-grade fibromyxoid sarcoma, sclerosing lymphoma, synovial sarcoma, fibroma, and fibrosarcoma.(1,3) Local recurrence and distant

1. Instituto Mario Penna, Hospital Luxemburgo, Belo Horizonte (MG) Brasil.

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Carvalho EĂ , Bonomi DO, Pinho AJM, Salles PGO, Vieira HC

Figure 2. Photomicrograph showing a neoplasm composed of ovoid epithelioid cells with hyperchromatic nuclei and inconspicuous nucleoli embedded in a densely collagenized stroma (H&E; magnification, Ă&#x2014;40).

An extremely rare tumor that few pathologists have encountered, SEF is often difficult to diagnose. Despite being low grade, SEF is a clinicopathologically distinct tumor with malignant potential, the rates of recurrence, metastasis, and mortality being considerable.(1,4) Figure 1. Surgical specimen showing en bloc resection of the left lung, pleura, and ribs.

metastases (most commonly to the lung, pleura, and bone) are observed in > 50% and > 40% of cases of fibrosarcoma, respectively.(5)

As is the case with soft tissue fibrosarcomas, surgery is the treatment of choice because other treatment options have little efficacy. Further studies are needed in order to determine whether the clinical progression of primary SEF of the pleura is the same as that of other SEFs, as well as to determine the best form of treatment for patients with primary SEF of the pleura.

REFERENCES 1. Ossendorf C, Studer GM, Bode B, Fuchs B. Sclerosing epithelioid fibrosarcoma: case presentation and a systematic review. Clin Orthop Relat Res. 2008;466(6):1485-91. https://doi.org/10.1007/ s11999-008-0205-8 2. Chow LT, Lui YH, Kumta SM, Allen PW. Primary sclerosing epithelioid fibrosarcoma of the sacrum: A case report and review of the literature. J Clin Pathol. 2004;57(1):90-4. https://doi.org/10.1136/ jcp.57.1.90 3. Smith PJ, Almeida B, Krajacevic J, Taylor B. Sclerosing epithelioid fibrosarcoma as a rare cause of ascites in a young man: a case report.

J Med Case Rep. 2008;2:248. https://doi.org/10.1186/1752-1947-2-248 4. Antonescu CR, Rosenblum MK, Pereira P, Nascimento AG, Woodruff JM. Sclerosing epithelioid fibrosarcoma: a study of 16 cases and confirmation of a clinicopathologically distinct tumor. Am J Surg Pathol. 2001;25(6):699-709. https://doi.org/10.1097/00000478200106000-00001 5. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol. 1995;19(9):979-93. https://doi.org/10.1097/00000478199509000-00001

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Índice remissivo de assuntos do volume 43 (1-6) 2017 A Adolescente...............................................44, 368 Aerossóis/uso terapêutico................................. 302 Agonistas adrenérgicos beta.............................. 302 Alveolite alérgica extrínseca................................72 Anóxia.............................................................60 Anóxia/etiologia.............................................. 176 Ansiedade........................................................18 Antagonistas muscarínicos................................ 302 Apneia do sono tipo obstrutiva.................... 331, 373 Asma............................................................. 368 Asma/classificação......................................44, 264 Asma/epidemiologia....................................24, 163 Asma/etiologia..................................................44 Asma/mortalidade......................................24, 163 Asma/prevenção & controle............................... 264 Asma/quimioterapia...........................................24 Aspiração respiratória....................................... 313 Atitudes e prática em saúde.............................. 202 Audiometria de tons puros................................ 195 Avaliação de sintomas...................................... 169

B Broncodilatadores............................................ 302 Broncoscopia.................................................. 151

C Carcinoma pulmonar de células não pequenas/cirurgia............................................ 363 Cateteres....................................................... 190 Cirurgia torácica videoassistida.......................... 129 Cistos............................................................ 140 Combinação de medicamentos........................... 113 Comunicação.................................................. 357 Conhecimentos................................................ 202 Criança............................................................44 Cuidadores.......................................................18 Cuidados críticos............................................. 183 Cuidados paliativos............................................14

D Deambulação precoce...................................... 134 Depressão........................................................18 Derrame pleural maligno.............................14, 190 Desmame do respirador............................. 183, 253 Desnutrição.................................................... 337 Diafragma........................................................32 Diagnóstico diferencial..................................... 140 Diagnóstico por imagem................................... 270 Dispneia.................................................. 101, 151 Dispneia e Pressões respiratórias máximas............32 Doença de depósito de glicogênio tipo II...............54 Doença pulmonar obstrutiva crônica....................................... 32, 274, 302, 357 Doença pulmonar obstrutiva crônica/complicações....................................... 176 Doença pulmonar obstrutiva crônica/ prevenção & controle................................ 290, 351 Doença pulmonar obstrutiva crônica/terapia........ 290 Doença pulmonar obstrutiva crônica/ tratamento farmacológico................................. 290

492

Doenças Doenças Doenças Doenças Doenças

da traqueia........................................ 151 pulmonares..........................................72 pulmonares intersticiais................ 140, 393 pulmonares intersticiais/diagnóstico.........72 torácicas............................................ 270

E Edema pulmonar............................................. 253 Educação de graduação em medicina.................. 202 Efeitos colaterais e reações adversas relacionadas a drogas......................... 195 Efeitos psicossociais da doença............................18 Empiema pleural............................................. 344 Enfisema..........................................................95 Enfisema mediastínico...................................... 101 Enfisema subcutâneo....................................... 101 Epidemiologia................................................. 363 Espirometria............................................... 32, 38 Estudantes de medicina.................................... 285 Estudos de séries temporais.............................. 274 Estudos de validação........................................ 331 Exercício........................................................ 274 Extubação/efeitos adversos............................... 183

F Fadiga............................................................ 169 Fatores de risco........................................... 6, 106 Fenômenos fisiológicos respiratórios.....................95 Fibrose cística................................................. 337 Fibrose cística/complicações Guia de prática clínica...................................... 219 Fibrose cística/diagnóstico......................... 121, 219 Fibrose cística/prevenção & controle................... 121 Fibrose cística/terapia...................................... 219 Fibrose pulmonar............................................. 393 Força muscular................................................ 134 Fumaça.......................................................... 208

G Gerenciamento clínico...................................... 302 Granuloma de corpo estranho............................ 320 Grupos de risco............................................... 274

H Hábito de fumar.......................................... 6, 351 Hipercapnia......................................................60 Hipertensão.................................................... 373 Histologia....................................................... 363 HIV..........................................................51, 215 Hospitalização................................................. 163

I Infecções por Mycobacterium............................ 270 Inflamação..................................................... 208 Inquéritos e questionários...................264, 357, 380 Insuficiência pancreática exócrina...................... 337 Interferon gama.............................................. 215 intersticiais/etiologia..........................................72

L Lesão pulmonar.................................................95

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M Máscaras...................................................... 87 Metanálise.................................................. 373 Modalidades de fisioterapia........................... 134 Modelos animais............................................ 95 Mulheres........................................................ 6 Músculos respiratórios/patologia...................... 54 Mycobacterium tuberculosis/ isolamento & purificação............................... 380

N Neoplasias pulmonares....................18, 169, 363, Neoplasias pulmonares/complicações............. 129 Neoplasias pulmonares/terapia...................... 129 Neurocirurgia.............................................. 183 Nutrição em saúde pública.............................. 51

O Oxigenação por membrana extracorpórea......... 60

P Papiloma.................................................... 259 Perda auditiva de alta frequência................... 195 Pessoal de saúde......................................... 351 Pleurodese.................................................. 190 Pneumonia................................................. 344 Pneumonia/epidemiologia............................. 274 Pneumonia/mortalidade................................ 274 Pneumopatias............................................. 259 Pneumopatias obstrutivas............................... 38 Política de saúde......................................... 202 Pressão positiva contínua nas vias aéreas....... 373 Prevalência..............................................6, 368 Produtos do tabaco...................................... 202 Profissionais do sexo........................................ 6 Pulmão............................................... 313, 320

Q Qualidade de vida............................18, 285, 331

R Radiografia................................................. 253 Recidiva..................................................... 113

Recorrência................................................ 106 Renda........................................................ 380 Rinite alérgica............................................. 368

S Saccharum................................................. 208 Saúde pública............................................. 163 Síndrome do desconforto respiratório do adulto..................................... 60 Sistema respiratório..................................... 208 Sobrevivência............................................... 14 Sono.......................................................... 285 Suor.......................................................... 121

T Tabaco......................................................... 95 Técnicas de diagnóstico molecular/métodos..... 380 Termografia.................................................. 87 Teste tuberculínico....................................... 215 Testes de função respiratória...............38, 54, 337 Testes de liberação de interferon-gama........... 215 Testes sorológicos/métodos........................... 380 Tomografia................................................. 190 Tomografia computadorizada por raios X............................. 140, 259, 313, 393 Tomografia computadorizada por raios X/métodos..................................... 270 Toracoscopia............................................... 344 Traduções................................................... 331 Transplante de pulmão................................. 270 Transtornos do sonovigília/epidemiologia......... 176 Transtornos relacionados ao uso de cocaína..... 320 Tuberculose......................................... 106, 215 Tuberculose latente...................................... 215 Tuberculose pulmonar......................38, 113, 270 Tuberculose resistente a múltiplos medicamentos............................... 195 Tuberculose/diagnóstico............................... 380 Tuberculose/epidemiologia.............................. 51

U Unidades de terapia intensiva................. 134, 357

V Ventilação não invasiva.................................. 87

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Índice remissivo de autores do volume 43 (1-6) 2017 A Addy Lidvina Mejia Palomino...............................77 Adham do Amaral e Castro................................ 324 Adriano Costigliola........................................... 246 Adyléia Aparecida Dalbo Contrera Toro................ 121 Alberto Andrade Vergara................................... 219 Alberto Cukier................................................. 290 Alda Manique.................................................. 101 Aleksandar Bokan............................................ 351 Alessandro Vatrella.......................................... 322 Alfredo Nicodemos Cruz Santana.........................83 Aline dos Santos Machado................................. 134 Álvaro Augusto Cruz......................................... 159 Alvaro Javier Idrovo...........................................51 Álvaro Vigo..................................................... 363 Alyne Riane .....................................................95 Amadeu Antonio Vieira..................................... 106 Amanda Souza Araújo...................................... 169 Amparo Benito-Berlinches...................................71 Ana Carolina Peçanha Antonio........................... 253 Ana Karla Vieira Brüggemann..............................32 Ana Luisa Godoy Fernandes................................18 Ana Patricia Ovejero-Díaz...................................71 Ana Paula Zanardo........................................... 253 Ana Rita Coimbra Motta-Castro.......................... 215 Anamaria Mello Miranda Paniago ....................... 215 Andrea Akemi Morita........................................ 280 Andrea da Nóbrega Cirino Nogueira .....................87 Andrey Wirgues Sousa.......................................44 Anete Trajman................................................ 215 Ankit Chhoda.................................................. 320 Anna Lucia Barros Cabral....................................44 Anna Maria Buehler.......................................... 302 Antonio Fernando Lins de Paiva . ....................... 190 Antônio Fernando Ribeiro;................................. 121 Antonio George Cavalcante........................ 169, 219 Antonio Ruffino-Netto....................................... 215 Aquiles Assunção Camelier................................ 290 Arrabal Fernandes............................................ 202 Arthur Alves Rocha.......................................... 176 Astria Dias Ferrão Gonzales............................... 208

B Betina Scheeren 313 Bolanle Olufunlola Adefuye . ............................. 195 Bruna de Souza Sixel.........................................54 Bruno do Valle Pinheiro.......................................81 Bruno Guedes Baldi................................... 140, 249 Bruno Hochhegger.................4, 140, 270, 313, 329, 400, 85, 161, 251, 259, 319

C Camila de Castro Corrêa 385 Carla Cristina Souza Gomez.............................. 121 Carla Meneguzzi.............................................. 183 Carlos Alberto de Castro Pereira...........................72 Carlos Antônio Riedi ........................................ 219 Carlos Cezar Fritscher...................................... 290 Carlos Henrique Barrios ................................... 363 Carlos Roberto Ribeiro Carvalho......................... 140 Carlos Schuller Nin ......................................... 270 Carolina Althoff Souza...................................... 259

494

Carolina Finardi Brümmer ................................ 264 Caroline Semprebom de Medeiros........................32 Cassiano Teixeira............................................. 253 Cássio da Cunha Ibiapina.................................. 344 Cecilia Calabrese...................................... 246, 368 Cecilia Maria Patino............................................. 5 Celso Ricardo Fernandes de Carvalho...... 44, 86, 162, 252, 264, 330 Cesar Augusto Araujo Neto............................... 259 Christina Shiang................................................72 Clarice Emiko Fuzi........................................... 151 Clarice Rosa Olivo..............................................95 Cláudia Henrique da Costa................................ 290 Cláudia Ribeiro de Andrade............................... 344 Claudine Lacerda de Oliveira Abrahão.......... 337, 368 Cristian Roncada............................................. 163 Cristina Bárbara.............................................. 101 Cristina Gonçalves Alvim............................ 344, 368

D Dafne Dain Gandelman Horovitz..........................54 Daniela Aparecida de Brito Cervilha......................95 Danielle Rosal...................................................32 Danila Torres Leite........................................... 106 Dannuey Machado Cardoso............................... 134 Dante Luiz Escuissato....................................... 154 Davi de Souza Francisco.....................................32 Delia Goletti . .......................................... 380, 259 Diego Scherlon Pizzamiglio . ............................. 385 Dominique Piacenti Carneiro................................24 Douglas Zaione Nascimento.............................. 270 Dragana Milicic................................................ 351

E Eanes Delgado Barros Pereira .............................87 Edgar Fabian Manrique-Hernández.......................51 Edson Marchiori.................................... 4, 169, 290 Eduardo Kaiser Ururahy Nunes Fonseca.............. 324 Eduardo Leite Vieira Costa............. 60, 85, 140, 154, 161, 251, 259, 313, 319, 322, 329, 393, 399, 400 Elaine Paulin.....................................................32 Elenara da Fonseca Andrade Procianoy............... 219 Eliana Lourenço Borges......................................18 Elisa Maria Siqueira Lombardi............................ 202 Emerson Rodrigues da Silva ............................. 163 Emílio Pizzichini............................................... 264 Erika Veruska Paiva Ortolan....................... 385, 331 Erissandra Gomes............................................ 313 Ester Nei Aparecida Martins Coletta......................72 Ethel Leonor Noia Maciel ........................... 215, 151

F Fabio Pitta...................................................... 280 Fabiola Adelia Perin ......................................... 129 Fabíola Villac Adde........................................... 219 Fátima Caeiro................................................. 101 Felipe Augusto Rodrigues Mendes.........................44 Felipe da Silva Gomes ..................................... 208 Felipe Kazan de Oliveira.................................... 385 Felipe Mussi von Ranke..................................... 259 Fernanda Carvalho de Queiroz Mello .................. 113

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Fernanda Degobbi Tenório Quirino dos Santos Lopes......................................... 95, 380 Fernanda Kazmierski Morakami...................... 280 Fernanda Machado Kutchak........................... 183 Fernando Augusto Lima Marson..................... 121 Fernando Conrado Abrão................................ 14 Fernando Luiz Cavalcanti Lundgren................ 157 Festus Olukayode Soyinka...................... 195, 290 Filipa Fernandes.......................................... 150 Filomena Luís.............................................. 150 Flávia Del Castanhel..................................... 357 Flávia Roberta Rocha...................................... 32 Fouad Seghrouchni...................................... 380 Francisco José Caldeira Reis ......................... 219 Frederico Barth........................................... 129 Frederico Leon Arrabal Fernandes........... 202, 290

G Gabriela Cristofoli Barni................................ 337 Gabriela Valente Nicolau............................... 264 Gabriele Carra Forte..................................... 337 Gaetano Rea............................................... 246 Gianna Waldrich Bisca .......................... 280, 322 Gilberto Szarf................................................ 72 Giordano Alves............................................ 313 Giorgia Dalpiaz............................................ 322 Giovanni Battista Migliori.............................. 380 Gláucia Zanetti................................................ 4 Glória Maria Cardoso de Andrade Penque....54, 85, 161, 251, 259, 319, 329, 399 Graham Bothamley...................................... 380 Grupo Colaborativo de Estudos em Fibrose Cística............................................. 121 Grupo de Trabalho das Diretrizes Brasileiras de Diagnóstico e Tratamento da Fibrose Cística.... 219 Guilherme Nogueira Spinosa......................... 151 Guilherme Pinheiro da Silva.......................... 169 Guodong Du............................................... 373 Gustavo de Souza Portes Meirelles................. 393 Gustavo Faibischew Prado ............................ 202 Gustavo Silveira Graudenz.............................. 24

H Helena Rabahi............................................. 176 Helena Ribeiro Fortes................................... 259 Hiram Valenzuela-Jiménez............................... 51

I Igor Renato Louro Bruno de Abreu................... 14 Ilda de Godoy................................................. 6 Ilija Andrijevic............................................. 351 Ilka Lopes Santoro........................................... 3 Ingrid Correia Nogueira........................... 169, 18 Irai Luis Giacomelli...................................... 270 Irma Godoy................................................ 157 Isabella Martins de Albuquerque............. 134, 290 Israel Silva Maia.......................................... 302 Ivan Kopitovic............................................. 351

J Jane Kelly Oliveira-Friestino.......................... Janice Cristina Soares.................................. Januário Mourão Lima.................................. Jayme de Oliveira Rios................................. João Adriano de Barros................................. João Amadera ............................................ Johana Susan Paddison ............................... José Antônio de Figueiredo Pinto.................... José Carlos Felicetti..................................... José da Silva Moreira ..................................

274 134 208 363 154 302 169 363 129 270

José de Jesus Peixoto Camargo...................... 129 José Dirceu Ribeiro...................................... 121 José Eduardo Corrente..............................6, 219 José Eduardo Delfini Cançado........................ 290 José Franklin Soares Pompa-Filho.................... 14 José Gustavo Romaldini................................ 290 José Laerte Rodrigues Silva Júnior.................. 176 Jose Miguel Chatkin..................................... 290 José Roberto Jardim..................................... 290 José Tavares de Melo Júnior.......................... 264 Josiane Marques Felcar.......................... 280, 331 Josué Almeida Victorino ............................... 183 Juan Clinton Llerena Jr................................... 54 Juliana Carvalho Ferreira.................................. 5 Juliana Dias Lourenço.......... 95, 86, 162, 252, 330 Juliana Franceschini....................................... 18 Juliana Guarize.............................................. 76 Juliana Tiyaki Ito........................................... 95 Julio Croda................................................. 215

K Kai Li......................................................... Karina Couto Furlanetto ............................... Karla Poersch.............................................. Klaus Loureiro Irion .................................... Krislainy de Sousa Corrêa ............................

373 280 183 259 176

L Lei Ma........................................................ 373 Leila John Marques Steidle............................ 264 Leonardo Araujo Pinto.................................. 163 Lia D’Ambrosio............................................ 380 Lídia Alice Torres......................................... 219 Lídia Cristina Villela Ribeiro .......................... 208 Ligia Lopes Devóglio........................................ 6 Luanda Dias da Silva...................................... 54 Luis Felipe Forgiarini.................................... 337 Luis Gorospe ................................................ 71 Luís Martins................................................ 101 Luísa Boal................................................... 101 Luiz Alberto Forgiarini Junior......................... 183 Luiz Felipe Nobre......................................... 399 Luiz Henrique de Paula Melo ........................... 87 Luiz Vicente Ribeiro Ferreira da Silva Filho . .... 219 Luiza Helena Degani Costa.............................. 18

M Mara Graziele Maciel Silveira......................... 151 Marc Tebruegge........................................... 380 Marcela Munoz............................................ 380 Marcelo Alcantara Holanda.............................. 87 Marcelo Basso Gazzana................................ 253 Marcelo Bicalho de Fuccio............................. 219 Marcelo de Mello Rieder................................ 183 Marcelo Fouad Rabahi.................................. 176 Marcelo Park................................................. 60 Marcia Jacomelli..............................77, 290, 393 Marcia Margaret Menezes Pizzichini................ 264 Marco Antônio Bussacos............................... 202 Marcos Lázaro da Silva Guerreiro............ 208, 331 Marcos Ribeiro............................................ 280 Marcus Barreto Conde.................................. 176 Marcus Herbert Jones................................... 163 Maria Ângela Gonçalves de Oliveira Ribeiro . ... 121 Maria Auxiliadora Carmo Moreira.................... 393 Maria Cecília Nieves Maiorano de Nucci .......... 290 Maria da Gloria Bonecini-Almeida................... 215 Maria da Penha Uchoa Sales.......................... 290 Maria Fátima Servidoni................................. 121 Maria Gabriela Cavalcanti................................ 14 J Bras Pneumol. 2017;43(6):494-496

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Maria Helena Borgato....................................... 6 Maria Teresa Ruiz Tsukazan........................... 363 Maria Tereza Morano ................................... 169 Maria Vera Cruz de Oliveira Castellano ........... 151 Mariângela Pimentel Pincelli................... 302, 290 Marija Vukoja.............................................. 351 Marino Muxfeldt Bianchin.............................. 183 Mário Terra-Filho......................................... 202 Marisa Pereira............................................. 270 Marli Knorst................................................ 253 Massimo Amicosante.................................... 380 Matias Epifanio ........................................... 219 Maurício Guidi Saueressig............................... 76 Maurício Tatsch Ximenes Carvalho ................. 134 Michelle Gonçalves de Souza Tavares.............. 264 Miguel Abidon Aidé .............................. 290, 331 Mikhail Ivanovich Chushkin............................. 38 Milton de Arruda Martins . .............................. 95 Miroslav Ilic................................................ 351 Mônica de Cássia Firmida.............................. 219 Muse Olatunbosun Fadeyi............................. 195

N Nathalia Parente de Sousa Maia....................... 87 Nazaré Otilia Nazário . ................................. 264 Neiva Damaceno......................................... 219 Nicolette Celani Cavalcanti.............................. 54 Nidia Aparecida Hernandes........................... 280 Norberto Ludwig-Neto ................................. 219 Novel Njweipi Chegou................................... 380

O Oleg Nikolayevich Ots..................................... 38 Olívia Meira Dias.......................................... 140 Olusola Ayodele Sogebi................................ 195

P Patrícia Dionísio........................................... 101 Paula Silva Gomes......................................... 72 Paulo Augusto Moreira Camargos................... 368 Paulo de Tarso Roth Dalcin............................ 337 Paulo Francisco Guerreiro Cardoso................... 77 Paulo José Cauduro Maróstica........................ 219 Paulo José Zimermann Teixeira...................... 290 Paulo Manuel Pêgo-Fernandes....................... 190 Paulo Márcio Pitrez....................................... 163 Pedro Felipe de Bruin................................... 169 Pedro Henrique Xavier Nabuco de Araujo......... 190 Pedro Paulo Teixeira e Silva Torres................. 393 Pedro Vitale Mendes....................................... 60 Priscila Maria Stolses Bergamo Francisco......... 274 Priscilla de Souza Cassano............................ 270 Priscylla Souza Castro ................................. 253 Priyanka Pathania........................................ 320

Q Qiang Lei.................................................... 373

R Rafael Stelmach.......................................... Renata da Silva Schulz................................. Renato Batista Paceli.................................... Renato Maciel............................................. Renato Tetelbon Stein.................................. Ricardo de Amorim Corrêa ........................... Ricardo Mingarini Terra ................................ Rimarcs Gomes Ferreira................................ Rita Gomes................................................. Rita Macedo ...............................................

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159 208 202 290 163 290 190 154 150 101

Roberta Pulcheri Ramos.................................... 1 Roberto Schuhmacher Neto........................... 270 Roberto Stirbulov......................................... 290 Robson Rottenfusser.................................... 400 Rodolfo de Paula Vieira................................... 24 Rodrigo Abensur Athanazio........................... 219 Rodrigo Abensur Athanazio........................... 290 Rodrigo Caruso Chate................................... 190 Rodrigo Romualdo Pereira............................. 344 Rodrigo Russo............................................. 290 Rogério Souza .................................................. Rogério Souza............................................. 247 Rosella Centis............................................. 380 Rosemeire de Olanda Ferraz.......................... 274 Rosemeri Maurici......................................... 331 Rubia Rodrigues............................................ 95 Ruy Camargo Pires-Neto .............................. 134

S Samia Zahi Rached...................................... 219 Sandeep Sahay........................................... 320 Sandra Lisboa............................................... 54 Sandra Maria do Valle Leone de Oliveira.......... 215 Sanja Marinkovic......................................... 351 Sergio Eduardo Demarzo................................ 77 Sérgio Jamnik............................................... 18 Shruti Khurana............................................ 320 Silke Anna Theresa Weber............................. 385 Silvia de Souza Campos Fernandes................. 368 Solange Adreoni.......................................... 106 Sonia Catarina de Abreu Figueiredo................ 113 Spencer Marcantônio Camargo...................... 129 Stefania Damiani ........................................ 322 Stefano Donghi............................................. 76 Stella Regina Martins................................... 202 Stephan Adamour Soder............................... 129 Suely Grosseman......................................... 357 Susana Moreira........................................... 101 Suzana Fonseca de Oliveira Melo;.................. 219 Suzana Tanni Minamoto ............................... 290 Suzy Maria Montenegro Pontes........................ 87

T Tarcio Macena Oliveira.................................. 208 TB Diagnostic Survey Working Group.............. 380 Thiago Brasileiro Vasconcelos.......................... 87 Thiago da Silva Santos................................. 190 Thiago de Araujo Cardoso............................. 163 Thiago Gomes Romano................................... 60

U Ubiratan Paula Santos.................................. 202

V Vangie Dias da Silva..................................... 113 Vasco Pinheiro Diógenes Bastos....................... 87 Verena Sampaio Barbosa Matos..................... 208 Victor Figueiredo Leite.................................. 302 Vinícius Duval da Silva................................. 363 Viviane Rossi Figueiredo................................. 77

X Xuqing Li.................................................... 373

Y Yan Xiang................................................... 373 Yoshino Tamaki Sameshima........................... 324 Yunhui Lv................................................... 373

RELAÇÃO DOS REVISORES

J Bras Pneumol. 2017;43(6):497-500

Relação de revisores do volume 43 (1-6) 2017 Ada Clarice Gastaldi - Universidade de São Paulo - Ribeirão Preto - SP Adalberto Sperb Rubin - Universidade Federal de Ciências da Saúde de Porto Alegre - Porto Alegre - RS Adelmir Souza-Machado - Universidade Federal da Bahia - Salvador - BA Adriana Claudia Lunardi - Universidade de São Paulo - São Paulo - SP Adyleia Dalbo Contrera Toro - Universidade Estadual de Campinas - Campinas - SP Afrânio Lineu Kritski - Universidade Federal do Rio de Janeiro - Rio de Janeiro, RJ Agostinho Hermes de Medeiros Neto - Universidade Federal da Paraíba - João Pessoa - PA Alberto Cukier - Universidade de São Paulo - São Paulo - SP Alberto José de Araújo - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Albino Barraza Villarreal - Instituto Nacional de Salud Publica Cuernavaca - Mexico Alejandra Ramirez - Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico. Alexandre Dias Mançano - Hospital Anchieta - Taguatinga - DF Alexandre Ricardo Pepe Ambrozin - Universidade Estadual Paulista “Julio de Mesquita Filho” - Marília - SP Alexandre Simões Dias - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Alfredo Nicodemos Cruz Santana - HRAN da Faculdade de Medicina da ESCS - Brasília - DF Aline Almeida Gulart - Universidade do Estado de Santa Catarina - Florianópolis - SC Álvaro A. Cruz - Universidade Federal da Bahia - Salvador - BA Ana Carla Carvalho Coelho - Universidade Federal da Bahia - Salvador - BA Ana Cláudia Costa Carneiro - Hospital Otávio Mangabeira - Salvador - BH Ana Luisa Godoy Fernandes - Universidade Federal de São Paulo - São Paulo - SP Ana Paula B. Moschione Castro - Universidade de São Paulo - São Paulo - SP Ana Paula Santos - Universidade do Estado do Rio de Janeiro - Rio de Janeiro - RJ Anderson José - Universidade Nove de Julho - São Paulo - SP Andre Luis Pereira de Albuquerque - Universidade de São Paulo - São Paulo - SP Andrea Celtin - Universidade de São Paulo - Ribeirão Preto - SP Andréa da Nóbrega Cirino Nogueira - Universidade Estácio de Sá - Fortaleza - CE Andrea Toscanini - Universidade de São Paulo - São Paulo - SP Andréia Guedes Oliva Fernandes - Universidade Federal da Bahia - Salvador - BA Anete Trajman - Universidade Gama Filho - Rio de Janeiro - RJ Antônio Carlos Ponce de Leon - Universidade do Estado do Rio de Janeiro - Rio de Janeiro - RJ Antônio George De Matos Cavalcante - Universidade Federal do Ceará - Fortaleza - CE Aquiles Assunção Camelier - Universidade Federal da Bahia - Salvador - BA Arthur Oswaldo de Abreu Vianna - Clínica São Vicente - Rio de Janeiro - RJ Arthur Soares Souza Júnior - Faculdade de Medicina de São José do Rio Preto - São José do Rio Preto - SP Artur Katz - Hospital Sirio-Libanes - São Paulo - SP Asiye Kanbay - Istanbul Medeniyet Universitesi - Istanbul - Turkey Beatrice Feragalli - Universita degli Studi Gabriele d’Annunzio Chieti e Pescara - Chieti - Italy Benoit Bibas - Universidade de São Paulo - São Paulo - SP Bruno do Valle Pinheiro - Universidade Federal de Juiz de Fora - Juiz de Fora - MG Bruno Guedes Baldi - Universidade de São Paulo, São Paulo - SP Bruno Hochhegger - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Caio Júlio Cesar dos Santos Fernandes - Universidade de São Paulo - São Paulo - SP Caio Morais - Universidade de São Paulo - São Paulo - SP Camila Gimenes - Universidade do Sagrado Coração - Bauru - SP Camila Melo - Universidade Federal de São Paulo - São Paulo - SP Carla Hilário Cunha Dalto - Universidade Federal da Bahia - Salvador - BA Carlos Alberto Araújo - Universidade Federal do Rio Grande do Norte - Natal - RN Carlos Alberto de Castro Pereira - Universidade Federal de São Paulo - São Paulo - SP Carlos Antônio Riedi - Universidade Federal do Paraná - Curitiba - PR Carlos Camillo - Universidade Estadual de Londrina - Londrina - PR Carlos Jerjes Sanchez-Diaz - Instituto de Cardiologia y Medicina Vascular, TecSalud - Mexico Carlos Roberto Ribeiro de Carvalho - Universidade de São Paulo, São Paulo - SP Carlos Tietboehl - Secretaria de Estado da Saúde do Rio Grande do Sul - Porto Alegre - RS Carlos Uchoa - Universidade de São Paulo - São Paulo - SP Carlos Viana Poyares Jardim - Universidade de São Paulo, São Paulo - SP Carmen Sílvia Valente Barbas - Universidade de São Paulo - São Paulo - SP Carolina Luizaga - Fundação Oncocentro de São Paulo - São Paulo - SP Caroline knaut - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Cassio Ibiapina - Universidade Federal de Minas Gerais - Belo Horizonte - MG Celso Ricardo Fernandes de Carvalho - Universidade de São Paulo - São Paulo - SP Claudia Henrique Costa - Universidade Federal do Estado do Rio de Janeiro - Rio de Janeiro - RJ Claudia Vater - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Clemax Couto Sant`Anna - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Clovis Botelho - Universidade Federal do Mato Grosso do Sul - Cuiabá - MT Cristiane Nascimento - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Cristina Martins Coelho - Universidade Federal de Juiz de Fora - Governador Valadares- MG Cristino Oliveira - Universidade Federal de Juiz de Fora - Governador Valadares- MG © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

497

Dagoberto Vanoni de Godoy - Universidade de Caxias do Sul - Caxias do Sul - RS Daniel Antunes Pereira - A.C. Camargo Cancer Center - São Paulo - SP Daniel Deheinzelin - Hospital Sirio-Libanes - São Paulo - SP Daniel Oliveira Bonomi - Instituto Mario Penna - Belo Horizonte - BH Daniela Gardano Bucharles Mont’Alverne - Universidade Federal do Ceará - Fortaleza - CE Daniela Ponce - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Danielle Soares Rocha Vieira- Universidade Federal de Santa Catarina - Florianópolis - SC Dante Luiz Escuissato - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Dany Jasinowodolinski - Universidade de São Paulo - São Paulo - SP Darcy Ribeiro Pinto Filho - Universidade de Caxias do Sul - Caxias do Sul - RS Dario José Hart Pontes Signorini - Universidade do Estado do Rio de Janeiro - Rio de Janeiro - RJ Darlan Laurício Matte - Universidade do Estado de Santa Catarina - Florianópolis - SC Denise Arakaki-sanchez - Secretaria de Estado da Saúde do Distrito Federal - Brasília - DF Denise Rossato Silva - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Diane de Lima Oliveira - Universidade Federal de Santa Catarina - Florianópolis - SC Domingo Palmero - Hospital Muñiz - Argentina Dragan Subotic - Institute for Lung Diseases, Clinical Center of Serbia, Belgrade, Serbia Eanes Delgado Barros Pereira - Universidade Federal do Ceará - Fortaleza - CE Edilson Zancanella - Universidade Estadual de Campinas - Campinas - SP Edson Marchiori - Universidade Federal Fluminense, Niterói - RJ Eduardo Cadore - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Eduardo Campos Werebe - Hospital Israelita Albert Einstein - São Paulo - SP Eduardo Costa - Universidade de São Paulo - Ribeirão Preto - SP Eduardo Martins Netto - Universidade Federal da Bahia - Salvador - BA Eduardo Ponte - Faculdade de Medicina de Jundiaí - Jundiaí - SP Edwin Roger Parra - University of Texas MD Anderson Cancer Center - Texas - USA Élcio dos Santos Oliveira Vianna - Universidade de São Paulo - Ribeirão Preto - SP Eleny Guimarães Teixeira - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Eliana Dias Matos - Escola Bahiana de Medicina e Saúde Pública - Salvador - BA Elisa Maria Siqueira Lombardi - Universidade de São Paulo - São Paulo - SP Ellen Nascimento - Universidade de São Paulo - São Paulo - SP Eloara Vieira Machado Ferreira - Universidade Federal de São Paulo - São Paulo - SP Emel Aslan - Dicle Universitesi Tip Fakultesi - Diyarbakir - Turkey Emel Ceylan - Adnan Menderes University - Turkey Enrico lombardi - University Hospital Meyer - Florence- Italy Esther Wilches-Luna - Universidad del Valle Cali - Cali - Colombia Evelise Lima - Universidade de São Paulo - São Paulo - SP Fábio Aguiar - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Fabio Jose Haddad - A.C. Camargo Cancer Center - São Paulo - SP Fábio Pitta - Universidade Estadual de Londrina - Londrina - PR Fabrício Martins Valois - Universidade Federal do Maranhão - São Luis - MA Faik İlik - Baskent Universitesi Konya - Turkey Felipe Barbosa Madeira - Hospital Federal da Lagoa - Rio de Janeiro - RJ Felipe von Ranke - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Fernanda Camelier - Universidade Federal da Bahia - Salvador - BA Fernanda Carvalho de Queiroz Mello - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Fernanda Degobbi Tenorio dos Santos - Universidade de São Paulo - São Paulo - SP Fernanda Lanza - Universidade Nove de Julho - São Paulo - SP Fernando Augusto de Lima Marson - Universidade Estadual de Campinas - Campinas - SP Fernando Azevedo Pacheco - Hospital Federal dos Servidores do Estado - Rio de Janeiro - RJ Fernando Didier - Universidade de São Paulo - São Paulo - SP Fernando José Pinho Queiroga Júnior - Universidade Federal de São Paulo - São Paulo - SP Fernando Kay - Universidade de São Paulo - São Paulo - SP Fernando Luiz Westphal - Universidade Federal do Amazonas - Manaus - AM Flávia Baggio Nerbass - Universidade de São Paulo - São Paulo - SP Flavia de Souza Nunes Soares - Universidade de São Paulo - São Paulo - SP Flávia Marini Paro - Universidade Federal do Espírito Santo - Vitória - ES Flávio Arbex - Universidade Federal de São Paulo - São Paulo - SP Flávio Brito Filho - Hospital de Base do Distrito Federal - Brasília - DF Frederico Leon Arrabal Fernandes - Universidade de São Paulo - São Paulo - SP Gabriela Cristofoli Barni - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Gaetano Rea - AO dei Colli - Monaldi Hospital - Nápolis - Itália Gilberto Castro Junior - Instituto do Câncer do Estado de São Paulo - São Paulo - SP Giovanni Battista Migliori - Director WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate - Italy Giovanni Sotgiu - University of Sassari, Sassari - Italy Gláucia Zanetti - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Guadalupe Espitia - Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado Pulmonology - Magdalena de las Salinas - Mexico Guilherme Julian - Universidade Federal de São Paulo - São Paulo - SP Gustavo Faibischew Prado - Universidade de São Paulo - São Paulo - SP Herberto José Chong Neto - Universidade Federal do Paraná - Curitiba - PR Humberto Villacorta Junior - Universidade Federal Fluminense - Rio de Janeiro - RJ Iara Nely Fiks - Universidade de São Paulo - São Paulo - SP Ilka Lopes Santoro - Universidade Federal de São Paulo - São Paulo - SP Irene Torres-Sánchez - Universidade de Granada - Granada - Espanha

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J Bras Pneumol. 2017;43(6):497-500

Irma de Godoy - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Jaime Correia de Sousa - Life and Health Sciences Research Institute (ICVS) - Braga - Portugal Jamocyr Moura Marinho - Escola Bahiana de Medicina e Saúde Pública - Salvador - BA Jaquelina Sonoe Ota Arakaki - Universidade Federal de São Paulo - São Paulo - SP Jefferson Freitas - Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo - São Paulo - SP Jorge Afiune - Instituto Clemente Ferreira - São Paulo - SP José Antônio Baddini Martinez - Universidade de São Paulo - Ribeirão Preto - SP Jose Antonio Castro Rodriguez - Pontificia Universidad Catolica de Chile - Santiago - Chile José Dirceu Ribeiro - Universidade Estadual de Campinas - Campinas - SP José Eduardo Delfini Cançado - Universidade de São Paulo - São Paulo - SP José Miguel Chatkin - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS José Ribas Milanez de Campos - Universidade de São Paulo - São Paulo - SP José Roberto de Brito Jardim - Universidade Federal de São Paulo - São Paulo - SP José Ueleres Braga - Universidade do Estado do Rio de Janeiro - Rio de Janeiro - RJ Juliana Carvalho Ferreira - Universidade Federal de São Paulo - São Paulo - SP Juliana Lino - Universidade Federal do Ceará - Fortaleza - CE Julio Croda - Universidade Federal de Grande Dourados - Dourados - MS Julio Ramirez - University of Louisville - Kentucky - EUA Karina Ribeiro - Faculdade de Ciências Médicas da Santa Casa de São Paulo - São Paulo - SP Keyla Maia Silva - Universidade Federal de Mato Grosso - Cuiabá - MS Lara Kretzer - Universidade do Estado de Santa Catarina - Florianópolis - SC Lara Maris Nápolis - Universidade Federal de São Paulo - São Paulo - SP Leandro Fritscher - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Leila Steidle - Universidade Federal de Santa Catarina - Florianópolis - SC Leonardo Araújo Pinto - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Lessandra Michelim - Universidade de Caxias do Sul - Caxias do Sul - RS Letícia Cardenas - Universidade de São Paulo - São Paulo - SP Leticia Lauricella - Instituto do Câncer do Estado de São Paulo - São Paulo - SP Lilian Caetano - Universidade Federal de São Paulo - São Paulo - SP Liria Yamauchi - Universidade Federal de São Paulo - São Paulo - SP Luciana Chiavegato - Universidade Cidade de São Paulo - São Paulo - SP Luciana Malosa - Universidade Nove de Julho - São Paulo - SP Luciana Palombini - Universidade Federal de São Paulo - São Paulo - SP Luciene Scherer - Centro Universitário São Camilo - Porto Alegre - RS Ludmila Fiorenzano Baethgen - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Luiz Carlos Corrêa da Silva - Santa Casa de Porto Alegre - Porto Alegre - RS Luiz Eduardo Villaça Leão - Universidade Federal de São Paulo - São Paulo - SP Manuela Karloh - Universidade do Estado de Santa Catarina - Florianópolis - SC Marcel Koenigkam Santos - Universidade de São Paulo - Ribeirão Preto - SP Marcela Amorim Alves - Hospital Geral Otávio de Freitas - Recife - PE Marcelo Alcântara Holanda - Universidade Federal do Ceará - Fortaleza - CE Marcelo B Gazzana - Hospital de Clinicas de Porto Alegre - Porto Alegre - RS Marcelo Beraldo - Universidade de São Paulo - São Paulo - SP Marcelo Bicalho de Fuccio - Fundação Hospitalar do Estado de Minas Gerais, Hospital Júlia Kubitschek - Belo Horizonte - BH Marcelo Cordeiro-Santos - Universidade do Estado do Amazonas - Manaus - AM Marcelo de Mello Rieder - Centro Universitario Metodista - Porto Alegre - RS Marcelo Fouad Rabahi - Universidade Federal de Goiás - Goiânia - GO Marcelo Macchione - Faculdade de Medicina de Catanduva - Catanduva - SP Marcelo Park - Universidade de São Paulo - São Paulo - SP Marcelo Velloso - Universidade Federal de Minas Gerais - Belo Horizonte - MG Marcia Jacomelli - Universidade de São Paulo - São Paulo - SP Marcia Pinto - Fundação Oswaldo Cruz - Rio de Janeiro - RJ Márcia Pizzichini - Universidade Federal de Santa Catarina - Florianópolis - SC Marcos Abdo Arbex - Universidade Federal de São Paulo - São Paulo - SP Marcos Naoyuki Samano - Universidade de São Paulo - São Paulo - SP Marcos Ribeiro - Universidade Estadual de Londrina - Londrina - PR Marcus Herbert Jones - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Margareth Maria Pretti Dalcolmo - Centro de Referência Professor Hélio Fraga - Rio de Janeiro - RJ Maria Ignez Zanetti Feltrim - Universidade de São Paulo - São Paulo - SP Maria Paula Curado - Fundação Antonio Prudente - São Paulo - SP Maria Teresa Ruiz-Tsukazan - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Maria Vera Cruz de Oliveira - Hospital do Servidor Público Estadual de São Paulo - São Paulo - SP Maria Victorina Lopez - Hospital Maciel Pulmonology - Montevideo - Uruguay Mariana Rodrigues Gazzotti - Universidade Federal de São Paulo - São Paulo - SP Marina Almeida - Universidade de São Paulo - São Paulo - SP Mauro Musa Zamboni - Instituto Nacional do Câncer - Rio de Janeiro - RS Mauro Roberto Tucci - Universidade de São Paulo - São Paulo - SP Mayron Faria - Universidade de Fortaleza - Fortaleza - CE Michele Salati - AOU Ospedali Riuniti Ancona - Italy Miguel Lia Tedde - Universidade de São Paulo - São Paulo - SP Miguel R. Gonçalves - Universidade do Porto - Porto - Portugal Milena Mak - Instituto do Câncer do Estado de São Paulo - São Paulo - SP Mônica Corso Pereira - Pontifícia Universidade Católica de Campinas - Campinas - SP Monica Kramer de Noronha Andrade - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Nathalia Órfão - Universidade Federal de Rondonia Campus Jose Ribeiro Filho - Porto Velho - RO Nayeli Zayas - National Heart Institute - Mexico J Bras Pneumol. 2017;43(6):497-500

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Nelson Rosário - Universidade Federal do Paraná - Curitiba - PR Nikolaos Siafakas - University General Hospital of Heraklion “PAGNI” - Greece Nilton Haertel Gomes - Universidade Federal de Pelotas - Pelotas - RS Oliver Augusto Nascimento - Universidade Federal de São Paulo - São Paulo - SP Pablo Manriquez - Pontificia Universidad Catolica de Valparaiso - Valpaiso - Chile Pablo Rydz Pinheiro Santana - Hospital Beneficência Portuguesa de São Paulo - São Paulo - SP Patricia de Carvalho Mastroianni - Universidade Estadual Paulista Julio de Mesquita Filho - Araraquara - SP Paula Maria Eidt Rovedder - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Pauliane Santana - Universidade de São Paulo - São Paulo - SP Paulo Augusto Moreira Camargos - Universidade Federal de Minas Gerais - Belo Horizonte - MG Paulo de Biasi - Universidade Federal Fluminense - Rio de Janeiro - RJ Paulo de Tarso Roth Dalcin - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Paulo Francisco Guerreiro Cardoso - Universidade de São Paulo - São Paulo - SP Paulo José Cauduro Marostica - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Paulo José Zimermann Teixeira - Irmandade da Santa Casa de Misericórdia de Porto Alegre - Porto Alegre - RS Paulo Márcio Pitrez - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Pedro Caruso - Universidade de São Paulo - São Paulo - SP Pedro Henrique Xavier Nabuco de Araújo - Universidade de São Paulo - São Paulo - SP Pedro Rodrigues Genta - Universidade de São Paulo - São Paulo - SP Pedro Schwartzmann - Universidade de São Paulo - Ribeirão Preto - SP Petrúcio Sarmento - Hospital Universitário de João Pessoa - João Pessoa - PB Rafael Futoshi Mizutani - Universidade de São Paulo - São Paulo - SP Rafael Stelmach - Universidade de São Paulo - São Paulo - SP Rafaela Garcia - Universidade de São Paulo - São Paulo - SP Rajesh Bhagat - University of Mississippi Medical Center - Mississippi - USA Ranniery Acuña - Hospital Militar Central - Bogota - Colombia Raquel Pastrello Hirata - Universidade de São Paulo - São Paulo - SP Raquel R. Britto - Universidade Federal de Minas Gerais - Belo Horizonte - MG Raquel Ramos - Instituto Nacional do Câncer - Rio de Janeiro - RS Regiani Oliveira - Universidade de São Paulo - São Paulo - SP Renata Leborato - Instituto do Câncer do Estado de São Paulo - São Paulo - SP Renata Vanelli - Universidade Federal de São Carlos - São Carlos - SP Renato Tetelbom Stein - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre - RS Ricardo de Amorim Corrêa - Universidade Federal de Minas Gerais - Belo Horizonte - MG Ricardo Luiz de Menezes Duarte - Universidade Federal do Rio de Janeiro - Rio de Janeiro - RJ Ricardo Mingarini Terra - Universidade de São Paulo - São Paulo - SP Ricardo Steffen - Universidade Federal do Estado do Rio de Janeiro - Rio de Janeiro - RJ Rita Mattiello - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Roberta Karla Barbosa de Sales - Universidade de São Paulo - São Paulo - SP Roberta Pulcheri Ramos - Universidade Federal de São Paulo - São Paulo - SP Roberto Stirbulov - Faculdade de Ciências Médicas da Santa Casa de São Paulo - São Paulo - SP Rodrigo Abensur Athanazio - Universidade de São Paulo - São Paulo - SP Rogelio Pérez-Padilla - National Institute of Respiratory Diseases of Mexico - México Rogerio Souza - Universidade de São Paulo, São Paulo - SP Rosana Camara Agondi - Universidade de São Paulo - São Paulo - SP Rosemeri Maurici - Universidade Federal de Santa Catarina - Florianópolis - SC Rui Haddad - Pontifícia Universidade Católica do Rio de Janeiro - Rio de Janeiro - RJ Samia Zahi Rached - Universidade de São Paulo - São Paulo - SP Sandra Lisboa - Instituto Nacional de Saúde da Mulher, Criança e Adolescente Fernandes Figueira - Rio de Janeiro - RJ Selma Rodrigues Castilho - Universidade Federal Fluminense - Rio de Janeiro - RJ Sergio Baldisserotto - Pontifícia Universidade Católica do Rio Grande do Sul - Porto Alegre - RS Sérgio Campainha - Centro Hospitalar Vila Nova de Gaia/Espinho - Portugal Sergio Furuie - Universidade de São Paulo - São Paulo - SP Sergio Nemer - Hopsital da Polícia Militar de Niterói - Niterói - RJ Sergio Paiva - Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu - SP Sérvulo Azevedo Dias-Júnior - Universidade Federal do Rio Grande do Norte - Natal - RN Silvana Spíndola de Miranda - Universidade Federal de Minas Gerais - Belo Horizonte - MG Simon Tiberi - Barts Health NHS Trust Infection - London Simone Chaves Fagondes - Universidade Federal do Rio Grande do Sul - Porto Alegre - RS Simone Dal Corso - Universidade Nove de Julho - São Paulo - SP Spencer Marcantonio Camargo - Irmandade da Santa Casa de Misericórdia de Porto Alegre - Porto Alegre - RS Stella Regina Martins - Universidade de São Paulo - São Paulo - SP Suelen Roberta Klein - Universidade de Passo Fundo - Passo Fundo - RS Suzana Erico Tanni - Universidade Estadual Paulista “Julio de Mesquita Filho” - Botucatu - SP Sylvia Luisa Pincherle Cardoso Leão - Universidade Federal de São Paulo - São Paulo - SP Tereza Cristina Scatena Villa - Universidade de São Paulo - Ribeirão Preto - SP Thais Mauad - Universidade de São Paulo - São Paulo - SP Timur Ekiz - Elbistan State Hospital - Turkey Tomás Pulido - Instituto Nacional de Cardiología Ignacio Chávez - México Ubiratan de Paula Santos - Universidade de São Paulo - São Paulo - SP Vera Capelozzi - Universidade de São Paulo - São Paulo - SP Veronica Moreira Amado - Universidade de Brasília - Brasília - DF Wladimir Musetti Medeiros - Universidade Federal de São Paulo - São Paulo - SP Yara Hahr Marques Hökerberg - Universidade Estácio de Sá - Rio de Janeiro - RJ

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J Bras Pneumol. 2017;43(6):497-500

INSTRUCTIONS FOR AUTHORS

The Jornal Brasileiro de Pneumologia (J Bras Pneumol, Brazilian Journal of Pulmonology) ISSN1806-3713, published once every two months, is the official organ of the Sociedade Brasileira de Pneumologia e Tisiologia (Brazilian Thoracic Society) for the publication of scientific papers regarding Pulmonology and related areas. After being approved by the Editorial Board, all articles will be evaluated by qualified reviewers, and anonymity will be preserved throughout the review process. Articles that fail to present merit, have significant errors in methodology or are not in accordance with the editorial policy of the journal will be directly rejected by the Editorial Board, with no recourse. Articles may be written in Portuguese, Spanish or English. In the online version of the Journal (www.jornaldepneumologia.com.br, ISSN1806-3756), all articles will be made available in Spanish or Portuguese, as well as in English. Authors may submit color figures. However, the cost of printing figures in color, as well as any related costs, will be borne by the authors. For further clarification, please contact the Journal Secretary by e-mail or by telephone. The Jornal Brasileiro de Pneumologia upholds the World Health Organization (WHO) and International Committee of Medical Journal Editors (ICMJE) policies regarding the registration of clinical trials, recognizing the importance of these initiatives for the registration and international, open-access dissemination of information on clinical trials. Therefore, as of 2007, the Journal only accepts clinical trials that have been given an identification number by one of the clinical trials registries meeting the criteria established by the WHO and the ICMJE. This identification number must be included at the end of the abstract. Within this context, the Jornal Brasileiro de Pneumologia adheres to the definition of a clinical trial as described by the WHO, which can be summarized as “any study that prospectively assigns human beings to be submitted to one or more interventions with the objective of evaluation the effects that those interventions have on health-related outcomes. Such interventions include the administration of drugs, cells and other biological products, as well as surgical procedures, radiological techniques, the use of devices, behavioral therapy, changes in treatment processes, preventive care, etc

Authorship criteria An individual may be considered an author of an article submitted for publication only if having made a significant intellectual contribution to its execution. It is implicit that the author has participated in at least one of the following phases: 1) conception and planning of the study, as well as the interpretation of the findings; 2) writing or revision of all preliminary drafts, or both, as well as the final revision; and 3) approval of the final version. Simple data collection or cataloging does not constitute authorship. Likewise, authorship should not be conferred upon technicians performing routine tasks, referring physicians, doctors who interpret routine exams or department heads who are not directly involved in the research. The contributions made by such individuals may be recognized in the acknowledgements. The accuracy of all concepts presented in the manuscript is the exclusive responsibility of the authors. The number of authors should be limited to eight, although exceptions will be made for manuscripts that are considered exceptionally complex. For manuscripts with more than six authors, a letter should be sent to the Journal describing the participation of each.

Presentation and submission of manuscripts All manuscripts must be submitted online from the home-page of the journal. The instructions for submission are available at: www.jornaldepneumologia.com.br/sgp. Although all manuscripts are submitted online, they must be accompanied by a Copyright Transfer Statement and Conflict of Interest Statement signed by all the authors based on the models available at: www.jornaldepneumologia.com.br. It is requested that the authors strictly follow the editorial guidelines of the journal, particularly those regarding the maximum number of words, tables and figures permitted, as well as the rules for producing the bibliography. Failure to comply with the author instructions will result in the manuscript being returned to the authors so that the pertinent corrections can be made before it is submitted to the reviewers. Special instructions apply to the preparation of Special Supplements and Guidelines, and authors should consult the instructions in advance by visiting the homepage of the journal. The journal reserves the right to make stylistic, grammatical and other alterations to the manuscript. With the exception of units of measure, abbreviations should be used sparingly and should be limited only to those that are widely accepted. These terms are defined in the List of Abbreviations and Acronyms accepted without definition in the Journal. Click here (List of Abbreviations and Acronyms). All other abbreviations should be defined at their first use. For example, use “C-reactive protein (CRP)”, and use “CRP” thereafter. After the definition of an abbreviation, the full term should not appear again. Other than those accepted without definition, abbreviations should not be used in titles, and their use in the abstracts of manuscripts should be avoided if possible. Whenever the authors mention any substance or uncommon piece of equipment they must include the catalogue model/number, name of manufacturer, city and country of origin. For example: “. . . ergometric treadmill (model ESD-01; FUNBEC, São Paulo, Brazil) . . .” In the case of products from the USA or Canada, the name of the state or province should also be cited. For example: “. . . guinea pig liver tTg (T5398; Sigma, St. Louis, MO, USA) . . .”

Manuscript preparation Title Page: The title page should include the title (in Portuguese and in English); the full names, highest academic degrees and institutional affiliations of all authors; complete address, including telephone number, fax number and e-mail address, of the principal author; and a declaration of any and all sources of funding. Abstract: The abstract should present the information in such a way that the reader can easily understand without referring to the main text. Abstracts should not exceed 250 words. Abstracts should be structured as follows: Objective, Methods, Results and Conclusion. Abstracts for review articles may be unstructured. Abstracts for brief communications should not exceed 100 words. Summary: An abstract in English, corresponding in content to the abstract in Portuguese, should be included. Keywords: Three to six keywords in Portuguese defining the subject of the study should be included as well as the

corresponding keywords in English. Keywords in Portuguese must be based on the Descritores em Ciência da Saúde (DeCS, Health and Science Keywords), published by Bireme and available at: http://decs.bvs.br, whereas keywords in English should be based on the National Library of Medicine Medical Subject Headings (MeSH), available at: http://www.nlm.nih.gov/mesh/MBrowser.html. Text: Original articles: For original articles, the text (excluding the title page, abstracts, references, tables, figures and figure legends) should consist of 2000 to 3000 words. Tables and figures should be limited to a total of five. The number of references should not exceed 30. Original articles should be divided into the following sections: Introduction, Methods, Results, Discussion, Acknowledgments, and References. The Methods section should include a statement attesting to the fact the study has been approved by the ethics in human research committee or the ethics in animal research committee of the governing institution. There should also be a section describing the statistical analysis employed, with the respective references. In the Methods and Results sections, subheadings may be used, provided that they are limited to a reasonable number. Subheadings may not be used in the Introduction or Discussion. 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. 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. Correspondence: Authors may submit comments and suggestions related to material previously published in our journal. Such submissions should not exceed 500 words. Imaging in Pulmonary Medicine: Submissions should not exceed 200 words, including the title, text, and references (no more than three). Authors may include up to three figures, bearing in mind that the entire content will be published on a single page. 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. Rogério Souza 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 (Assistente Editorial - Luana Campos) Online submission of articles: www.jornaldepneumologia.com.br

Estaduais da Sociedade Brasileira de Pneumologia e Tisiologia ASSOCIAÇÃO ALAGOANA DE DOENÇAS DO TÓRAX

SOCIEDADE DE PNEUMOLOGIA DO MATO GROSSO

ASSOCIAÇÃO CATARINENSE DE PNEUMOLOGIA E TISIOLOGIA

SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO MATO GROSSO DO SUL

Presidente: Secretário: Endereço: CEP: Telefone: E-mail: Presidente: Secretário: Endereço: CEP: Telefone: E-mail:

Tadeu Peixoto Lopes Artur Gomes Neto Rua Professor José Silveira Camerino, nº 1085 - Sala 501, Pinheiro, 57057-250- Maceió – AL (82) 30321967 (82) | (82) 996020949 sociedadealagoana.dt@gmail.com tadeupl@hotmail.com Márcio Andrade Martins Antônio Cesar Cavallazzi Rodovia SC, 401 Km 4 – 3854 - Saco Grande 88.032 - 005 - Florianópolis – SC (48) 32310314 acapti@acapti.org.br | www.acapti.org.br

ASSOCIAÇÃO DE PNEUMOLOGIA E CIRUGIA TORÁCICA DO ESTADO DO RIO GRANDE DO NORTE Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Paulo Roberto de Albuquerque Suzianne Ruth Hosannah de Lima Pinto Av. Campos Sales, 762 - Tirol 59.020-300 - Natal – RN (84) 32010367 – (84) 99822853 paulo213@uol.com.br

ASSOCIAÇÃO MARANHENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Maria do Rosario da Silva Ramos Costa Denise Maria Costa Haidar Travessa do Pimenta, 46 - Olho D‘Água 65.065-340 - São Luís – MA (98) 3226-4074 | Fax: (98) 3231-1161 rrcosta2904@gmail.com

ASSOCIAÇÃO PARAENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretária: Endereço: CEP: Tel: E-mail:

José Tadeu Colares Monteiro Lilian França dos Santos Monteiro Pereira Passagem Bolonha, 134, Bairro Nazaré 66053-060 - Belém – PA (91)989346998 spapnt@gmail.com | tadeucolares@hotmail.com

ASSOCIAÇÃO PIAUIENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Braúlio Dyego Martins Vieira Tatiana Santos Malheiros Nunes Avenida Jose dos Santos e Silva, 1903 Núcleo de Cirurgia Torácica 64001-300- Teresina – PI (86) 32215068 brauliodyego@gmail.com

SOCIEDADE AMAZONENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Secretário: Endereço: CEP: Telefone: E-mail:

José Correa Lima Netto Evandro de Azevedo Martins Av. Joaquim Nabuco, 1359, Centro – Hospital Beneficente Portuguesa – Setor Cirurgia Torácica 69020030 - Manaus – AM (92) 3234-6334 aapctmanaus@gmail.com

SOCIEDADE BRASILIENSE DE DOENÇAS TORÁCICAS Presidente: Secretário: Endereço: CEP: Tel/fax: E-mail:

Bianca Rodrigues Silva Edgar Santos Maestro Setor de Clubes Sul, Trecho 3, Conj. 6 70.200-003 - Brasília – DF (61) 3245-8001 sbdt@ambr.org.br

SOCIEDADE CEARENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretário: Endereço: CEP: Telefone: E-mail:

Mara Rúbia Fernandes de Figueiredo Thiago de Oliveira Mendonça Av. Dom Luis, 300, sala 1122, Aldeota 60160-230 - Fortaleza – CE (85) 3087-6261 - 3092-0401 assessoria@scpt.org.br | site: www.scpt.org.br

SOCIEDADE DE PNEUMOLOGIA DA BAHIA Presidente: Secretária: Endereço: CEP: Tel/fax: E-mail:

Guilherme Sóstenes Costa Montal Dalva Virginia Oliveira Batista Neves ABM - Rua Baependi,162. Sala 03 - Terreo - Ondina 40170-070 - Salvador – BA (71) 33326844 pneumoba@gmail.com | spba@outlook.com.br

SOCIEDADE DE PNEUMOLOGIA DO ESPÍRITO SANTO Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Cilea Aparecida Victória Martins Karina Tavares Oliveira Rua Eurico de Aguiar, 130, Sala 514 –Ed. Blue Chip. Praia do Campo 29.055-280 - Vitória – ES (27) 3345-0564 Fax: (27) 3345-1948 cilea38@hotmail.com

Presidente: Secretário: Endereço: CEP: Cidade: Telefone: E-mail:

Carlos Fernando Gossn Garcia Paulo Cesar da Silva Neves Av. Miguel Sutil, n 8000, Ed. Santa Rosa Tower, sala 1207. Bairro: Santa Rosa 78040-400 Cuiaba - MT (65) 99681445 cfggarcia@yahoo.com.br

Presidente: Henrique Ferreira de Brito Secretário: Luiz Armando Pereira Patusco Endereço: Rua 15 de novembro,2552 - Edifício One Offices Sala 901 CEP: 79020-300- Campo Grande - MS Telefone: (67)981628382 E-mail: hfbrito_med35@hotmail.com

SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO ESTADO DO RIO DE JANEIRO Presidente: Secretário: Endereço: CEP: Tel/fax: E-mail | Site:

Rogério Lopes Rufino Alves Alexandre Ciminelli Malizia Largo do Machado, 21 - GR. 08 - sala 914 - Catete 22221-020 - Rio de Janeiro – RJ (21) 3852-3677 sopterj@sopterj.com.br | www.sopterj.com.br

SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO RIO GRANDE DO SUL Presidente: Vice: Endereço: CEP: Telefone: E-mail:

Paulo Roberto Goldenfum Adalberto Sperb Rubin Av. Ipiranga, 5.311, sala 403 90.610-001 - Porto Alegre – RS (51) 3384-2889 Fax: (51) 3339-2998 sptrs.secretaria@gmail.com | www.sptrs.org.br

SOCIEDADE GOIANA DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Karla Cristina de Moraes Arantes Curado Roseliane de Souza Araújo Galeria Pátio 22 - Rua 22, nº 69, Sala 17 – Setor Oeste 74.120-130 - Goiânia – GO (62) 3251-1202 / (62) 3214-1010 sgpt2007@gmail.com | karlacurado1@hotmail.com

SOCIEDADE MINEIRA DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Secretária: Endereço: CEP: Tel/fax: E-mail | Site:

Rodrigo Luís Barbosa Lima Leonardo Brant Rodrigues Av. João Pinheiro, 161 - sala 203 - Centro 30.130-180 - Belo Horizonte – MG (31) 3213-3197 - (31)987978337 smpct@smpct.org.br | www.smpct.org.br

SOCIEDADE PARAIBANA DE PNEUMOLOGIA E CIRURGIA TORÁCICA Presidente: Ronaldo Rangel Travassos Júnior Secretária: Gerlânia Simplício Sousa Endereço: Rua José Florentino Jr. 333– Tambauzinho CEP: 58042-040 – João Pessoa – PB Telefone: (83)991219129 E-mail: rangelr@uol.com.br

SOCIEDADE PARANAENSE DE TISIOLOGIA E DOENÇAS TORÁCICAS Presidente: Secretária Geral: Endereço: CEP: Tel/fax: E-mail | Site:

Lêda Maria Rabelo Daniella Porfírio Nunes Av. Sete de Setembro, 5402 - Conj. 105, 10ª andar Batel 80240-000 - Curitiba – PR (41) 3342-8889 - (41)91794203 contato@pneumopr.org.br | www.pneumopr.org.br

SOCIEDADE PAULISTA DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Regina Maria de Carvalho Pinto Silvia Carla Sousa Rodrigues Rua Machado Bittencourt, 205, 8° andar, conj. 83 - Vila Clementino 04.044-000 São Paulo – SP 0800 17 1618 sppt@sppt.org.br | www.sppt.org.br

SOCIEDADE PERNAMBUCANA DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretária: Endereço: CEP: Tel/fax: E-mail:

Adriana Velozo Gonçalves Ana Lúcia Pereira Lima Alves Dias Rua João Eugênio de Lima , 235 - Boa Viagem 51030-360 - Recife – PE (81) 3326-7098 pneumopernambuco@gmail.com

SOCIEDADE SERGIPANA DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretário: Endereço: CEP: Telefone: E-mail:

Anaelze Siqueira Tavares Tojal Ostílio Fonseca do Vale Av. Gonçalo Prado Rollemberg, 211, Sala 11 Bairro São José 49050-370- Aracaju - SE (79) 21071412 anaelze.tojal@gmail.com

O ESTADO DE GOIÁS RECEBERÁ UMA ILUSTRE VISITA: O principal congresso brasileiro de pneumologia e tisiologia. A SBPT convida você a agregar novos conhecimentos através de uma grade cientíˋca cuidadosamente elaborada, que vai abranger a maioria das doenças do sistema respiratório junto com um renomado time de congressistas estrangeiros e nacionais. Será uma oportunidade única para você levar mais conhecimento para dentro do seu consultório e para seus pacientes, e também conhecer as belezas do Estado de Goiás, do dia 4 a 8 de agosto de 2018!

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XXXIX Congresso Brasileiro de Pneumologia e Tisiologia e XV Congresso Brasileiro de Endoscopia Respiratória CENTRO DE CONVENÇÕES DE GOIÂNIA/GO • DE 4 A 8 DE AGOSTO DE 2018.