JBP - Volume 42, number 4, July-August 2016 by Jornal Brasileiro Pneumologia

ISSN 1806-3713

Volume 42, Number 4

July | August 2016

www.jbp.org.br

Volume 42, Number 4 July | August 2016

HIGHLIGHT

Smoking control

Inflammatory profile in COPD patients

Radial-probe EBUS and peripheral pulmonary lesions

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.42, number 4, p. 237-306 July/August 2016 EDITOR-IN-CHIEF

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

EXECUTIVE EDITORS

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

Associação Brasileira de Editores Científicos

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 Álvaro A. Cruz - Universidade Federal da Bahia, Salvador, BA Andre Luis Pereira de Albuquerque - Universidade de São Paulo - São Paulo - SP Ascedio Jose Rodrigues - 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 Gilberto de Castro Junior - 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 Irma de Godoy - Universidade Estadual Paulista, Botucatu - SP Marcelo Alcântara Holanda - Universidade Federal do Ceará - Fortaleza - CE Oliver Augusto Nascimento - Universidade Federal de São Paulo - São Paulo - SP 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 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 Ana C. Krieger - New York School of Medicine, New York - USA Ana Luiza Godoy Fernandes - Universidade Federal de São Paulo, São Paulo - SP Antonio Segorbe Luis - Universidade de Coimbra, Coimbra - Portugal Brent Winston - Department of Critical Care Medicine, University of Calgary, Calgary - Canada Carlos Alberto de Assis Viegas - Universidade de Brasília, Brasília - DF Carlos 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 Chris T. Bolliger - University of Stellenbosch, Stellenbosch - South Africa Dany Jasinowodolinski - Universidade Federal 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 Gustavo Rodrigo - Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevidéu - Uruguay Ilma Aparecida Paschoal - Universidade de Campinas, Campinas - SP Isabela C. Silva - Vancouver General Hospital, Vancouver, BC - Canadá J. Randall Curtis - University of Washington, Seattle, Wa - USA John J. Godleski - Harvard Medical School, Boston, MA - USA José Alberto Neder - Universidade Federal de São Paulo, São Paulo - SP 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 - Hospital Clinic, Barcelona - España 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 Paul Noble - Duke University, Durham, NC - USA Paulo Francisco Guerreiro Cardoso - Universidade de São Paulo, São Paulo - SP Paulo Pego Fernandes - Universidade de São Paulo, São Paulo - SP Peter J. Barnes - National Heart and Lung Institute, Imperial College, London - UK Renato Sotto - Mayor - Hospital Santa Maria, Lisboa - Portugal Richard W. Light - Vanderbili University, Nashville, TN, USA Rik Gosselink - University Hospitals Leuven - Bélgica Robert Skomro - University of Saskatoon, Saskatoon - Canadá Rubin Tuder - University of Colorado, Denver, CO - USA 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 (2015-2016 biennium): President: Dr. Renato Maciel - MG Secretary-General: Dr. Paulo Henrique Ramos Feitosa - DF Director, Professional Advocacy: Dr. Jose Eduardo Delfini Cançado - SP CFO: Dr. Saulo Maia Davila Melo - SE Scientific Director: Dr. Miguel Abidon Aide - RJ Director, Education and Professional Practice: Dr. Clystenes Odyr Soares Silva - SP Director, Communications: Dra. Simone Chaves Fagondes - RS President, BTS Congress 2016: Marcus Barreto Conde - RJ President Elect (2017/2018 biennium): Fernando Luiz Cavalcanti Lundgren - PE Chairman of the Board: Jairo Sponholz Araújo (PR) AUDIT COMMITTEE: Active Members: Clóvis Botelho (MT), Benedito Francisco Cabral Júnior (DF), Rafael de Castro Martins (ES) Alternates: Maurício Meireles Góes (MG), Alina Faria França de Oliveira (PE), Paulo Cesar de Oliveira (MG) COORDINATORS, BTS DEPARTMENTS: Programmatic Initiatives – Alcindo Cerci Neto (PR) Thoracic Surgery – Darcy Ribeiro Pinto Filho (RS) Sleep–disordered Breathing – Marcelo Fouad Rabahi (GO) Respiratory Endoscopy – Mauro Musa Zamboni (RJ) Pulmonary Function – John Mark Salge (SP) Imaging – Bruno Hochhegger (RS) Lung Diseases – Ester Nei Aparecida Martins Coletta (SP) Clinical Research – Oliver Augusto Nascimento (SP) Pediatric Pulmonology – Paulo Cesar Kussek (PR) Residency – Alberto Cukier (SP) COORDINATORS, BTS SCIENTIFIC COMMITTEES: Asthma – Emilio Pizzichini (SC) Lung Cancer – Teresa Yae Takagaki (SP) Pulmonary Circulation – Carlos Viana Poyares Jardim (SP) Advanced Lung Disease – Dagoberto Vanoni de Godoy (RS) Interstitial Diseases – José Antônio Baddini Martinez (SP) Environmental and Occupational Respiratory Diseases – Ana Paula Scalia Carneiro (MG) COPD – Roberto Stirbulov (SP) Epidemiology – Frederico Leon Arrabal Fernandes (SP) Cystic Fibrosis – Marcelo Bicalho of Fuccio (MG) Respiratory Infections and Mycoses – Mauro Gomes (SP) Pleura – Roberta Karla Barbosa de Sales (SP) International Relations – José Roberto de Brito Jardim (SP) Smoking – Luiz Carlos Corrêa da Silva (RS) Intensive Care – Marco Antônio Soares Reis (MG) Tuberculosis – Fernanda Carvalho de Queiroz Mello (RJ) 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: 3.500 copies Distribution: Free to members of the BTS and libraries Printed on acid-free paper SUPPORT:

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Published once every two months J Bras Pneumol. v.42, number 4, p. 237-306 July/August 2016

EDITORIAL 237 - Eosinophils in COPD: why should I care? Frederico Leon Arrabal Fernandes

CONTINUING EDUCATION: IMAGING 239 - Conglomerate masses Edson Marchiori, Bruno Hochhegger, Gláucia Zanetti

CONTINUING EDUCATION: SCIENTIFIC METHODOLOGY 240 - Test for trend: evaluating dose-response effects in association studies Cecilia Maria Patino, Juliana Carvalho Ferreira

Contents

ORIGINAL ARTICLE 241 - Inflammatory and immunological profiles in patients with COPD: relationship with FEV1 reversibility Cleriston Farias Queiroz, Antonio Carlos Moreira Lemos, Maria de Lourdes Santana Bastos, Margarida Célia Lima Costa Neves, Aquiles Assunção Camelier, Natália Barbosa Carvalho, Edgar Marcelino de Carvalho 248 - Radial-probe EBUS for the diagnosis of peripheral pulmonary lesions Marcia Jacomelli, Sergio Eduardo Demarzo, Paulo Francisco Guerreiro Cardoso, Addy Lidvina Mejia Palomino, Viviane Rossi Figueiredo 254 - Growth, lung function, and physical activity in schoolchildren who were very-low-birth-weight preterm infants Aline Dill Winck, João Paulo Heinzmann-Filho, Deise Schumann, Helen Zatti, Rita Mattiello, Marcus Herbert Jones, Renato Tetelbom Stein 261 - Lack of association between viral load and severity of acute bronchiolitis in infants Ana Paula Duarte de Souza, Lidiane Alves de Azeredo Leitão, Fernanda Luisi, Rodrigo Godinho Souza, Sandra Eugênia Coutinho, Jaqueline Ramos da Silva, Rita Mattiello, Paulo Márcio Condessa Pitrez, Renato Tetelbom Stein, Leonardo Araújo Pinto 266 - STOP-Bang questionnaire: translation to Portuguese and cross-cultural adaptation for use in Brazil Lorena Barbosa de Moraes Fonseca, Erika Aparecida Silveira, Nathalia Meireles Lima, Marcelo Fouad Rabahi

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Published once every two months J Bras Pneumol. v.42, number 4, p. 237-306 July/August 2016

273 - Influence of heart failure on resting lung volumes in patients with COPD Aline Soares de Souza, Priscila Abreu Sperandio, Adriana Mazzuco, Maria Clara Alencar, Flávio Ferlin Arbex, Mayron Faria de Oliveira, Denis Eunan O’Donnell, José Alberto Neder 279 - Evaluation of pulmonary function and respiratory symptoms in pyrochlore mine workers Ritta de Cássia Canedo Oliveira Borges, José Cerqueira Barros Júnior, Fabrício Borges Oliveira, Marisa Andrade Brunherotti, Paulo Roberto Veiga Quemelo

BRIEF COMMUNICATION 286 - Recent transmission of drug-resistant Mycobacterium tuberculosis in a prison population in southern Brazil Ana Julia Reis, Simone Maria Martini de David, Luciana de Souza Nunes, Andreia Rosane de Moura Valim, Lia Gonçalves Possuelo

Contents

REVIEW ARTICLE 290 - Smoking control: challenges and achievements Luiz Carlos Corrêa da Silva, Alberto José de Araújo, Ângela Maria Dias de Queiroz, Maria da Penha Uchoa Sales, Maria Vera Cruz de Oliveira Castellano ; Comissão de Tabagismo da SBPT

LETTER TO THE EDITOR 299 - Resistance profile of strains of Mycobacterium fortuitum isolated from clinical specimens Debora Ribeiro de Souza Santos, Maria Cristina Silva Lourenço, Fábrice Santana Coelho, Fernanda Carvalho Queiroz Mello, Rafael Silva Duarte 302 - Management of pericardial cyst in the mediastinum: a single-port approach Dario Amore, Antonio Mazzella, Alessandro Izzo, Antonio Cennamo, Fabio Perrotta 304 - Not every irreversible airflow obstruction is COPD José Baddini-Martinez

CORRESPONDENCE 306 - The rapid shallow breathing index as a predictor of successful mechanical ventilation weaning: clinical utility when calculated from ventilator data Luiz Alberto Forgiarini Junior, Antonio M. Esquinas

J Bras Pneumol. 2016;42(4):237-238 http://dx.doi.org/10.1590/S1806-37562016000400001

EDITORIAL

Eosinophils in COPD: why should I care? Frederico Leon Arrabal Fernandes1

What defines a disease? Intuitively, it is very simple to differentiate between disease and health, but it is surprisingly difficult to define what “disease” is. Physicians are extensively trained to recognize signs and symptoms in patients and to attribute such signs and symptoms to a single disease. In practice, this unicist model transforms clinical findings into labels.(1) The problem is that, when patients are given labels, they receive standard treatments that often ignore the particularities of their cases. International consensus guidelines by the Global Initiative for Asthma and the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which cover asthma and COPD, respectively, have been of great value in systematizing care and standardizing the treatment of these conditions, but, in fact, they are simplifications of a multitude of clinical presentations that combine characteristics of both airway diseases. In an attempt to correct this inaccuracy, the concept of an overlap syndrome has been proposed: the asthma and COPD overlap syndrome (ACOS). Several criteria have been advocated to define patients as having ACOS, and the proportion of such cases can be as high as 30% among COPD patients. However, this new entity is just another simplification of a complex set of clinical characteristics, and its relevance has been questioned.(2) It has long been debated whether asthma and COPD are distinct diseases or two sides of the same coin. The presence of individuals in whom a diagnosis of either asthma or COPD cannot be established, as well as of individuals who present with characteristics of both diseases, reinforces the concept that asthma and COPD are spectra of the same disease. Not even biological markers, such as sputum examination, can definitively separate these two conditions. A recent study compared sputum characteristics in COPD and in asthma. It was possible to divide the results into three groups: one group with clear Th2 eosinophilic-predominant inflammation; one group with a neutrophil-predominant profile; and one group, comprising one third of the patients evaluated, in which there was no clear distinction between the two diagnoses.(3) Another study evaluated the presence of sputum eosinophilia in COPD patients, who were then treated with a systemic corticosteroid for two weeks.(4) Eosinophilia was a marker of clinical response to the corticosteroid. It has been demonstrated that a systematic evaluation of sputum eosinophilia can help to prevent exacerbations.(5) It has been established that there is a strong correlation between sputum eosinophilia and peripheral eosinophilia

in COPD.(6) Peripheral eosinophilia is a biomarker of response to inhaled corticosteroids (ICs). Subgroup analyses performed in three large-scale studies showed that the benefit of ICs in preventing exacerbations was found only in the subgroup of patients with an eosinophil count greater than 2%.(7) The response to ICs in terms of the rate of decline in pulmonary function also seems to be marked by eosinophilia. When treated with ICs, patients with an eosinophil count greater than 2% showed a marked reduction in the annual rate of decline in FEV1 (from 74.5 mL to 40.6 mL). In the absence of this marker, there was no change in the rate of decline in pulmonary function.(7) In their study published in this issue of the JBP, Queiroz et al.(8) investigated the inflammatory profile in the sputum from 37 patients with COPD, dividing them into those with and those without a bronchodilator response. The principal findings were as follows: patients with a bronchodilator response had greater sputum eosinophilia, regardless of an asthma diagnosis or clinical and laboratory markers of atopy (including the levels of measured cytokines); and the proportion of eosinophils in the sputum correlated inversely with FEV1, especially in patients with GOLD stage III COPD. Paradoxically, there were no eosinophils in the sputum from patients with GOLD stage IV COPD. Despite the limitations imposed by the cross-sectional design of and the small number of recruited patients to the study by Queiroz et al.,(8) its results lead to important considerations. The first of these considerations is that the evaluation of eosinophilia in COPD does not depend on an asthma diagnosis. The presence of eosinophils in the sputum, rather than being only another finding in patients with a history or characteristics of atopy, is a strong marker of severity and bronchodilator response. This underscores the need for laboratory characterization of the type of inflammatory process. Another interesting finding is that, in agreement with previous studies, the presence of eosinophils in the airway is associated with disease severity and progression, but, at some point in the natural history of COPD, the inflammatory process is reduced, with its markers becoming less evident as FEV1 decreases. This finding helps to demonstrate the complexity of COPD, which behaves differently and apparently in a contradictory manner, in the various stages of the disease. Because of that, clinical trials have shown the benefit of treatment of earlier disease (stages II or III) when the inflammatory process is intense.(9) Rather than labeling diseases, ignoring that variations of a rule are more common than the rule itself, we should understand that there are objective markers that help to

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Eosinophils in COPD: why should I care?

construct the clinical and laboratory profile, allowing the proper choice of treatment. Eosinophilia has been establishing itself as one of the most important markers. The approach to treating obstructive airway diseases based on labels disregards the biological complexity of these conditions and ignores the multiplicity of clinical presentations. It leads to underprescription or

overprescription of medications and limits the progress of research, given that patients who do not fit any one definition are excluded from clinical trials. By taking into account eosinophils in COPD, we are ensuring treatment with a higher likelihood of response and fewer adverse effects, thereby offering personalized quality medicine.(10)

REFERENCES 1. Scully JL. What is a disease? EMBO reports. 2004;5(7):650-3. http:// dx.doi.org/10.1038/sj.embor.7400195 2. Bujarski S, Parulekar AD, Sharafkhaneh A, Hanania NA. The asthma COPD overlap syndrome (ACOS). Curr Allergy Asthma Rep. 2015;15(3):509. http://dx.doi.org/10.1007/s11882-014-0509-6 3. Ghebre MA, Bafadhel M, Desai D, Cohen SE, Newbold P, Rapley L, et al. Biological clustering supports both “Dutch” and “British” hypotheses of asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2015;135(1):63-72. http://dx.doi.org/10.1016/j. jaci.2014.06.035 4. Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356(9240):1480-5. http:// dx.doi.org/10.1016/S0140-6736(00)02872-5 5. Siva R, Green RH, Brightling CE, Shelley M, Hargadon B, McKenna S, et al. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Resp J. 2007;29(5):906-13. http:// dx.doi.org/10.1183/09031936.00146306 6. Rufino R, Costa CH, Souza HS, Madi K, Silva JR. Induced sputum and

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peripheral blood cell profile in chronic obstructive pulmonary disease. J Bras Pneumol. 2007;33(5):510-8. 7. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3(6):435-42. http://dx.doi.org/10.1016/S2213-2600(15)00106-X 8. Queiroz CF, Lemos AC, Bastos ML, Neves MC, Camelier AA, Carvalho NB, et al. Inflammatory and immunological profiles in patients with COPD: relationship with FEV1 reversibility. J Bras Pneumol. 2016;42(4):241-7. 9. Eagan TM, Ueland T, Wagner PD, Hardie JA, Mollnes TE, Damas JK, et al. Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study. Eur Resp J. 2010;35(3):540-8. http:// dx.doi.org/10.1183/09031936.00088209 10. Agusti A, Anto JM, Auffray C, Barbe F, Barreiro E, Dorca J, et al. Personalized respiratory medicine: exploring the horizon, addressing the issues. Summary of a BRN-AJRCCM workshop held in Barcelona on June 12, 2014. Am J Respir Crit Care Med. 2015;191(4):391-401. http://dx.doi.org/10.1164/rccm.201410-1935PP

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J Bras Pneumol. 2016;42(4):239-239 http://dx.doi.org/10.1590/S1806-37562016000000161

Conglomerate masses Edson Marchiori1,2, Bruno Hochhegger3,4, Gláucia Zanetti2,5

A 37-year-old man presented with dry cough and progressive dyspnea on moderate and severe exertion. The patient worked as a sandblaster in a shipyard for fourteen years, and the final diagnosis was silicosis.

associated with masses of fibrous tissue, typically most marked in the upper lobes. Fibrotic masses are often associated with bronchial dilation. This combination is typical of sarcoidosis.

Conglomerate masses are basically caused by four diseases: talcosis; sarcoidosis; coal worker’s pneumoconiosis (CWP); and silicosis. Talcosis can be found in people who worked in talc mines and were engaged in milling, packaging, or transporting the product, as well as in soapstone workers. Another form of exposure is intravenous injection of drugs intended for oral use. An HRCT scan can show nodules, conglomerate perihilar masses, eventually containing areas of high attenuation caused by talc deposition, and panlobular emphysema in the lower lobes. These findings are highly suggestive of pulmonary talcosis.

As the name suggests, CWP results from inhalation of coal dust particles. The conglomerate masses seen in CWP are similar to those seen in silicosis. The presence of eggshell calcifications in patients with CWP indicates that there is a small amount of silica in the coal dust particles inhaled.

In sarcoidosis, progressive fibrosis also leads to abnormal central conglomeration of perihilar bronchi and vessels,

Figure 1. HRCT scan showing heterogeneous conglomerate masses in the upper lobes bilaterally, containing areas of architectural distortion and small adjacent nodules.

Silicosis is a chronic fibrosing lung disease caused by prolonged exposure to dusts containing free silica. The diagnosis of silicosis requires the combination of a history of exposure to silica and characteristic imaging findings. The classic radiological findings are small nodules, which tend to be located in the posterior upper lung zones but can be scattered over the lungs. These nodules can agglomerate, forming conglomerate masses. Calcifications can be seen in masses and in lymph nodes. Peripheral calcifications of lymph nodes—eggshell calcifications—are suggestive of silicosis. The association with tuberculosis is the most common cause of mass cavitation. Although the identification of conglomerate masses limits the diagnostic possibilities to the four aforementioned diseases, the clinical and occupational history is essential for the diagnostic conclusion. Not only the present occupational history but also the past occupational history is crucial for the final diagnoses of silicosis and CWP. With regard to talcosis, besides a possible occupational history (especially workers engaged in talc mining or packaging), the possibility of patients being drug users, especially those who inject drugs intended for oral use intravenously, leading to pulmonary embolization by the product, should be carefully evaluated. If the patient’s history does not include any of these characteristics, the most likely diagnosis is sarcoidosis.

RECOMMENDED READING 1. Webb WR, Muller NL, Naidich DP, editors. High-resolution CT of the lung. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

1. Universidade Federal Fluminense, Niterói (RJ) Brasil. 2. Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 3. Santa Casa de Misericórdia de Porto Alegre, Porto Alegre (RS) Brasil. 4. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre (RS) Brasil. 5. Faculdade de Medicina de Petrópolis, Petrópolis (RJ) Brasil. © 2016 Sociedade Brasileira de Pneumologia e Tisiologia

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J Bras Pneumol. 2016;42(4):240-240 http://dx.doi.org/10.1590/S1806-37562016000000225

Test for trend: evaluating dose-response effects in association studies Cecilia Maria Patino1,2, Juliana Carvalho Ferreira2,3 PRACTICAL SCENARIO In a prospective cohort study, the association between maternal stress and asthma in children was evaluated. The authors were interested in determining the effect that increasing levels of maternal stress has on the prevalence of asthma in offspring by 6 years of age. Maternal stress was measured using a questionnaire and categorized as 0, 1-2, 3-4, or ≥ 5 negative pre- and post-natal life events; asthma was diagnosed by physicians. The authors reported that increasing levels of maternal stress, compared with zero negative events, were associated with increasing odds of offspring having asthma during childhood: for 1-2 events, OR = 1.30 (95% CI: 0.72-2.37); for 3-4 events, OR = 1.92 (95% CI: 1.03-3.57); and for ≥ 5 events, OR = 3.52 (95% CI: 1.79-6.93). The p for trend (ptrend) was < 0.01 (Figure 1).

BACKGROUND When conducting studies that evaluate the association between a risk factor with more than two categories and with a natural ordering—in our example, maternal stress is an ordinal variable with four levels—we can choose to evaluate the association between each category of the risk factor and the outcome by comparing it with a reference 8 ptrend < 0.01

OR of asthma

level or determining whether increasing or decreasing levels of the risk factor are associated with increasing or decreasing levels of the outcome.(1,2) This analysis is called testing for dose-response or testing for trend of the effect of the risk factor on the outcome.(3) In our example, the authors were interested in determining whether an increasing number of maternal stressful life events was associated with increased odds of offspring being diagnosed with asthma. They first reported the effects that each level of maternal stress had on the diagnosis of asthma in offspring by reporting the OR and 95% CI compared with the lowest level of such stress; then, they reported the dose-response effect or trend of the effect of maternal stress on asthma in offspring by calculating and reporting the ptrend, which was statistically significant. If we consider the OR for each level of stress, compared with zero negative events, we see that all levels of exposure to maternal stress increased the risk of asthma in offspring (all ORs > 1.0), although only 3-4 events and ≥ 5 events were statistically significant, indicated by the fact that the corresponding 95% CI did not include 1.0. However, the ptrend indicates that increasing maternal stress across all levels increases the odds of physician-diagnosed asthma in offspring. Regression methods are commonly used to test for trend.(3) When reporting a test for trend, we usually list each category of the risk factor and the strength of the effect (i.e., odds ratio) of each category on the outcome compared with the reference level, the p value at each level, and additionally the ptrend. The ptrend is the unique information we need in order to determine whether there is a dose-response effect.

WHY TEST FOR TREND? 2

1-2 3-4 Stressful events

≥5

Figure 1. Association between the number of maternal preand post-natal stressful events and the odds of childhood asthma in offspring. Black squares represent ORs, and error bars are the 95% confidence intervals. A dose-response effect is confirmed with the test for trend (ptrend)(2).

As shown in our example, a test for trend can demonstrate a dose-response association between the risk factor and the outcome even if the association is not statistically significant for any particular level of exposure. Translated to clinical decision-making, knowledge of a dose-response association can help clinicians and patients understand that any increase in the level of exposure to a modifiable risk factor (e.g., maternal stress, cigarette smoking, and air pollution) increases the effect of that risk factor on a particular outcome.

RECOMMENDED READING 1. Lee A, Mathilda Chiu YH, Rosa MJ, Jara C, Wright RO, Coull BA, et al. Prenatal and postnatal stress and asthma in children: Temporal- and sex-specific associations. J Allergy Clin Immunol. Mar 4. pii: S0091-6749(16)00191-3. [Epub ahead of print] http://dx.doi.org/10.1016/j.jaci.2016.01.014 2. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95 Suppl 1:S144-50. http://dx.doi.org/10.2105/ AJPH.2004.059204 3. Vitinghoff E, Glidden DV, Shiboski ST, McCulloch. Regression Methods in Biostatistics. Linear, Logistic, Survival and Repeated Measure Models. 2nd ed. New York, NY: Springer; 2012. 1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 2. Methods in Epidemiologic, Clinical and Operations Research–MECOR–program, American Thoracic Society/Asociación Latinoamericana del Tórax. 3. Divisão de Pneumologia, Instituto do Coração – InCor – Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.

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J Bras Pneumol. 2016;42(4):241-247 http://dx.doi.org/10.1590/S1806-37562015000000122

ORIGINAL ARTICLE

Inflammatory and immunological profiles in patients with COPD: relationship with FEV1 reversibility Cleriston Farias Queiroz1, Antonio Carlos Moreira Lemos1, Maria de Lourdes Santana Bastos1, Margarida Célia Lima Costa Neves1, Aquiles Assunção Camelier2, Natália Barbosa Carvalho3 , Edgar Marcelino de Carvalho3 1. Serviço de Pneumologia, Ambulatório Magalhães Neto, Complexo Hospitalar Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador (BA) Brasil. 2. Universidade do Estado da Bahia, Salvador (BA) Brasil. 3. Serviço de Imunologia, Complexo Hospitalar Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador (BA) Brasil. Submitted: 25 May 2015. Accepted: 9 May 2016. Study carried out in the Serviço de Pneumologia, Ambulatório Magalhães Neto, Complexo Hospitalar Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador (BA) Brasil.

ABSTRACT Objective: To determine whether COPD severity correlates with sputum cell counts, atopy, and asthma. Methods: This was a cross-sectional study involving 37 patients with COPD and 22 healthy subjects with normal lung function (controls). Sputum cell counts were determined by microscopy after centrifugation of samples. Skin prick tests were performed, and serum cytokines were determined by ELISA. Results: Patients were stratified by bronchodilator response: a non-reversible airflow limitation (nonRAL) group comprised 24 patients showing no significant post-bronchodilator change in FEV1; and a partially reversible airflow limitation (partialRAL) group comprised 13 patients showing FEV1 reversibility (post-bronchodilator FEV1 increase ≥ 12%). The proportion of eosinophils in sputum was higher in the partialRAL group than in the nonRAL group (p < 0.01), and there was an inverse correlation between the proportion of eosinophils and FEV1 (p < 0.05). However, none of the patients had a history of asthma and skin prick test results did not differ between the two groups. In the patient sputum samples, neutrophils predominated. Serum levels of TNF, IL-6, IL-8, and RANTES (CCL5) were higher in patients than in controls (p < 0.001) but did not differ between the two patient groups. Conclusions: COPD patients with partial FEV1 reversibility appear to have higher sputum eosinophil counts and greater airway hyperresponsiveness than do those with no FEV1 reversibility. However, we found that COPD severity did not correlate with atopy or with the cytokine profile. Keywords: Pulmonary disease, chronic obstructive; Cytokines; Chemokines; Eosinophils; Sputum/cytology; Forced expiratory volume.

INTRODUCTION COPD is an inflammatory disorder that affects the airways, pulmonary parenchyma, and pulmonary vessels, progressing slowly to irreversible airway obstruction. Although studies have shown that neutrophil and eosinophil counts are both elevated during COPD exacerbations, neutrophilic inflammation is the norm in COPD.(1) However, even in the stable phase of the disease, eosinophils are found in up to 40% of patients.(2) It is thought that this feature is related to a COPD subtype—COPD with asthma, also known as the asthma-COPD overlap syndrome.(2) Patients with that syndrome show FEV1 reversibility after bronchodilator use. The inflammatory response of the airways has received special attention in recent years.(3,4) Levels of inflammatory mediators such as C-reactive protein, IL-8, IL-6, TNF, and RANTES (CCL5) have been found to be elevated in COPD.(5-7) In addition, neutrophil counts are higher in smokers with COPD, as are levels of IL-8 and eosinophil cationic protein.(4) According to Lapperre et al.,(8) it is possible that inflammation associated with

smoking occurs in two stages: an initial phase, during which neutrophils and macrophages are present in the epithelium and submucosa, and a late stage, with the additional participation of lymphocytes and eosinophils. Nevertheless, the association between COPD and asthma has been controversial, and the influence that eosinophils have on airway inflammation and on the severity of COPD is not completely understood. The severity of airflow obstruction can be determined by quantifying the magnitude of the decrease in FEV1, and the stages of COPD are based on the post-bronchodilator FEV1.(9) Once the diagnosis of COPD has been made, pulmonary function tests are useful for quantitative monitoring of the course of the disease. To determine the severity of COPD, FEV1 and its reversibility are reconciled with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification.(10) The aim of the present study was to determine whether COPD severity correlates with FEV1 reversibility, asthma, and atopy. In addition, we evaluated the relationship between serum cytokine levels and COPD subtypes based on FEV1 reversibility.

Correspondence to:

Cleriston Farias Queiroz. Serviço de Pneumologia, Ambulatório Magalhães Neto, Complexo Hospitalar Universitário Professor Edgard Santos, Rua Padre Feijó, 240, Canela, CEP 40110-170, Salvador, BA, Brasil. Tel.: 55 71 3283-8378. Fax: 55 71 3237-5353. E-mail: cleri2107@yahoo.com.br Financial support: None. © 2016 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Inflammatory and immunological profiles in patients with COPD: relationship with FEV1 reversibility

METHODS This was a cross-sectional study involving 37 patients diagnosed with COPD on the basis of the GOLD criteria.(11) All patients were under treatment in the Pulmonology Department of Professor Edgard Santos University Hospital, in the city of Salvador, Brazil. The study was approved by the Research Ethics Committee of the Hospital (Protocol no. 113/2012), and all participating patients gave written informed consent. All of the patients completed questionnaires designed to evaluate the history of asthma in childhood, smoking, passive smoking, and allergic rhinitis. All patients also underwent physical examinations and pulmonary function tests with an emphasis on the functional parameters FEV1, FVC, and FEV1/FVC ratio. According to the GOLD criteria,(11) an FEV1/FVC ratio ≤ 70% of the predicted value is diagnostic of COPD. Spontaneous or induced sputum samples were obtained, skin prick tests were performed in order to assess sensitivity to allergens, and 10-mL blood samples were collected for determination of serum cytokine levels. A group of 22 healthy subjects without COPD (with normal lung function) were used as controls. On the basis of the pulmonary function test parameters established in the 2010 GOLD guidelines and the response to bronchodilator, the COPD patients were divided into two groups: non-reversible airflow limitation (nonRAL), comprising the patients who showed no significant post-bronchodilator change in FEV1 (n = 24); and partially reversible airflow limitation (partialRAL), comprising the patients who showed FEV1 reversibility (n = 13). Post-bronchodilator FEV1 reversibility was defined as a ≥ 12% increase in FEV1, as proposed in the joint American Thoracic Society (ATS)/European Respiratory Society (ERS)/ GOLD guidelines.(12) The control group was composed of (N = 22) healthy subjects without COPD and with normal lung function. All patients underwent spirometry in accordance with the ATS/ERS/GOLD joint guidelines.(12) Bronchodilator testing was performed with 100 µg/mL of albuterol sulfate (Aerolin® [Ventolin®]; GlaxoSmithKline Brasil Ltda., Rio de Janeiro, Brazil). In brief, four puffs (400 µg/mL) were administered with the aid of a spacer (Fumax®; GlaxoSmithKline Brasil Ltda.). At 15 min after administration of the bronchodilator, the pulmonary function tests were repeated. Patients were submitted to the immediate hypersensitivity skin prick tests, as described by Pepys et al.(13) and modified by Osterbalee and Weeke.(14) The allergens tested included dog dander, cat dander, airborne fungi (Aspergillus fumigatus), cockroach allergens (from Blattella germanica and Periplaneta americana), and dust mite allergens (from Dermatophagoides pteronyssinus and Blomia tropicalis). Reagents were obtained from Immunotech ([a division of] FDA Allergenic Ltda., Rio de Janeiro, Brazil). Sputum induction was performed in accordance with the modified protocol described by Pavord et al.,(15) with 242

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inhalation of hypertonic saline solution (3%, 4%, and 5%) in an ultrasonic nebulizer (Fisoneb®; Canadian Medical Products, Ltd, Markham, Ontario, Canada) at a low flow rate (0.87 L/min). Peripheral blood samples (10 mL each) were centrifuged at 2,000 rpm for 10 min. Serum was collected and stored at −20°C for subsequent cytokine measurements. Cytokines and chemokines were quantified by sandwich ELISA according to the manufacturer’s protocol (R&D Systems, Minneapolis, MN, USA). To quantify TNF and IL-6, we used high sensitivity kits (Quantikine HS ELISA; R&D Systems). To quantify RANTES (CCL5) and IL-8, we used DuoSet ELISA kits (R&D Systems). In the statistical analysis, we used measures of central tendency, including means and medians, for demographic and clinical variables. Data were analyzed using the Statistical Package for the Social Sciences, version 17.0 for Windows (SPSS Inc., Chicago, IL, USA). The values obtained for the variables body mass index, SpO2, and lung function, which typically have a normal distribution, were analyzed with Student’s t-tests. For the comparison between sputum cell counts and the stages of COPD severity, we used the Mann-Whitney test. The correlation between eosinophils in sputum and FEV1 (before and after bronchodilator use) was analyzed by Spearman’s correlation coefficient. The comparisons among the nonRAL, partialRAL, and control groups, in terms of cytokine production, sputum cell counts, and COPD severity, were made with the Kruskal-Wallis test, followed by Dunn’s post-test for multiple comparisons. RESULTS

Characteristics of the sample The demographic features, smoking status, and pulmonary function test results of the COPD patients, by group (with or without post-bronchodilator FEV1 reversibility), are shown in Table 1. There were no differences between the two patient groups regarding age, gender, or smoking status. There were also no differences between the two groups in terms of the body mass index, SpO2, or age at the onset of symptoms. All patients in the sample had an FEV1/FVC ratio ≤ 70% of the predicted value. The median values for pre- and post-bronchodilator FEV1 were 48.2% (range, 30-66%) and 51% (range, 35-71%), respectively, in the nonRAL group, compared with 35% (range, 28-44%) and 47% (range, 36-52%), respectively, in the partialRAL group (p < 0.04), whereas they were 79% (range, 65-82%) and 84% (range, 69-89%), respectively, in the control group. None of the control subjects were smokers or former smokers.

COPD severity, sputum cell counts, and atopy As can be seen in Table 2, the severity of COPD was assessed in accordance with the 2010 GOLD guidelines. The 24 patients in the nonRAL group were fairly equally distributed among the COPD stages II, III, and IV, whereas 12 (92.3%) of the 13 patients in

Queiroz CF, Lemos ACM, Bastos MLS, Neves MCLC, Camelier AA, Carvalho NB, Carvalho EM

the partialRAL group were categorized as having stage III COPD. Although neutrophil counts increased in proportion with the severity of COPD, eosinophils were not detected in patients with stage IV COPD (data not shown). In both patient groups, we performed differential counts of neutrophils and eosinophils in the sputum samples (Table 2). The neutrophil counts did not differ between the two groups (p > 0.05). However, the median eosinophil count was significantly higher in the partialRAL group than in the nonRAL group (p < 0.01). In our evaluation of atopy, with the skin prick test, we found no difference between the two patient groups in terms of positivity for any of the antigens tested (Table 2). Of the 24 patients in the nonRAL group, 5

(21%) had at last one positive test, compared with 4 (31%) of the 13 patients in the partialRAL group (p > 0.05). Moreover none of the patients in either patient group had a history of asthma. In 2 of the patients in the nonRAL group, the response to histamine was negative.

Relationship between the proportion of eosinophils and FEV1

The relationship between the proportion of eosinophils in the sputum and FEV1 (before and after bronchodilator use) is shown in Figure 1. There was an inverse relationship between the proportion of eosinophils in the sputum and FEV1 before and after bronchodilator use (p < 0.01).

Table 1. Demographic, clinical, and pulmonary function characteristics of patients with COPD.a

Characteristic

Gender, n (%) Male Female Age, years Smoking, n (%) Former smokers, n (%) Body mass index, kg/m2 SpO2, % Age at symptom onset, years FEV1/FVC ratio, % of predicted Pre-BD Post-BD FEV1, % of predicted Pre-BD Post-BD FVC, % of predicted Pre-BD Post-BD

Group

RAL non (n = 24)

RAL partial (n = 13)

11 (45.8) 13 (54.2) 66 (57-73) 8 (27.3) 16 (72.7) 22 (19-25) 96 (94-97) 54 (42-58)

6 (46.2) 7 (53.8) 69 (59-76) 4 (30.8) 9 (69.2) 18 (18-21) 95 (93-97) 55 (43-56)

64 (53-70) 66 (51-62)

59 (53-69) 62 (57-68)

0.44

48 (30-66) 51 (35-71)

35 (28-42) 40 (35-50)

0.04

69 (57-84) 76 (64-89)

58 (53-66) 69 (59-77)

0.06

0.72 0.88 0.67 0.43 0.001 0.93 0.97

RAL: non-reversible airflow limitation; partialRAL: partially reversible airflow limitation; and BD: bronchodilator. Values expressed as median (interquartile range), except where otherwise indicated. *Studentâ&#x20AC;&#x2122;s t-test (twotailed); level of statistical significance set at p < 0.05.

non a

Table 2. Cell counts in induced sputum samples, by COPD stage, and results of allergy testing in patients with COPD, by group.a

Variable

Group

GOLD stage II III IV Skin prick test Positive Negative Proportion of neutrophilsb Proportion of eosinophilsb

RAL (n = 24)

RAL (n = 13)

6 (27.3) 12 (45.5) 6 (27.3)

0 (0.0) 12 (92.3) 1 (7.7)

0.03 0.77 0.43

5 (20.8) 17 (70.8) 38 (24-52) 0 (0-7)

4 (30.8) 9 (69.2) 37 (26-47) 9 (2-15)

0.58 0.09 0.67 0.01

non

partial

RAL: non-reversible airflow limitation; partialRAL: partially reversible airflow limitation; and GOLD: Global Initiative non for Chronic Obstructive Lung Disease. aValues expressed as n (%). bValues expressed as median (interquartile range). *Mann-Whitney test (two-tailed); level of statistical significance set at p < 0.05. J Bras Pneumol. 2016;42(4):241-247

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Inflammatory and immunological profiles in patients with COPD: relationship with FEV1 reversibility

DISCUSSION COPD is a severe progressive inflammatory disease and is the fourth leading cause of death in the United States.(16) The prevalence of and mortality associated with COPD continue to rise. In addition, COPD has become a major cause of death and disability worldwide.(17) Two COPD subtypes, based on FEV1 reversibility, have recently been identified. Here, we attempted to determine whether those subtypes are associated with sputum cell counts, cytokine levels, and symptom severity. We found that COPD patients with reversibility of FEV1 had higher sputum eosinophil counts and greater airway hyperresponsiveness than did those without such reversibility, and that there was an inverse correlation between the proportion of eosinophils in the sputum and the FEV1 before and after bronchodilator use. Furthermore, we showed that COPD with FEV1 reversibility was not associated with atopy or asthma. In fact, our findings corroborate those of previous studies showing that, although IL-6, IL-8 and TNF levels are higher in COPD patients than in healthy subjects, the production of those cytokines is comparable between the two types of COPD. Historically, the incidence of COPD has been highest among males and among smokers. However, the proportional representation of women has been increasing.(18) In addition, a marked female predominance has been reported among patients with an early onset of severe COPD.(19) In the present study, the proportional distribution of males and females was 244

J Bras Pneumol. 2016;42(4):241-247

similar between the two patient groups, as was the proportion of smokers. The analysis of sputum is an useful tool in the evaluation of inflammation of the airways.(15) Induced sputum was initially used for the diagnosis of lung cancer and later for infectious diseases. In the early 1990s, this method was employed in the investigation of bronchial inflammation associated with asthma.(20) More recently, because of its safety, reproducibility and low cost, it has been used for investigation of the pathogenesis of asthma and COPD. Local neutrophil recruitment in inflammation is a hallmark of COPD, as is an increase in the levels of inflammatory mediators in the airways and in circulating blood.(21) The release of neutrophil elastase, acid phosphatase, and myeloperoxidase that occurs during neutrophilic inflammation is characteristic of COPD.(22-24) Neutrophils are the predominant cells in the sputum of COPD patients, and high proportions of neutrophils were found in the sputum of the patients in both of the COPD groups evaluated in the present study.(3) However, it is also possible that the hypertonic 30 % of Eosinophils in induced sputum

The cytokine and chemokine levels in the nonRAL group, partialRAL group, and control group are shown in Figure 2. The median TNF levels were 2.9 pg/mL (range, 0.95-6.03 pg/mL) in the nonRAL group and 3.2 pg/mL (range, 2.65-5.50 pg/mL) in the partialRAL group, both of which were significantly higher than the 0.35 pg/mL (range, 0-1.9 pg/mL) observed for the controls (p < 0.01). The median IL-6 levels were also significantly higher in the nonRAL group, and partialRAL group than in the control groupâ&#x20AC;&#x201D;1.4 pg/mL (range, 0.42-2.10 pg/mL) and 0.92 pg/mL (range, 0.37-1.89 pg/mL), respectively, versus 0 pg/mL (p < 0.01). In addition, IL-8 levels were significantly higher in the RAL group than in the control group (p < 0.05) and non RANTES (CCL5) levels did not differ significantly between the two patient groups or between either patient group and the control group (p > 0.05 for all). As depicted in Figure 2, the median IL-8 values for the nonRAL, RAL, and control groups were 0 (range, 0-57.50), 0 partial (range, 0-51.75), and 0 (range, 0-0), respectively, the difference between the nonRAL group and the control group being statistically significant (p < 0.05). There were no statistical differences among the three groups in terms of the serum levels of RANTES (CCL5; Figure 2). The severity of COPD did not correlate significantly with the serum levels of TNF, IL-6, IL-8, or RANTES (CCL5; data not shown).

25 20 15 10 5 Linear R2 = 0.088

0 30

FEV1 before BD (%) 30 % of Eosinophils in induced sputum

Immunological profile

25 20 15 10 5 Linear R2 = 0.151

0 40

FEV1 after BD (%) Figure 1. Scatter plots showing the proportion of eosinophils in induced sputum and the FEV1 of COPD patients with nonreversible airflow limitation or partially reversible airflow limitation, before and after bronchodilator (BD) use (A and B, respectively). Statistics derived by Spearmanâ&#x20AC;&#x2122;s correlation coefficient; level of statistical significance set at p < 0.05.

Queiroz CF, Lemos ACM, Bastos MLS, Neves MCLC, Camelier AA, Carvalho NB, Carvalho EM

† 40

30 20

400

200

10 0 HC (n = 22)

RAL (n = 24) non

RAL (n = 13) partial

HC (n = 22)

RAL non (n = 24)

RAL partial (n = 13)

HC (n = 22)

RAL non (n = 24)

RAL partial (n = 13)

†

‡

D 2500

30 20

2000

10 6

CCL5 (pg/mL)

IL-6 (pg/mL)

600

† IL-8 (pg/mL)

TNF- (pg/mL)

1500 1000 500

0 HC (n = 20)

RAL (n = 24) non

RAL (n = 13) partial

Figure 2. Dot plots of serum levels of the cytokines TNF (A), IL-6 (B), and IL-8 (C), as well as those of RANTES (CCL5; D), in healthy controls (HC), COPD patients with non-reversible airflow limitation (nonRAL), and COPD patients with partially reversible airflow limitation (partialRAL). *p < 0.05, †p < 0.01, and ‡p < 0.001; Kruskal-Wallis test followed by Dunn’s post-test for multiple comparisons.

saline solution used for the induced sputum techniques contributes to increasing the number of neutrophils.(25) The role that eosinophils in the sputum play in COPD is not clear. It was once thought that the presence of eosinophils was related to a subgroup of COPD patients with features of asthma(2,5) and that it was associated with a better response to corticosteroid therapy.(26) In fact, an association between asthma and COPD would further the development of strategies for the therapeutic management of COPD.(27,28) However, our data argue against the occurrence of asthma in patients who show post-bronchodilator FEV1 reversibility. None of our patients had a personal or family history of asthma, and the prevalence of atopy, as determined with the skin prick test, was comparable between the two patient groups. In addition, the immunological profile (cytokine and chemokine production) was similar in the two groups, and there was no increase in RANTES (CCL5), which is a typical Th2 cytokine in COPD patients with post-bronchodilator FEV1 reversibility. In a previous study, we found an association between nasal eosinophils and atopy in patients with COPD.(29) However, in the present study, the presence of eosinophils in the sputum was not found to be associated with atopy

or asthma. Although the role that eosinophils play in COPD is not completely understood, we observed that eosinophil counts were increased in COPD patients with post-bronchodilator FEV1 reversibility. We also identified an inverse correlation between the proportion of eosinophils in the sputum and the decrease in FEV1. Although our findings might suggest that eosinophils are related to the severity of COPD, no eosinophils were found in the sputum of the patients with stage IV COPD. It is possible that, as in the later stages of the disease, the numbers of inflammatory cells are decreased in that phase of the disease. Increased levels of IL-6, IL-1β, TNF, and IL-8 have been observed in the induced sputum of patients with stable COPD.(5) There is also evidence of a relationship between elevated cytokine levels in COPD and cigarette smoking.(6,30) However, the relationship that chemokines have with eosinophils in the sputum or with FEV1 reversibility has not been evaluated. Serum IL-6 is considered the best biomarker of COPD severity when associated with the degree of airway obstruction and has been associated with mortality.(7) We found that the severity of COPD did not correlate with the serum levels of IL-6, IL-8, TNF, or RANTES (CCL5). In the J Bras Pneumol. 2016;42(4):241-247

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Inflammatory and immunological profiles in patients with COPD: relationship with FEV1 reversibility

present study, it was possible to evaluate the levels of cytokines (IL-6 and TNF) and chemokines—IL-8 and RANTES (CCL5)—in COPD patients with and without FEV1 reversibility after bronchodilator use. However, the cytokine and chemokine levels were similar between the two patient groups. Eosinophilic airway inflammation has been associated with COPD exacerbations.(31) A reduction in sputum eosinophil counts has been associated with a reduction in COPD exacerbations.(31) Because this was a cross-sectional study, we did not assess the relationship between the inflammatory response and exacerbation. However, we found an association between eosinophil inflammation and airway obstruction. That supports the relationship between eosinophilic airway inflammation and COPD exacerbation,(31) as well as the association between the peripheral blood eosinophil count and death from exacerbations of COPD.(32)

One limitation of the present study is the small number of participants. However, it is clear that patients in the partialRAL group had greater airway hyperresponsiveness. In addition, the observation that COPD with FEV1 reversibility was not related to asthma but was associated with increased numbers of eosinophils in the sputum, together with the inverse correlation observed between the proportion of eosinophils in the sputum and FEV1, suggests that eosinophils play an important role in the inflammatory response in COPD patients with post-bronchodilator FEV1 reversibility. Our data do not support the occurrence of asthma-COPD overlap syndrome in patients who show airway responsiveness to bronchodilator use. Although we cannot rule out the possibility that eosinophilic inflammation is a subtype of COPD, our data indicate that it is a phase of the disease that is associated with greater airway obstruction.

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Queiroz CF, Lemos ACM, Bastos MLS, Neves MCLC, Camelier AA, Carvalho NB, Carvalho EM

27. Kanazawa M. Diseases to differentiate from COPD, with emphasis on bronchial asthma [Article in Japanese]. Nihon Rinsho. 2007;65(4):675-81. 28. Miravitlles M, Morera J. Itâ&#x20AC;&#x2122;s time for an aetiology-based definition of chronic obstructive pulmonary disease. Respirology. 2007;12(3):3179. http://dx.doi.org/10.1111/j.1440-1843.2007.01082.x 29. Neves MC, Neves YC, Mendes CM, Bastos MN, Camelier AA, Queiroz CF, et al. Evaluation of atopy in patients with COPD. J Bras Pneumol. 2013;39(3):296-305. http://dx.doi.org/10.1590/S180637132013000300006 30. Kuschner WG, Dâ&#x20AC;&#x2122;Alessandro A, Wong H, Blanc PD. Dose-dependent

cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J. 1996;9(10):1989-94. http://dx.doi.org/10.1183/0903193 6.96.09101989 31. Siva R, Green RH, Brightling CE, Shelley M, Hargadon B, McKenna S, et al. Eosinophilic airway inflammation and exacerbations of COPD: a randomized controlled trial. Eur Respir J. 2007;29(5):906-13. http:// dx.doi.org/10.1183/09031936.00146306 32. Hospers JJ, Schouten JP, Weiss ST, Rijcken B, Postma DS. Asthma attacks with eosinophilia predict mortality from chronic obstructive pulmonary disease in a general population sample. Am J Respir Crit Care Med. 1999;160(6):1869-74. http://dx.doi.org/10.1164/ ajrccm.160.6.9811041

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ORIGINAL ARTICLE

Radial-probe EBUS for the diagnosis of peripheral pulmonary lesions Marcia Jacomelli1, Sergio Eduardo Demarzo1, Paulo Francisco Guerreiro Cardoso2, Addy Lidvina Mejia Palomino1, Viviane Rossi Figueiredo1

1. Serviço de Endoscopia Respiratória, Divisão de Pneumologia, Instituto do Coração – InCor – Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. 2. Departamento de Cardiopneumologia, Disciplina de Cirurgia Torácica, Instituto do Coração – InCor – Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. Submitted: 10 April 2015. Accepted: 2 July 2015. Study performed at the Serviço de Endoscopia Respiratória, Instituto do Coração–InCor–Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

ABSTRACT Objective: Conventional bronchoscopy has a low diagnostic yield for peripheral pulmonary lesions. Radial-probe EBUS employs a rotating ultrasound transducer at the end of a probe that is passed through the working channel of the bronchoscope. Radial-probe EBUS facilitates the localization of peripheral pulmonary nodules, thus increasing the diagnostic yield. The objective of this study was to present our initial experience using radial-probe EBUS in the diagnosis of peripheral pulmonary lesions at a tertiary hospital. Methods: We conducted a retrospective analysis of 54 patients who underwent radial-probe EBUS-guided bronchoscopy for the investigation of pulmonary nodules or masses between February of 2012 and September of 2013. Radial-probe EBUS was performed with a flexible 20-MHz probe, which was passed through the working channel of the bronchoscope and advanced through the bronchus to the target lesion. For localization of the lesion and for collection procedures (bronchial brushing, transbronchial needle aspiration, and transbronchial biopsy), we used fluoroscopy. Results: Radial-probe EBUS identified 39 nodules (mean diameter, 1.9 ± 0.7 cm) and 19 masses (mean diameter, 4.1 ± 0.9 cm). The overall sensitivity of the method was 66.7% (79.5% and 25.0%, respectively, for lesions that were visible and not visible by radialprobe EBUS). Among the lesions that were visible by radial-probe EBUS, the sensitivity was 91.7% for masses and 74.1% for nodules. The complications were pneumothorax (in 3.7%) and bronchial bleeding, which was controlled bronchoscopically (in 9.3%). Conclusions: Radial-probe EBUS shows a good safety profile, a low complication rate, and high sensitivity for the diagnosis of peripheral pulmonary lesions. Keywords: Diagnostic techniques, respiratory system; Lung/ultrasonography; Bronchoscopy/ methods; Bronchoscopy/instrumentation.

INTRODUCTION Bronchoscopy has been used worldwide for the diagnosis of pulmonary nodules and centrally located masses. However, for the diagnosis of smaller lesions, the reported sensitivity of routine bronchoscopy remains low (34%; range, 5-76%), albeit higher for larger lesions (63%; range, 31-82%).(1) The use of fluoroscopic guidance increases the diagnostic accuracy of conventional bronchoscopy from 14% to 71%, depending on factors such as location of the nodule, lesion size, presence of the bronchus sign, and other technical aspects of the procedure.(2) However, fluoroscopy has some limitations, because it is not a tridimensional method and there is therefore no guarantee that the lesion is adequately sampled, as well as because it exposes patients to radiation. Although transthoracic needle aspiration (TTNA) has been shown to have excellent diagnostic sensitivity (approximately 90% in most studies), it can provoke pneumothorax or bleeding, requiring interventions such as chest tube drainage and transfusion (7% and 18%, respectively), which are a serious concern in clinical practice.(3-5)

Radial-probe EBUS has emerged as a widely accepted procedure that can increase sensitivity and accuracy for the diagnosis of peripheral pulmonary nodules.(6-8) Radial-probe EBUS can precisely locate pulmonary nodules or masses based on differences in echogenicity between normal lung parenchyma and the lesion itself. Studies have shown that radial-probe EBUS improves diagnostic rates for peripheral pulmonary nodules, particularly for lesions smaller than 2 cm in diameter. Although it is not mandatory, the routine use of fluoroscopy plus radial-probe EBUS has been shown to produce better results than does either technique alone.(9-11) The aim of this study was to evaluate our initial experience in using radial-probe EBUS for the diagnosis of peripheral pulmonary lesions in a tertiary hospital setting. METHODS This was a retrospective, cross-sectional analysis of radial-probe EBUS procedures performed in patients with peripheral pulmonary nodules or masses who were seen at the Heart Institute of the University of São Paulo

Correspondence to:

Marcia Jacomelli. Serviço de Endoscopia Respiratória, Instituto do Coração – InCor– Hospital das Clínicas, Rua Dr. Enéas de Carvalho Aguiar, 44, Bloco II, Andar Térreo (CAPI – guichê 13), Cerqueira César, CEP 05403-000, São Paulo, SP, Brasil. Tel.: 55 11 2661-5612. E-mail: jacomelli.marcia@yahoo.com.br Financial support: None.

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School of Medicine Hospital das Clínicas, in the city of São Paulo, Brazil, between February of 2012 and September of 2013. The data were obtained from the Heart Institute database. The study was approved by the Hospital das Clínicas Research Ethics Committee. To measure the lesion and locate the corresponding bronchial segment, CT scans of the chest were evaluated. The inclusion criterion was the referral for the diagnosis of an indeterminate pulmonary nodule or mass. Patients were excluded if an endobronchial lesion was observed during conventional bronchoscopy or if they were lost to follow-up. Patients with pulmonary masses (defined as lesions with a diameter greater than 3 cm) were referred for radial-probe EBUS if a previous bronchoscopy was nondiagnostic.

completion of the conventional bronchoscopy, a 20-MHz radial probe (UM-3R; Olympus Medical Systems Corp.) was inserted through the 2.8-mm working channel of the bronchoscope toward the lesion in the lung parenchyma (Figure 1). In most cases, fluoroscopy was used in order to check the position of the probe after its correct positioning (within or adjacent to the lesion) had been ascertained by radial-probe EBUS (Figures 2 and 3). Thereafter, collection procedures were performed, such procedures including bronchial brushing, for cytology; transbronchial needle aspiration (TBNA), using a 21-gauge needle, for cytological and cell-block analysis; and transbronchial biopsy (TBB), for histological analysis. When infectious disease (especially granulomatous disease) was suspected, BAL fluid was collected for microbiological analysis.

All radial-probe EBUS procedures were preceded by conventional bronchoscopy with a flexible bronchoscope (BF-1T180; Olympus Medical Systems Corp., Tokyo, Japan), in order to access the airways and identify any endobronchial lesions. All patients were under conscious sedation (with midazolam and fentanyl) and topical anesthesia (with 1% lidocaine). Upon

Sample collection followed standardized routine protocols.(6) Biopsy fragments were transported in 10% formaldehyde; TBNA aspirates were handled carefully to ensure that an adequate amount of material was sent for analysis (mounting on glass slides for cytology, fixation in formaldehyde for cell-block analysis, and, when necessary, storage in a sterile device for

Figure 1. Radial-probe EBUS: (a) probe drive unit; (b) distal end of the radial probe outside the bronchoscope; c) radial probe being inserted into the working channel of the bronchoscope; and d) bronchoscopic image of the probe within the segmental bronchus. J Bras Pneumol. 2016;42(4):248-253

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Figure 2. Comparison between CT and radial-probe EBUS: a) CT of the chest, showing a 2.4 cm nodule in the left upper lobe; and (b) radial-probe EBUS image with well-defined, echogenic borders (probe positioned within the lesion). The final diagnosis in this case was non-small cell lung cancer (squamous cell lung carcinoma).

Figure 3. Comparison between CT and radial-probe EBUS: a) CT of the chest, showing a 2.5 cm nodule in the middle lobe; and (b) radial-probe EBUS image with the probe positioned adjacent to the lesion. The final diagnosis in this case was non-small cell lung cancer (adenocarcinoma).

microbiology); and samples obtained by bronchial brushing were mounted on glass slides for direct examination.(12) Rapid on-site evaluation (ROSE) was used in order to determine the quality of the cytology specimens obtained from some patients. The radial-probe EBUS procedure was considered successful if it resulted in the specific diagnosis of malignancy or inflammatory processes. The procedure was also classified as a success if a lesion determined to present nonspecific benign disease by radial-probe EBUS was subsequently proven to be benign by further investigation, or if the lesion remained stable for six months on CT scans.

Statistical analysis Sensitivity was calculated as the number of successful diagnoses made by radial-probe EBUS-guided bronchoscopy, divided by the total number of procedures. We performed descriptive analysis of absolute and relative frequencies. Patients with pulmonary nodules and patients with pulmonary masses were compared 250

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by Fisherâ&#x20AC;&#x2122;s exact test. The IBM SPSS Statistics software package, version 19.0 (IBM Corporation, Armonk, NY, USA) was used for all analysis. RESULTS A total of 54 patients underwent flexible bronchoscopy with radial-probe EBUS. There was predominance of females, who accounted for 57.4% of the sample, and the mean patient age was 64.8 Âą 11.1 years (range, 43-87 years). Three patients (5.5%) were excluded because they were lost to follow-up, and a final diagnosis was therefore neither obtained nor confirmed for those patients. Consequently, we analyzed 51 patients, of whom 37 (72.5%) were referred for the investigation of pulmonary nodules and 14 (27.5%) were referred for the investigation of pulmonary masses. The overall sensitivity of radial-probe EBUS was 66.7% for the diagnosis of pulmonary nodules or masses (Table 1). The pulmonary lesions were visible and not visible by radial-probe EBUS in 39 patients (76.5%) and 12

Jacomelli M, Demarzo SE, Cardoso PFG, Palomino ALM, Figueiredo VR

patients (23.5%), respectively, the latter category including 10 nodules (1.3 ± 0.6 cm) and 2 masses (3.7 ± 0.7 cm). The sensitivity of the procedure was 79.5% and 25.0% for the diagnosis of lesions that were visible and not visible by radial-probe EBUS, respectively (p = 0.005).

Nodules Among the 37 patients referred for the investigation of pulmonary nodules, the nodules were visible by radial-probe EBUS in 27 (73.0%). The probe was positioned adjacent to the lesion in 17 (63.0%) of those 27 cases. Comparing the cases in which the probe was positioned adjacent to the lesion and those in which it was positioned within the lesion, we found that the mean size of the nodules was significantly smaller in the former group (1.7 ± 0.3 cm vs. 2.3 ± 0.3 cm, p = 0.033). Among those same 27 cases, the diagnosis was obtained by radial-probe EBUS and confirmed surgically in 20 (74.1%), compared with only 3 (30.0%) of the 10 cases in which the nodule was not visible by radial-probe EBUS (Table 1). Malignant nodules were found in 14 (51.8%) of the 27 cases, with a predominance of non-small cell lung cancer. The radial-probe EBUS results were positive in 10 (71.4%) of those 14 malignant nodules. The bronchus sign was present on CT scans in 16 (59.3%) of the 27 cases. Neither bronchus sign nor probe location were found to correlate with the final diagnosis (p = 0.895). In 15 patients (56.0%), cytology specimens were submitted to ROSE, the results of which were positive in 8 (54.0%) of those 15. Fluoroscopic guidance was possible in 16 (59.3%) of the 27 patients with nodules that were visible by radial-probe EBUS.

Masses Lesions that were visible by radial-probe EBUS were identified in 12 (85.7%) of the 14 patients referred for the investigation of pulmonary masses. Among those 12 patients, a definitive diagnosis was obtained in 11 (91.7%), 10 (83.3%) being diagnosed with tumors and 1 (8.3%) being diagnosed with bronchiolitis obliterans organizing pneumonia. In 9 (75.0%) of those same

12 cases, CT showed the bronchus sign, and the radial probe was positioned within the lesion in all 12 cases. Fluoroscopic guidance was used in 7 (58.3%). In 10 (83.3%) of the 12 cases, cytology specimens were submitted to ROSE, the results of which were positive in 8 (80.0%) of the 10. A definitive diagnosis was obtained by TTNA in only 1 patient (8.3%). The final diagnoses and sensitivity of radial-probe EBUS are summarized in Table 2.

Complications Procedure related complications occurred in 7 (13.0%) of the 54 patients. Pneumothorax requiring chest tube drainage occurred in 2 (3.7%) and moderate bleeding occurred in 5 (9.3%) and were managed with topical application of cold saline solution with epinephrine. All complications occurred in patients with pulmonary nodules. DISCUSSION This is a report of our initial experience with radial-probe EBUS for the diagnosis of peripheral pulmonary lesions in patients treated in Brazil. Since 2001, when it was introduced into clinical practice, radial-probe EBUS has been used as an adjunct to TBB and to other bronchoscopic procedures for the evaluation of peripheral pulmonary lesions. The equipment consists of a thin, flexible catheter with a small probe at the end that can capture 360° ultrasound images of the lung parenchyma and the target lesion. Although it is easy to perform, radial-probe EBUS requires training because the operator must visually differentiate among normal lung parenchyma, vessels, and specific intrapulmonary lesions (e.g., nodules and masses). Pulmonary lesions are hypoechoic and usually have sharply defined borders, due to the strong reflective interface between the aerated lung and the lesion itself. Radial-probe EBUS can be a valuable tool for localizing pulmonary lesions and guiding tissue sampling, particularly for small nodules.(8,13,14) In a prospective randomized trial,(13) the diagnostic accuracy of radial-probe EBUS-guided TBB was found

Table 1. Visibility of lesions on radial-probe EBUS, lesion size, and diagnostic sensitivity.

Visibility All lesions n (%) Size (cm), mean ± SD Identified by radial-probe EBUS, n (sensitivity) Lesions visible by radial-probe EBUS n (%) Size (cm), mean ± SD Identified by radial-probe EBUS, n (sensitivity) Lesions not visible by radial-probe EBUS n (%) Size (cm), mean ± SD Identified by radial-probe EBUS, n (sensitivity)

(N = 51)

Pulmonary lesions Nodules Masses

2.5 ± 1.3 34 (66.7%)

37 (72.5) 1.9 ± 0.7 23 (62.2%)

14 (27.5) 4.1 ± 0.9 11 (78.6%)

39 (76.5) 2.6 ± 1.2 31 (79.5%)

27 (69.2) 1.9 ± 0.7 20 (74.1%)

12 (30.8) 3.9 ± 0.9 11 (91.7%)

12 (23.5) 1.6 ± 1.1 3 (25.0%)

10 (83.3) 1.3 ± 0.6 3 (30.0%)

2 (16.7) 3.7 ± 0.7 0 (0.0)

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Table 2. Final diagnoses of the lesions that were visible by radial-probe EBUS and sensitivity of the procedure.

Diagnosis

Pulmonary lesions Nodules

Malignancy Non-small cell lung cancer Small cell lung cancer Adenoid cystic carcinoma Hamartoma Metastatic breast cancer Tuberculosis or fungal infection Inflammatory disease Nonspecific benign disease Total

Sensitivity N diagnosed (%) 10 (71.4) 7 (70.0) 2 (100.0) 1 (100.0) 0 (0.0)

4 (14.8) 3 (11.1) 6 (22.2) 27 (100.0)

2 (50.0) 3 (100.0) 6 (100.0) 20 (74.1)

to be similar to that of CT-guided TTNA (87.5% and 93.3%, respectively), although the complication rate was significantly higher in the latter (27% vs. 3%). Paone et al. demonstrated that radial-probe EBUS-guided TBB has a sensitivity of 75% and 71% for detecting lesions that are < 2 cm and < 3 cm in diameter, respectively, compared with 31% and 23%, respectively, for conventional TBB.(15) The authors also found that, although radial-probe EBUS-guided TBB and fluoroscopy-guided bronchoscopic biopsy provide comparable results, the radiation exposure associated with the latter constitutes a major disadvantage. Our preliminary experience with radial-probe EBUS indicates that the procedure has high sensitivity for nodules and masses (74.1% and 92%, respectively), which is in agreement with the findings of other studies.Â (16) Various studies have focused on factors affecting the diagnostic yield of radial-probe EBUS, such factors including nodule size, the capacity to visualize the lesion, and whether the probe is positioned within the lesion. Huang et al.(17) found that lesion size and ultrasound visualization were important factors for the diagnostic yield. Steinfort et al.(13) reported higher diagnostic accuracy when the probe was positioned within the lesion. In our study, nodules were visible by radial-probe EBUS in 27 (73%) of the 37 cases and the probe was positioned within the nodule in 10 (37%). The sensitivity of the procedure tripled for lesions that were visible by radial-probe EBUS compared to those that were not visible (73% vs. 25%). The diagnostic sensitivity was also better for masses than for nodules (92% vs. 74%). The presence of the bronchus sign can also influence the results of radial-probe EBUS. In the present study, this finding correlated to a better diagnostic sensitivity as reported by other authors.(18) The bronchus sign was seen in 9 (75.0%) of the 12 patients with pulmonary masses that were visible by radial-probe EBUS, and the position of the lesion was determined by the radial probe. Among the pulmonary nodules that were visible by radial-probe EBUS, the bronchus sign was seen in 16 (59.3%), although no correlation was found between 252

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Masses

Cases N (%) 14 (51.8) 10 (37.0) 2 (7.4) 1 (3.7) 1 (3.7)

Cases N (%) 10 (83.3) 8 (66.7) 1 (8.3)

Sensitivity N diagnosed (%) 9 (90.0) 7 (87.5) 1 (100.0)

1 (8.3)

1 (100.0)

2 (16.7)

2 (100.0)

12 (100.0)

11 (91.7)

the presence of the bronchus sign, the position of the probe or the diagnosis. In 2004, Kurimoto et al.(8) reported the use of a guide sheath, which is a flexible guide catheter that acts like an extension to the working channel of the bronchoscope. The guide sheath is left in place at the target site after the radial probe has been retracted. It is radiopaque and allows biopsy, brushing, or needle aspiration in the regions of interest defined by the radial-probe EBUS. It also enables repeat collection procedures to be performed at those same sites and minimizes the associated risk of bleeding. Some studies have shown that using a guide sheath during radial-probe EBUS-guided TBB provides higher diagnostic yields for pulmonary masses and nodules,(12-15) especially for smaller lesions. In our study, we did not use a guide sheath, because the device is still awaiting regulatory approval for use in Brazil. The differential diagnosis between malignancy and infectious disease is important in Brazil. In the present study, we identified non-neoplastic disease in 13 (48.1%) of the 27 pulmonary nodules that were visible by radial-probe EBUS and in 2 (16.7%) of the 12 pulmonary masses that were visible by radial-probe EBUS, the final diagnoses including fungal infections and tuberculosis. Those diagnoses were subsequently confirmed by surgical methods, and the patients were treated accordingly. It is important to include infectious diseases, especially tuberculosis, in the differential diagnosis of pulmonary nodules and masses. Our study has limitations. Due to the small sample size, we analyzed the various bronchoscopic methods (BAL, TBB, Brush, and needle aspiration) collectively, rather than separately. It is important to standardize the procedure; to choose the best method to use in each case; to collect as much material as possible; and to send the material for cytological, cell-block, histological, and microbiological analysis, as needed, although such tests are not universally available. In our patients, the cell-block analysis of material obtained from needle aspiration was important for the diagnosis, particularly in pulmonary nodules. Three

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of our patients were lost to follow-up reducing the sample size. In addition, fluoroscopy and ROSE were not employed in all cases. In general, EBUS is a safe procedure with a low complication rate. Steinfort et al.(13) studied the effectiveness and complications of radial-probe EBUSguided TBB, in comparison with those of CT-guided TTNA. They found that the incidence of pneumothorax was much higher in CT-guided TTNA, and that the diagnostic accuracy of radial-probe EBUS-guided TBB

was comparable to CT-guided TTNA. In our study, we found that pneumothorax requiring chest tube drainage occurred in only approximately 4% of the patients, and that bleeding (mild to moderate), which was controlled with local hemostatic measures, occurred in less than 10% of the patients. All such complications occurred in patients with pulmonary nodules. In conclusion, radial-probe EBUS showed a good safety profile and a high diagnostic yield for peripheral pulmonary masses and nodules.

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J Bras Pneumol. 2016;42(4):254-260 http://dx.doi.org/10.1590/S1806-37562015000000159

ORIGINAL ARTICLE

Growth, lung function, and physical activity in schoolchildren who were very-low-birthweight preterm infants Aline Dill Winck1,2, João Paulo Heinzmann-Filho3, Deise Schumann4, Helen Zatti4, Rita Mattiello3,5, Marcus Herbert Jones3,5, Renato Tetelbom Stein3,5 1. Universidade de Caxias do Sul, Caxias do Sul (RS) Brasil. 2. Rede Metodista de Educação do Sul – IPA – Porto Alegre (RS) Brasil. 3. Programa de Pós-Graduação em Pediatria e Saúde da Criança, Centro Infant, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. 4. Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. 5. Faculdade de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. Submitted: 6 July 2015. Accepted: 3 January 2016. Study carried out under the auspices of the Programa de Pós-Graduação em Pediatria e Saúde da Criança, Centro Infant, Instituto de Pesquisas Biomédicas, and at Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil.

ABSTRACT Objective: To compare somatic growth, lung function, and level of physical activity in schoolchildren who had been very-low-birth-weight preterm infants (VLBWPIs) or normal-birth-weight full-term infants. Methods: We recruited two groups of schoolchildren between 8 and 11 years of age residing in the study catchment area: those who had been VLBWPIs (birth weight < 1,500 g); and those who had been normal-birth-weight full-term infants (controls, birth weight ≥ 2,500 g). Anthropometric and spirometric data were collected from the schoolchildren, who also completed a questionnaire regarding their physical activity. In addition, data regarding the perinatal and neonatal period were collected from the medical records of the VLBWPIs. Results: Of the 93 schoolchildren screened, 48 and 45 were in the VLBWPI and control groups, respectively. No significant differences were found between the groups regarding anthropometric characteristics, nutritional status, or pulmonary function. No associations were found between perinatal/neonatal variables and lung function parameters in the VLBWPI group. Although the difference was not significant, the level of physical activity was slightly higher in the VLBWPI group than in the control group. Conclusions: Among the schoolchildren evaluated here, neither growth nor lung function appear to have been affected by prematurity birth weight, or level of physical activity. Keywords: Premature birth; Birth weight; Respiratory function tests; Motor activity; Pediatrics.

INTRODUCTION Surfactant therapy and prenatal steroid use have been reported to result in a significant reduction in mortality among very-low-birth-weight (VLBW) infants.(1) However, many preterm infants require prolonged oxygen supplementation or mechanical ventilation, which can lead to irreversible damage to the lung parenchyma.(2) Controversy remains regarding the effects of prematurity, low birth weight, and certain neonatal factors on lung function in school-age children, despite the fact that several studies have examined this issue. Although some studies have shown a reduction in FEV1, FVC, and lung volumes in preterm infants,(3,4) others have shown preserved lung function during childhood.(5,6) To date, there have been no studies conducted in Brazil and evaluating lung function in school-age children who were VLBW infants. In preterm infants, the natural development of the lungs and airways is affected by the fact that part of the process of lung development occurs after birth.(7) In an immature respiratory system, remodeling patterns occur in accordance with the affected developmental stage.(8) Previous studies have shown that neonatal and perinatal factors can trigger a sequence of events that

can affect lung structures and increase the incidence of respiratory disease.(7,9) Among school-age children, the risk of health complications and delayed development is higher in those who were preterm infants and in those born at extremely low birth weight than in those who were full-term infants.(10) In addition, studies suggest that, in preterm infants, catch-up growth is delayed and the risk of growth restriction in the first years of life is high,(11,12) and that the subnormal weight and height observed in the first months of life can persist throughout childhood, adolescence, and adulthood.(13) In the last two decades, there has been a significant reduction in the level of physical activity and an increase in sedentary behavior among pediatric patients.(14,15) This can be attributed to changes in the types of activities in which young people engage, active activities involving increased energy expenditure having been replaced with long hours spent using the computer, playing video games, and watching television.(14) However, there is currently little information regarding the level of physical activity among schoolchildren who were preterm infants, low-birth-weight infants, or both.(16,17)

Correspondence to:

Aline Dill Winck. Rua Santo Antônio, 924, apto. 601, CEP 90220-010, Porto Alegre, RS, Brasil. Tel.: 55 54 8100-5757. E-mail: alinelem@yahoo.com.br Financial support: None.

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The present study was motivated by the contradictory findings regarding lung function in school-age children who were low-birth-weight preterm infants, the possibility of retardation of growth (weight and height) in such children, and the significant changes in the types of activities in which they engage. The specific objectives of the study were to evaluate growth, lung function, and the level of physical activity in schoolchildren who were in the 8- to 11-year age bracket and who had been VLBW preterm infants and to compare their growth, lung function, and level of physical activity with those of schoolchildren who were in the same age bracket and who had been normal-birth-weight (NBW) full-term infants. METHODS This was a case-control study. The study included schoolchildren who were in the 8- to 11-year age bracket at the time of the study, who had been preterm infants whose birth weight was ≤ 1,500 g, and who had been admitted to the Caxias do Sul General Hospital Neonatal ICU, in the city of Caxias do Sul, Brazil, between January of 2001 and December of 2005. For logistical reasons, only children residing in municipalities located within up to 100 km of Caxias do Sul were invited to participate in the study. Prospective participants were contacted by telephone. The control group comprised children who had been full-term infants (≥ 37 weeks of gestational age) whose birth weight was ≥ 2,500 g, who had no respiratory symptoms, as determined by the International Study of Asthma and Allergies in Children questionnaire,(18) and who were recruited from among those attending public schools in Caxias do Sul. Children with heart disease, those with neuromuscular disease, those with cognitive limitations, and those who were unable to perform spirometry were excluded from the study. Data were collected by two trained researchers at the University of Caxias do Sul in the period between July and December of 2013. The study was approved by the Research Ethics Committee of the Pontifical Catholic University of Rio Grande do Sul (Protocol no. 12323413.7.0000.5336), located in the city of Porto Alegre, Brazil, and the parents or legal guardians of the children who agreed to participate in the study gave written informed consent. Data regarding the perinatal and neonatal periods for the children who had been VLBW preterm infants (the VLBWPI group) were collected from the neonatal ICU database. We collected data on the following variables: use of antenatal corticosteroids; premature rupture of membranes; duration of oxygen therapy; length of hospital stay; birth weight; use of continuous positive airway pressure; hyaline membrane disease; and surfactant use. Weight was measured with a digital scale (Glass 1 FW; G-Tech, Rio de Janeiro, Brazil), and height was measured with a portable stadiometer (Alturaexata; TBW, São Paulo, Brazil). On the basis of height and

weight, nutritional status was normalized to heightfor-age, weight-for-age, and BMI-for-age Z scores.(19) Spirometry was performed with a portable spirometer (Koko; Ferraris Respiratory, Louisville, CO, USA). All tests were performed in accordance with the American Thoracic Society standards and acceptability and reproducibility criteria.(20) The children were verbally encouraged to perform a maximal expiratory maneuver at maximal effort following a maximal inspiratory maneuver.(20) The following spirometric parameters were assessed: FVC; FEV1; and FEF25-75%. The results were expressed as absolute values and normalized to Z scores.(21) The level of physical activity was assessed by an adapted questionnaire consisting of items regarding the activities performed in the last seven days.(14) The questionnaire gathered information on the type of activity, time spent commuting to school, work, or both, and frequency of/time spent in leisure-time physical activity. On the basis of their level of physical activity, the schoolchildren were classified as active (> 300 min/week) or inactive (≤ 300 min/week); those who were classified as having sedentary behaviors were subdivided into two groups, on the basis of their daily screen time (> 2 h/day or ≤ 2 h/day).(22) A sample of 25 individuals per group was calculated to be sufficient to detect a 14% difference in percent predicted FEV1, a standard deviation of 12% for the control group and of 17% for the VLBWPI group being assumed (on the basis of a previous study, with a power of 90% and a significance level of 5%).(23) Given the possibility of losses, the number of individuals per group was increased to 30, totaling 60 participants. The study variables were assessed by the Kolmogorov-Smirnov test. Variables with normal distribution were expressed as mean and standard deviation, whereas those with non-normal distribution were expressed as median and interquartile range. Categorical variables were expressed as absolute and relative frequencies. The study outcomes were compared between the two groups by the Student’s t-test for independent samples, the Wilcoxon U test, and Pearson’s chi-square test. Univariate and multivariate linear regression models were used in order to evaluate the association between outcome variables (FEV1, FVC, and FEF25-75%) and predictor variables (birth weight, length of hospital stay, gestational age, premature rupture of membranes, use of surfactant, use of antenatal corticosteroids, duration of oxygen therapy, duration of mechanical ventilation, use of continuous positive airway pressure, and hyaline membrane disease). All analyses were performed with the Statistical Package for the Social Sciences, version 18.0 (SPSS Inc., Chicago, IL, USA), and differences were considered significant at p < 0.05. RESULTS Of the 338 VLBW preterm infants admitted to the neonatal ICU during the data collection period, 219 (64.79%) survived. Of those, 91 (41.55%) were J Bras Pneumol. 2016;42(4):254-260

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located, and only 62 (28.31%) were selected for the study. Figure 1 shows the data regarding the selection of participants in the VLBWPI group. Of the 62 VLBW preterm infants selected, 7 were excluded because of technically inadequate spirometry tests and 7 were excluded because of cognitive deficits that prevented them from undergoing spirometry. Therefore, 48 (77.41%) participated in the study. Table 1 shows the information regarding the perinatal and neonatal periods for the VLBWPI group. There were no significant differences between the individuals who were included in the VLBWPI group and those who were not regarding neonatal and perinatal factors. In addition to the individuals who were selected for inclusion in the VLBWPI group, 52 controls were selected. Of those, 5 were excluded because they failed spirometry and 2 were excluded because they had cognitive deficits, a total of 45 controls (86.53%) being included in the study. Therefore, the final study sample consisted of 93 children: 48 in the VLBWPI 338 VLBWPIs admitted to the neonatal ICU 119 deaths (35.2%) 219 eligible infants 63 residing outside the study catchment area 156 participants 65 (41.7%) were not located 91 were located

62 were selected

5 deaths 6 residing outside the study catchment area 18 did not agree to participate in the study 14 were excluded at study enrollment

48 were evaluated Figure 1. Flowchart of inclusion and exclusion of very-lowbirth-weight preterm infants (VLBWPIs).

group and 45 in the control group. There were no significant differences between the two groups regarding anthropometric characteristics or nutritional status (Table 2). With regard to lung function data, there were no significant differences between the VLBWPI group and the control group regarding mean spirometric variables (Table 3). Most of the study sample had normal spirometric values, i.e., Z scores above −1.645 for the variables analyzed. In the VLBWPI group, 6 participants had reduced FEV1. Mean gestational age (28.1 ± 0.9 weeks; p = 0.006) and mean birth weight (1,015.0 ± 122.7 g; p = 0.008) were significantly lower in those 6 than in the remaining 42 participants in the VLBWPI group. Although there were differences regarding the length of hospital stay [median number of days = 54.0 (42.0-66.0); p = 0.249] and the need for oxygen therapy for more than 28 days [n = 3 (60%); p = 0.083], they were not significant. The univariate and multivariate linear regression analyses revealed no significant associations of perinatal and neonatal factors with lung function data in the schoolchildren in the present study. Table 4 shows the associations found in the univariate analysis. With regard to the level of physical activity, 34 (36.5%) of the participants were classified as active, and 59 (63.4%) were classified as inactive. Although the level of physical activity was slightly higher in the VLBWPI group than in the control group, the difference was not significant (p = 0.055; Figure 2A). In the VLBWPI and control groups, the most common leisure-time physical activities were soccer (37.5% vs. 22.2%; p = 0.108), running (27.9% vs. 22.2%; p = 0.936), and cycling (14.6% vs. 31.1%; p = 0.057). The mean time spent in active commuting was 20.55 ± 5.89 min and 19.75 ± 6.78 min (p = 0.737), respectively. Finally, although screen time was found to be > 2 h/ day in 90 (96.7%) of the participants, there were no significant differences (p = 0.596) between the VLBWPI group and the control group regarding daily screen time (Figure 2B).

Table 1. Comparison of perinatal and neonatal variables between the very-low-birth-weight preterm infants who were included in the present study and those who were not.a

Variable Antenatal corticosteroid use Surfactant use HMD MV PROM Oxygen therapy > 28 days CPAP Length of hospital stay, daysb Birth weight, gc Gestational age, weeksc

Included in the study (n = 48) 31 (64.6) 31 (64.6) 34 (70.8) 31 (64.6) 06 (12.5) 09 (18.7) 27 (56.2) 46.0 (35.5-60.0) 1.210.42 ± 168.72 30.4 ± 4.5

Not included in the study (n = 171) 100 (58.5) 100 (58.5) 112 (65.5) 100 (58.5) 25 (14.6) 38 (22.2) 105 (61.4) 43.0 (36.0-57.0) 1.226.07 ± 210.85 32.0 ± 5.8

p 0.379 0.349 0.324 0.349 0.720 0.623 0.317 0.571 0.278 0.615

HMD: hyaline membrane disease; MV: mechanical ventilation; PROM: premature rupture of membranes; and CPAP: continuous positive airway pressure. aValues expressed as n (%), except where otherwise indicated. bValues expressed as median (interquartile range). cValues expressed as mean ± SD.

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Table 2. Comparison of anthropometric characteristics and nutritional status between the schoolchildren who had been very-low-birth-weight preterm infants and those who had been normal-birth-weight full-term infants (controls).a

Variable Age, years Height, cm Height-for-age, Z score Weight, kg Weight-for-age, Z score BMI, kg/m2 BMI-for-age, Z score

Controls (n = 45)

(n = 48)

VLBWPIs

10.23 ± 1.27 141.72 ± 10.29 −0.10 ± 1.08 37.64 ± 9.95 −0.03 ± 0.89 18.49 ± 3.42 −0.38 ± 1.15

10.18 ± 1.39 138.53 ± 11.29 0.13 ± 1.22 34.66 ± 10.36 0.27 ± 1.02 17.71 ± 3.32 −0.30 ± 1.27

p 0.860 0.159 0.323 0.161 0.123 0.260 0.740

VLBWPIs: very-low-birth-weight preterm infants. aValues expressed as mean ± SD. Table 3. Comparison of lung function variables between the schoolchildren who had been very-low-birth-weight preterm infants and those who had been normal-birth-weight full-term infants (controls).a

Spirometric variable FEV1, L FEV1, Z score FVC, L FVC, Z score FEV1/FVC, L FEV1/FVC, Z score FEF25-75%, L FEF25-75%, Z score

Controls (n = 45)

(n = 48)

2.23 ± 0.52 0.71 ± 1.12 2.59 ± 0.61 0.83 ± 1.03 0.86 ± 0.58 −0.23 ± 0.95 2.60 ± 0.74 −0.69 ± 1.04

2.03 ± 0.59 0.40 ± 1.62 2.38 ± 0.66 0.66 ± 1.44 0.85 ± 0.89 −0.38 ± 1.13 2.36 ± 0.77 −0.14 ± 1.37

VLBWPIs

0.092 0.284 0.121 0.525 0.498 0.507 0.139 0.392

VLBWPIs: very-low-birth-weight preterm infants. aValues expressed as mean ± SD. Table 4. Association of perinatal and neonatal variables with lung function in the schoolchildren who had been verylow-birth-weight preterm infants (univariate analysis).

Variable Birth weight Length of hospital stay Gestational age PROM Surfactant use Duration of oxygen therapy, days Mechanical ventilation CPAP HMD Corticosteroid use

FEV1 0.139 0.336 0.071 0.138 0.214 0.165 0.155 0.324 0.548 0.406

FVC 0.526 0.996 0.136 0.079 0.472 0.456 0.143 0.377 0.730 0.499

FEF25-75% 0.066 0.164 0.274 0.252 0.200 0.279 0.669 0.454 0.415 0.484

PROM: premature rupture of membranes; CPAP: continuous positive airway pressure; and HMD: hyaline membrane disease.

DISCUSSION In the present study, the schoolchildren who had been VLBW preterm infants and those who had been NBW full-term infants were found to be similar in terms of growth (weight and height) and lung function. In addition, the schoolchildren in the VLBWPI group were found to be slightly more active than those in the control group. Previous studies evaluating the growth of VLBW infants from discharge to early adulthood have shown that such monitoring plays an important role in identifying growth deficits and their consequences.(11,12) Some of the aforementioned studies have shown that low birth weight is a risk factor for growth and BMI deficits.(11,24) However, it has been reported that genetic factors

and socioeconomic status have a greater influence on growth in schoolchildren than does low birth weight.(25) These findings are consistent with those of the present study, in which schoolchildren who had been VLBW preterm infants and those who had been NBW full-term infants were found to have similar anthropometric characteristics and nutritional status. Although prematurity and the interventions that follow from it can affect respiratory system development,(9) the present study showed no evidence of reduced lung function nearly a decade later in the schoolchildren in the VLBWPI group when compared with those in the control group. These results are consistent with those of previous studies showing preserved lung function(5,6) in schoolchildren and adults who had been low-birth-weight preterm infants. One of the most J Bras Pneumol. 2016;42(4):254-260

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A 80

B p = 0.055

120

73.3

54.2 45.8

40 26.7 20

Observed frequency (%)

100

p = 0.596 Controls

97.8

95.8

VLBWPIs

80 60 40 20 4.2

2.2

0 Active

Inactive

Active

Inactive

≥2h

<2h

≥2h

<2h

Figure 2. Comparison of physical activity level (in A) and daily screen time (sedentary behavior; in B) between the schoolchildren who had been normal-birth-weight full-term infants (controls) and those who had been very-low-birthweight preterm infants (VLBWPIs).

compelling hypotheses to explain that is that pulmonary changes are more apparent in the first years of life and less so during childhood because parents provide respiratory health care, periodically monitoring lung function and being alert to any respiratory changes in their children.(7) In addition, physical activity and adequate nutrition can contribute to the functional recovery of such individuals.(7) Although some studies have suggested that socioeconomic and ethnic factors can influence lung function in such individuals,(26,27) the present study did not evaluate that. Our finding of preserved lung function is inconsistent with previous studies showing impaired lung function in schoolchildren who had been VLBW preterm infants. (3,28,29) In a recent study, schoolchildren who had been born at a gestational age of less than 32 weeks and who had not received surfactant therapy were shown to be at an increased risk of pulmonary involvement. (30) These conflicting results can be attributed, at least in part, to differences in designs, lung evaluation methods, reference equations, prematurity definitions, and low birth weight classifications across studies.(3,6,31) In the present study, only 6 of the schoolchildren in the VLBWPI group were found to have reduced lung function (as assessed by spirometry). This can be explained by the greater clinical severity of those 6 participants at birth; in comparison with the remaining VLBWPI group participants, they were born at a lower gestational age (< 32 weeks), had lower birth weight (< 1,200 g), had longer hospitalizations, and received supplemental oxygen for longer. In the present study, perinatal and neonatal variables were not associated with lung function in schoolchildren. This result is in agreement with those of a recent study, in which no perinatal factor was significantly associated with respiratory function variables.(32) In addition, our result is similar to that of another study, in which low birth weight and gestational age were not associated with reduced lung function in schoolchildren.(31) In contrast, other studies have shown 258

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that weight and gestational age have an influence on the duration of oxygen therapy and mechanical ventilation in VLBW preterm infants.(9,33) In the present study, the schoolchildren in the VLBWPI group had undergone oxygen therapy, mechanical ventilation, or both in the first days of life. However, a previous study has shown that any lung function abnormality in schoolchildren who have previously undergone oxygen therapy, mechanical ventilation, or both is more closely related to prematurity than to neonatal lung injury itself.(34) Previous studies conducted in our laboratory have shown that maximal expiratory flows are reduced in preterm infants(35) and remain so until the second year of life. (36) In the present study, the VLBWPI group showed no reduction in lung function. Our data suggest that lung function remains reduced until the second year of life and normalizes when the children reach school age, in parallel with a reduction in respiratory morbidity. Given the high cost of objective assessment devices such as pedometers and accelerometers, physical activity assessment by self-report questionnaires is a viable and practical alternative for quantifying sedentary behavior among young people.(14) In the present study, a questionnaire proposed by Hallal et al.(14) was used. The questionnaire quantifies the time spent commuting from home to school, work, or both, as well as the time spent in leisure-time activities. Although the questionnaire has been widely used in and appears to be well understood by the pediatric population,(14,37) it does not quantify the time spent in activities of different intensities and therefore might limit the understanding and interpretation of physical activity in such individuals. In the present study, more than 60% of the sample was classified as inactive; according to previous studies conducted in Brazil,(14,37) this constitutes sedentary behavior, which is a major public health problem. No significant difference was found between the VLBWPI and control groups in the present study

Winck AD, Heinzmann-Filho JB, Schumann D, Zatti H, Mattiello R, Jones MH, Stein RT

regarding the level of physical activity, a finding that is consistent with those of a study comparing children who had been preterm infants with those who had been full-term infants.(38) Although there were no significant differences between the two groups of children, those in the VLBWPI group were found to be slightly more active than those in the control group. This can be attributed to family factors, such as parental preferences for certain physical activities serving as encouragement for the children to engage in those activities, or to parental overprotection. (38) However, the influence of the aforementioned factors was not evaluated in the present study. More than 90% of the schoolchildren in the present study were found to spend more than 2 h per day watching television, playing video games, or using a computer. This finding appears to confirm those of national and international studies(39,40) showing high levels of sedentary behavior in pediatric patients. Therefore, there is a need for strategic measures to combat sedentary behavior, given that sedentary behavior

in pediatric patients is a risk factor for physical inactivity in adulthood.(39) The main limitation of the present study is that our sample of VLBW preterm infants consisted of less than half of the total number of individuals available for recruitment. Most of those children were not located, resided in municipalities outside the catchment area, did not agree to participate, or died. However, we believe that the aforementioned limitation had no influence on the results obtained, given that perinatal and neonatal factors were similar between the VLBW preterm infants who were included in the present study and those who were not. In conclusion, the schoolchildren in the VLBWPI group and those in the control group were found to be similar in terms of growth (weight and height) and lung function. In addition, the schoolchildren in the VLBWPI group were found to be slightly more active than those in the control group. Furthermore, perinatal and neonatal variables were not associated with lung function in the schoolchildren studied.

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Child Nutr. 2011;7(3):295-306. http://dx.doi.org/10.1111/j.17408709.2009.00233.x 26. Yüksel B, Greenough A. Ethnic origin and lung function of infants born prematurely. Thorax. 1995;50(7):773-6. http://dx.doi.org/10.1136/ thx.50.7.773 27. Stocks J, Henschen M, Hoo AF, Costeloe K, Dezateux C. Influence of ethnicity and gender on airway function in preterm infants. Am J Respir Crit Care Med. 1997;156(6):1855-62. http://dx.doi. org/10.1164/ajrccm.156.6.9607056 28. Doyle LW; Victorian Infant Collaborative Study Group. Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992. Pediatr Pulmonol. 2006;41(6):570-6. http://dx.doi.org/10.1002/ppul.20412 29. Ronkainen E, Dunder T, Peltoniemi O, Kaukola T, Marttila R, Hallman M. New BPD predicts lung function at school age: Follow-up study and meta-analysis. Pediatr Pulmonol. 2015;50(11):1090-8. http:// dx.doi.org/10.1002/ppul.23153 30. Choukroun M, Feghali H, Vautrat S, Marquant F, Nacka F, Leroy V, et al. Pulmonary outcome and its correlates in school-aged children born with a gestational age ≤ 32 weeks. Respir Med. 2013;107(12):196676. http://dx.doi.org/10.1016/j.rmed.2013.06.020 31. Vom Hove M, Prenzel F, Uhlig HH, Robel-Tillig E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. J Pediatr. 2014;164(1):40-5.e4. http://dx.doi.org/10.1016/j. jpeds.2013.07.045 32. Zanudin A, Gray PH, Burns Y, Danks M, Watter P, Poulsen L. Perinatal factors in non-disabled ELBW school children and later performance. J Paediatr Child Health. 2013;49(1):E62-7. http://dx.doi. org/10.1111/jpc.12022

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33. Jobe AH. An unknown: lung growth and development after very preterm birth. Am J Respir Crit Care Med. 2002;166(12 Pt 1):152930. http://dx.doi.org/10.1164/rccm.2209012 34. Kulasekaran K, Gray PH, Masters B. Chronic lung disease of prematurity and respiratory outcome at eight years of age. J Paediatr Child Health. 2007;43(1-2):44-8. http://dx.doi.org/10.1111/j.14401754.2007.01001.x 35. Friedrich L, Stein RT, Pitrez PM, Corso AL, Jones MH. Reduced lung function in healthy preterm infants in the first months of life. Am J Respir Crit Care Med. 2006;173(4):442-7. http://dx.doi.org/10.1164/ rccm.200503-444OC 36. Friedrich L, Pitrez PM, Stein RT, Goldani M, Tepper R, Jones MH. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med. 2007;176(12):1269-73. http://dx.doi.org/10.1164/ rccm.200703-476OC 37. da Silva KS, Nahas MV, Peres KG, Lopes Ada S. Factors associated with physical activity, sedentary behavior, and participation in physical education among high school students in Santa Catarina State, Brazil [Article in Portuguese]. Cad Saude Publica. 2009;25(10):2187-200. 38. Clemm H, Røksund O, Thorsen E, Eide GE, Markestad T, Halvorsen T. Aerobic capacity and exercise performance in young people born extremely preterm. Pediatrics. 2012;129(1):e97-e105. http://dx.doi. org/10.1542/peds.2011-0326 39. Dumith SC, Hallal PC, Menezes AM, Araújo CL. Sedentary behavior in adolescents: the 11-year follow-up of the 1993 Pelotas (Brazil) birth cohort study. Cad Saude Publica. 2010;26(10):1928-36. http://dx.doi. org/10.1590/S0102-311X2010001000009 40. Hamar P, Biddle S, Soós I, Takács B, Huszár A. The prevalence of sedentary behaviours and physical activity in Hungarian youth. Eur J Public Health. 2010;20(1):85-90. http://dx.doi.org/10.1093/eurpub/ ckp100

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ORIGINAL ARTICLE

Lack of association between viral load and severity of acute bronchiolitis in infants Ana Paula Duarte de Souza1, Lidiane Alves de Azeredo Leitão2, Fernanda Luisi2, Rodrigo Godinho Souza2, Sandra Eugênia Coutinho2, Jaqueline Ramos da Silva2, Rita Mattiello2, Paulo Márcio Condessa Pitrez2, Renato Tetelbom Stein2, Leonardo Araújo Pinto2 1. Laboratório de Imunologia Clínica e Experimental, Instituto de Pesquisas Biomédicas, Centro Infant, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. 2 Laboratório de Respirologia Pediátrica, Instituto de Pesquisas Biomédicas, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. Submitted: 22 September 2015. Accepted: 25 February 2016. Study carried out at the Centro Infant, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil.

ABSTRACT Objective: To investigate the correlation between respiratory syncytial viral load and length of hospitalization in infants with acute wheezing episodes. Methods: This was a two-year, cross-sectional study of infants ≤ 12 months of age with bronchiolitis at the time of admission to a tertiary hospital. For the identification of respiratory viruses, nasopharyngeal secretions were collected. Samples were analyzed (throughout the study period) by direct immunofluorescence and (in the second year of the study) by quantitative real-time PCR. We screened for three human viruses: rhinovirus, respiratory syncytial virus, and metapneumovirus. Results: Of 110 samples evaluated by direct immunofluorescence, 56 (50.9%) were positive for a single virus, and 16 (14.5%) were positive for two or more viruses. Among those 72 samples, the most prevalent virus was respiratory syncytial virus, followed by influenza. Of 56 samples evaluated by quantitative real-time PCR, 24 (42.8%) were positive for a single virus, and 1 (1.7%) was positive for two viruses. Among those 25 samples, the most prevalent virus was again respiratory syncytial virus, followed by human rhinovirus. Coinfection did not influence the length of the hospital stay or other outcome s. In addition, there was no association between respiratory syncytial virus load and the length of hospitalization. Conclusions: Neither coinfection nor respiratory syncytial viral load appears to influence the outcomes of acute bronchiolitis in infants. Keywords: Bronchiolitis; Coinfection; Viral load; Hospitalization; Respiratory syncytial virus, human.

INTRODUCTION Respiratory distress and wheezing are very common respiratory symptoms in children and may be the clinical expression of a wide variety of problems in the respiratory tract. Regardless of the cause, wheezing is a frequent reason for seeking medical care in the emergency room, especially during the first years of life.(1) The main cause of wheezing in infants is acute viral bronchiolitis, which is often accompanied by other risk factors, such as maternal smoking and premature birth. One study reported that almost half of a population under one year of age seen in an emergency department presented with respiratory symptoms.(2) In another study, it was reported that 17% of children with wheezing had been hospitalized at least once during the first year of life.(3) The leading cause of hospitalization among those infants was acute bronchiolitis caused by infection with viruses of the family Paramyxoviridae, which includes the human respiratory syncytial virus (RSV), of the genus Pneumovirus. Other agents that have been often linked to bronchiolitis and recurrent wheezing: viruses of the family Adenoviridae, including the various human adenoviruses within the genus Mastadenovirus; viruses

of the family Picornaviridae, such as those of the genus Enterovirus, which comprises several human rhinoviruses (HRVs), including the species Human rhinovirus A, B, and C; other viruses of the Paramyxoviridae family, especially the various Human parainfluenza virus species of the Respirovirus genus and the Human metapneumovirus (HMPV) species of the genus Metapneumovirus; and viruses of the family Orthomyxoviridae, which includes the genera Influenza virus A, B, and C. The rate of coinfection is also high. In one study, RSV occurred as a single infection in 68.8% of children with wheezing, whereas nearly a third were coinfected with another respiratory virus.(4) The viruses most frequently associated with RSV are HMPV and HRVs.(5) Such infections result in high costs to the health system, as well as impairing the quality of life of the infants and the family. One major question that is still open to debate is the role that the viral load, especially that of RSV, plays in determining the severity of acute wheezing episodes.(6) In the present study, we evaluated the occurrence of infection and coinfection with respiratory viruses in infants with wheezing at the time of hospital admission, as well as the association between viral load and outcomes related to disease severity.

Correspondence to:

Leonardo A. Pinto, Instituto de Pesquisas Biomédicas, Hospital São Lucas da PUCRS, Avenida Ipiranga, 6690, 2º andar, Instituto de Pesquisas Biomédicas, CEP 90.610000, Porto Alegre, RS, Brasil. Tel.: 55 51 3320-2313. Fax: 55 51 3320-3312. E-mail: leonardo.pinto@pucrs.br Financial support: This study received financial support from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Foundation for the Support of Research in the State of Rio Grande do Sul) and the Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). © 2016 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Lack of association between viral load and severity of acute bronchiolitis in infants

METHODS This was a cross-sectional study of infants up to 12 months of age with acute bronchiolitis who were admitted to a tertiary hospital—Hospital São Lucas, operated by the Pontifical Catholic University of Rio Grande do Sul—in the city of Porto Alegre, Brazil, between September of 2009 and August of 2011. The inclusion criteria were being ≤ 12 months of age; having been admitted with a clinical diagnosis of acute bronchiolitis (based on prodromal symptoms, with wheezing, crackles, and tachypnea); having been recruited within the first 48 h of hospitalization; and having a ≤ 72-h history of clinical manifestations of lower respiratory tract infection (wheeze or respiratory distress). Patients with a history of lung disease related to prematurity (such as bronchopulmonary dysplasia) were excluded, as were those with congenital heart disease, chronic lung disease (cystic fibrosis or bronchiolitis obliterans), or clinical symptoms suggestive of Bordetella pertussis infection, as well as those who had used macrolides previously. Data regarding clinical conditions at the time of hospital admission, vital signs, and signs of respiratory distress were obtained from medical charts. Medical histories were collected from parents or guardians with a standardized questionnaire. Information regarding the clinical course of the disease until discharge, such as the length of hospital stay, duration of oxygen therapy, and wheezing, was collected by the study physicians and researchers, as was information related to demographic variables at admission. On the first day of hospitalization, all patients underwent nasopharyngeal lavage for the identification of respiratory viruses. To avoid the inclusion of infants in the convalescence period, we recruited and collected samples only from patients who had a ≤ 72-h history of clinical manifestations of lower respiratory tract infection (wheeze or respiratory distress). Sample collection and immunofluorescence are routine in the assessment of infants with bronchiolitis at Hospital São Lucas., although PCR is not. All samples collected during the second year of the study were frozen at −80°C and stored for subsequent PCR testing. Direct immunofluorescence (DIF) for RSV, adenovirus, parainfluenza, and influenza was performed for the detection of antigens in nasopharyngeal secretions. For DIF, a specific antibody labeled with fluorochrome conjugate (Biotrin, Dublin, Ireland) was used for the monoclonal antibody group-specific and type-specific detections and culture confirmation. This test was performed in all patients evaluated during the study period (September of 2009 to August of 2011) and was used in order to investigate the role that the number of different viruses plays in determining the severity of acute bronchiolitis. We defined two groups of patients: those infected with a single virus; and those infected with two or three viruses. Samples collected in the second year of the study were submitted to real-time PCR for RSV, HRV, and HMPV. Total RNA was extracted by the TRIzol method (Life Technologies, Carlsbad, CA, USA) according to the manufacturer’s instructions. cDNA was synthesized with a Superscript III kit (Invitrogen, Karlsruhe, Germany) and quantified with the Qubit assay (DNA HS; Invitrogen). The quality of the cDNA for each patient was tested by amplification of the endogenous β-actin gene with a real-time PCR system (StepOne™; Applied Biosystems, 262

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Foster City, CA, USA), including TaqMan Master Mix (Applied Biosystems) and specific primers (Applied Biosystems). Samples that did not amplify β-actin were excluded from the analysis. Quantitative real-time PCR reactions were performed to amplify HRV-, RSV-, HMPV-specific genes using 4 ng of cDNA in triplicate for each patient. Primer sequences, synthesized and cloned into pUC57 plasmids (GenScript, Piscataway, NJ, USA), were used in order to perform a 10-fold dilution and generate a standard curve starting at 4 ng. This test was performed in all patients during the second year of the study (September 2010 to August 2011) and was used in order to investigate the effect that viral load has on the markers of bronchiolitis severity. The viral load (in copies/mL) was calculated from the amount of cDNA used in the PCR. Statistical analysis of the viral load was performed using GraphPad Prism, version 5.02 (Graphpad Software, San Diego, CA, USA). The study was approved by the Research Ethics Committee of the Pontifical Catholic University of Rio Grande do Sul (Protocol no. 09/04 678). The parents or legal guardians of all participants gave written informed consent. Data were summarized as mean ± standard deviation or as or median and interquartile range, depending on their distribution. Characteristics were compared between the two groups. The variables presented nonparametric distribution. The nonparametric Kruskal-Wallis test was used in order to compare continuous variables between the groups. To correlate continuous variables (e.g., viral load and length of hospitalization), we used Pearson’s or Spearman’s correlation tests. The level of statistical significance was set at p ≤ 0.05. Data analysis was performed with the Statistical Package for the Social Sciences, version 17.0 (SPSS Inc., Chicago, IL, USA). RESULTS Between September of 2009 and August of 2011, we recruited 127 patients, 110 of whom met all of inclusion criteria (first wheezing episode). Clinical information was collected for all of the patients included. In all 110 patients, the nasal samples collected were adequate for analysis by DIF, and 56 samples were submitted to quantitative real-time PCR in order to identify specific respiratory viruses (HRV, RSV, and HMPV). The mean age of the patients was 3.21 months, and 62 (56.3%) of the 110 patients were male (Table 1). Of the 110 infants evaluated, 109 (99.1%) had subcostal or intercostal retractions and required oxygen therapy. The mean hospital stay was 6 days, and none of these infants were admitted to the intensive care unit or needed mechanical ventilation (Table 1). Of the 110 samples analyzed by DIF, 72 (65.4%) tested positive for a virus and 38 (34.6%) tested negative. The most common virus was RSV, which was identified in 65 (90.2%) of the 72 positive samples, followed by influenza, identified in 15 (20.8%); parainfluenza, identified in 10 (13.8%); and adenovirus, identified in 3 (4.1%). In the sample as a whole, 56 (50.9%) of the 110 patients tested positive for one virus and 16 (14.5%) tested positive for two or three viruses. Coinfection was not found to influence the

Souza AP, Leitão LA, Luisi F, Souza RG, Coutinho SE, Silva JR, Pitrez PM, Stein RT, Pinto LA

length of the hospital stay or any other variable (Table 2). Among the 56 samples analyzed with quantitative real-time PCR (during the second year of the study), specifically to evaluate the impact of viral load, RSV was again the virus most often detected, being identified in 19 (76%) of the 25 positive samples, followed by HRV, which was identified in 4 (16%), and HMPV, which was identified in 2 (8%). The quantitative real-time PCR analysis showed that, in the second year of the study, 31 (55.3%) of the 56 patients tested negative, 24 (42.8%) tested positive for one virus, and 1 (1.7%) tested positive for two viruses. The mean viral loads for RSV, HRV, and HMPV were 1,340,000 copies/mL, 614,000 copies/mL, and 175,000 copies/mL, respectively. As can be seen in Figure 1, the RSV viral load in the nasal secretions, as determined by real-time PCR, showed no significant correlation with markers of clinical severity in our study sample (p > 0.05). We found that viral loads did not influence the length of hospitalization or the duration of wheezing episodes. DISCUSSION In our study, RSV viral loads in infants with wheezing did not influence the length of the hospital stay, which was used as a marker of the severity of acute bronchiolitis or wheezing episodes. Given the role of viral infections in wheezing, the hypothesis that higher viral loads or coinfection with different types of viruses

could influence the natural history of acute wheezing is reasonable and logical.(7) However, the association between viral loads and severity remains unclear and controversial in the literature, as does that between coinfection and severity.(8-11) In clinical practice, the size of the viral load and infection with more than one virus may generate uncertainty about the prognosis of such infections.(4) In the present study, the severity of acute wheezing was not affected by the RSV viral loads in nasopharyngeal secretions. When we used DIF in order to diagnose infection with respiratory viruses (influenza, parainfluenza, adenovirus, or RSV), we found that approximately 65% of the samples were positive for at least one such pathogen. Our DIF results are similar to those obtained in previous studies in the literature, in which the reported rate of infection with respiratory viruses among children with respiratory symptoms ranges from 45% to 70%.(12) In the present study, RSV was the most prevalent pathogen, whether alone or together with another virus. Real-time PCR was positive for RSV, HRV, and HMPV in 44.6% of the analyzed samples. That rate of positivity is in contrast with the 93.5% reported in a study that used conventional and real-time PCR for 12 different respiratory viruses.(13) However, it is similar to the rates reported in studies using only real-time PCR, which ranged from 44% to 64%.(14,15) Our study was underpowered to analyze the impact of coinfection on disease severity. Currently, the reported effects of

Table 1. Characteristics of patients according to the questionnaire completed at admission and variables associated with clinical severity.a

Characteristic Age, months Male gender, n (%) Current weight, kg Siblings, n (%) Length of hospital stay, days Respiratory rate, breaths/min SpO2 on admission, % Retractions, n (%) Mechanical ventilation, n (%) Use of oral steroids, n (%)

Acute bronchiolitis (first wheezing episode) (N = 110) 3.21 ± 2.5 62 (56.3) 5.66 ± 1.90 67 (60.9) 6.05 ± 3.22 50.58 ± 11.60 95.27 ± 3.42 109 (99.1) 0 (0.0) 8 (7.3)

Results presented as mean ± standard deviation, except where otherwise indicated.

Table 2. Severity associated with the number of respiratory viruses identified by direct immunofluorescence.a

Variable

Age, months Current weight, kg Respiratory rate, breaths/min SpO2 on admission, % Days on oxygen therapy Length of hospital stay, days Duration of wheezing, days

Number of viruses identified 1 2-3 (n = 56) (n = 16) 3.00 ± 2.47 2.38 ± 2.42 5.51 ± 1.88 5.50 ± 1.90 51.09 ± 12.51 49.06 ± 10.53 95.14 ± 3.46 94.63 ± 3.52 6.17 ± 2.93 5.44 ± 2.96 6.83 ± 3.22 5.63 ± 3.22 4.51 ± 2.93 3.81 ± 3.01

0.373 0.974 0.557 0.601 0.377 0.188 0.402

Results presented as mean ± standard deviation. *Comparisons by Student’s t-test.

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B RSV viral load (copies/mL)

A 1.5x107 1.0x107 5.0x106 100 80 60 40 20 0

5 10 Days of hospitalization

RSV viral load (copies/mL)

Lack of association between viral load and severity of acute bronchiolitis in infants

1.5x107 1.0x107 5.0x106 100 80 60 40 20 0

Days of oxigen use

RSV viral load (copies/mL)

C 1.5x107 1.0x107 5.0x106 100 80 60 40 20 0

5 10 Days of wheezing

Figure 1. Respiratory syncytial virus (RSV) viral load, in correlation with days of hospitalization (A*), days of oxygen use (B), and days of wheezing (C). *r = −0.217; p = 0.372.

coinfection on the burden of disease among children are inconsistent and controversial. One possible explanation is that such effects occur only in specific circumstances, such as RSV/HRV coinfection(5) or RSV/ HMPV coinfection. In addition, several environmental factors can also be determinants of the severity of respiratory viral infections, as can genetic variations in genes linked to the immune response against infections.(13-15) In the present study, we believe that the lack of an association between viral load and outcome measures of severity stands out as the main result. In such analysis, one could have expected a correlation or a trend in the plot between the variables viral load and length of hospitalization. However, there was absolutely no trend or correlation between the two. Previous studies on viral load and severity have also reported conflicting findings. Few studies have investigated the association between disease severity and viral load. Fodha et al.(10) described a positive correlation between RSV viral load and disease severity (determined by respiratory rate, length of hospital stay, and need for admission to the intensive care unit) in children hospitalized with respiratory infection. Zhou et al.(16) and Hasegawa et al.(17) showed that a higher mean RSV viral load was associated with greater disease severity, as well as with a longer duration of hospitalization and symptoms.

Nevertheless, there have also been reports of negative and inverse associations. Martin et al.(11) reported that an increasing viral load in RSV-infected children was associated with decreases in inpatient admissions, antibiotic use, and respiratory rates. In comparison with our patient sample, the sample evaluated by those authors was considerably larger, comprising 1,264 infants, 418 of whom tested positive for RSV by quantitative PCR. The authors detected borderline inverse associations (e.g., OR = 0.80; 95% CI: 0.70-0.99 for hospital admission). Considering these findings, we have to raise the possibility of random associations or lack of an association between viral load and disease severity in acute wheezing episodes. Our study has some relevant limitations, such as the small sample size, single nasal sample collection, and the use of PCR tests only in a subsample. However, our findings add to the current knowledge by suggesting that there is no correlation between viral load and the severity of respiratory illness in infants. In conclusion, on the basis of our results, neither coinfection nor viral load appears to influence the major outcomes of acute bronchiolitis. We also found that RSV viral loads in infants with wheezing did not influence the severity of the acute wheezing episodes in the first year of life. Further studies investigating the effects of viral load and viral combinations may help clarify this important and controversial issue.

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12. Calegari T, Queiroz DA, Yokosawa J, Silveira HL, Costa LF, Oliveira TF, et al. Clinical-epidemiological evaluation of respiratory syncytial virus infection in children attended in a public hospital in midwestern Brazil. Braz J Infect Dis. 2005;9(2):156-61. http://dx.doi.org/10.1590/ S1413-86702005000200006 13. Martin ET, Kuypers J, Wald A, Englund JA. Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children. Influenza Other Respir Viruses. 2012;6(1):71-7. http://dx.doi.org/10.1111/j.1750-2659.2011.00265.x 14. Canducci F, Debiaggi M, Sampaolo M, Marinozzi MC, BerrĂ¨ S, Terulla C, et al. Two-year prospective study of single infections and coinfections by respiratory syncytial virus and viruses identified recently in infants with acute respiratory disease. J Med Virol. 2008;80(4):71623. http://dx.doi.org/10.1002/jmv.21108 15. Jennings LC, Anderson TP, Werno AM, Beynon KA, Murdoch DR. Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections. Pediatr Infect Dis J. 2004;23(11):1003-7. http:// dx.doi.org/10.1097/01.inf.0000143648.04673.6c 16. Zhou L, Xiao Q, Zhao Y, Huang A, Ren L, Liu E. The impact of viral dynamics on the clinical severity of infants with respiratory syncytial virus bronchiolitis. J Med Virol. 2015;87(8):1276-84. http://dx.doi. org/10.1002/jmv.24111 17. Hasegawa K, Jartti T, Mansbach JM, Laham FR, Jewell AM, Espinola JA, et al. Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: multicenter cohort studies in the United States and Finland. J Infect Dis. 2015;211(10):1550-9. http://dx.doi.org/10.1093/infdis/jiu658

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ORIGINAL ARTICLE

STOP-Bang questionnaire: translation to Portuguese and cross-cultural adaptation for use in Brazil Lorena Barbosa de Moraes Fonseca1,2, Erika Aparecida Silveira2,3, Nathalia Meireles Lima3, Marcelo Fouad Rabahi1,2,3,4 1. Hospital Alberto Rassi-Hospital Geral de Goiânia, Goiânia (GO) Brasil. 2. Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Goiás, Goiânia (GO) Brasil. 3. Faculdade de Medicina, Universidade Federal de Goiás, Goiânia (GO) Brasil. 4. Clínica do Aparelho Respiratório, Goiânia (GO) Brasil. Submitted: 29 September 2015. Accepted: 9 May 2016. Study carried out at Clínica do Aparelho Respiratório and Hospital Alberto RassiHospital Geral de Goiânia, Goiânia, Brazil.

ABSTRACT Objective: To translate and perform a cross-cultural adaptation of the Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender (STOP-Bang) questionnaire so that it can be used as a screening tool for the diagnosis of obstructive sleep apnea in Brazil. Methods: Based on the principles of good practice for the translation and cross-cultural adaptation of such instruments, the protocol included the following steps: acquisition of authorization from the lead author of the original questionnaire; translation of the instrument to Brazilian Portuguese, carried out by two translators; reconciliation; back-translation to English, carried out by two English teachers who are fluent in Portuguese; review of the back-translation; harmonization; review and approval of the questionnaire by the original author; cognitive debriefing involving 14 patients who completed the questionnaire; analysis of the results; and review and preparation of the final version of the instrument approved by the review committee. Results: The final version of the STOP-Bang questionnaire for use in Brazil showed a clarity score > 9 (on a scale of 1-10) for all of the questions. The Cronbach’s alpha coefficient was 0.62, demonstrating the internal consistency of the instrument. The means and standard deviations of the age, body mass index, and neck circumference of the patients studied were 46.8 ± 11.2 years, 43.7 ± 8.5 kg/m2, and 41.3 ± 3.6 cm, respectively. Conclusions: The STOP-Bang questionnaire proved to be understandable, clear, and applicable. The original instrument and the translated version, cross-culturally adapted for use in Brazil, were consistently equivalent. Therefore, it can become a widely used screening tool for patients with suspected obstructive sleep apnea. Keywords: Sleep apnea, obstructive; Questionnaires; Translations.

INTRODUCTION Obstructive sleep apnea (OSA) is a sleep disorder characterized by repeated interruption of ventilation during sleep caused by upper airway closure.(1) Studies have shown that, even when asymptomatic, OSA is independently associated with increased morbidity and mortality.(2-4) It has been estimated that moderate to severe OSA goes undiagnosed in approximately 80% of males and 93% of females.(5,6) A major obstacle to the diagnosis of OSA is that polysomnography, which is the gold standard for diagnosis, is time-consuming and expensive, and there are not enough sleep medicine specialists.(1) Various screening tests have been developed. Such tests are aimed at identifying patients at high risk for OSA—all of whom should undergo sleep studies—and low-risk patients, thus avoiding unnecessary tests.(1,7-11) Questionnaires have been shown to be adequate screening instruments, given that they are easily applied and are part of routine medical practice.(12) Various questionnaires have been developed/ validated for that purpose, including the Wisconsin

Sleep Questionnaire, the Apnea Score, a questionnaire developed by Haraldsson et al., the Sleep Apnea of Sleep Disorders Questionnaire, the American Society of Anesthesiologists checklist, the Berlin questionnaire (BQ), the Snoring, Tiredness, Observed apnea, and high blood Pressure (STOP) questionnaire, and the STOP-Body mass index, Age, Neck circumference, and Gender (Bang) questionnaire.(11) For predicting the presence of moderate to severe OSA, the BQ and the STOP-Bang questionnaire have been found to have the highest sensitivity and specificity, respectively. The BQ, however, has a large number of questions and a complicated scoring system.(13) The STOP questionnaire and the STOP-Bang questionnaire have greater methodological validity, with reasonable accuracy, and features that are easy to use and remember. Because it is more comprehensive, the STOP-Bang questionnaire is the preferred instrument,(11) having been developed and validated as an English-language screening tool for OSA in surgical patients.(14) The STOP-Bang questionnaire is a very practical instrument because it is concise, is apparently easy to

Correspondence to:

Lorena Barbosa de Moraes Fonseca. Avenida B, 483, Setor Oeste, CEP 74110-030, Goiânia, GO, Brasil. Tel.: 55 62 3521-3333. E-mail: lorena_bmf@hotmail.com Financial support: None.

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memorize, has a simple scoring system, and requires only a few minutes to be completed.(1,15,16) It consists of eight questions regarding snoring, tiredness/ fatigue/sleepiness, observed apnea during sleep, blood pressure, body mass index (BMI), age, neck circumference, and gender.(14) The questions can be answered affirmatively (“yes”, 1 point) or negatively (“no”, 0 points), the total score ranging from 0 to 8. The present study is relevant because the STOP-Bang questionnaire had yet to be translated to Portuguese and culturally adapted for use in Brazil. Therefore, the objective of the present study was to translate and perform a cross-cultural adaptation of the STOP-Bang questionnaire so that it can be used as a screening tool for the diagnosis of OSA in Brazil. METHODS The present study was approved by the Research Ethics Committee of Hospital Alberto Rassi-Hospital Geral de Goiânia, located in the city of Goiânia, Brazil. Before completing the questionnaire, all patients gave written informed consent. Based on the principles of good practice for the translation and cross-cultural adaptation of such instruments established by Wild et al.,(17) Guillemin et al.,(18) and Beaton et al.,(19) the protocol included the following steps (Figure 1): 1. Preparation: The lead author of the STOP-Bang questionnaire was initially contacted. The University Health Network, which owns the copyright of the STOP-Bang questionnaire, granted a license for use of the instrument. 2. Translation: The original, English-language version of the STOP-Bang questionnaire was translated to Brazilian Portuguese by two pulmonologists residing in Brazil and fluent in English. They translated the questionnaire independently. Both sought to translate it conceptually rather than literally. 3. Reconciliation: The review committee, which consisted of four pulmonologists (including the two translators, the project coordinator, and a sleep medicine specialist), compared the two translations. The most appropriate version was arrived at by consensus, being designated Version 1 of the STOP-Bang questionnaire for use in Brazil. 4. Back-translation to English: Version 1 of the STOP-Bang questionnaire for use in Brazil was back-translated to English, which is the language in which the STOP-Bang questionnaire was originally written. Version 1 of the STOP-Bang questionnaire for use in Brazil was back-translated to English by two English teachers originally from English-speaking countries and fluent in Portuguese. Neither had access to the original version of the STOP-Bang questionnaire, and both were instructed to perform a literal translation. 5. Review of the back-translation: The review committee compared the two back-translations to ensure their conceptual equivalence.

6. Harmonization: The review committee compared the two back-translations to English with the original questionnaire to determine whether there were any discrepancies and thus ensure that the translated version was consistent with the original instrument. Version 2 of the STOP-Bang questionnaire for use in Brazil was thus arrived at. 7. Review and approval of the questionnaire by the original author: After harmonization, the Brazilian Portuguese version of the STOP-Bang questionnaire and the back-translation to English were submitted to the original author for consideration, as initially requested by the author. The back-translation was fully approved, no modifications being required. 8. Cognitive debriefing: The objective of this step was to determine the clarity, understandability, and acceptability of the translated questionnaire in the target population. An attempt was made to identify problematic questions in order to improve understanding and reduce uncertainty among respondents. The Brazilian Portuguese version of the STOP-Bang questionnaire was administered to a group of 14 patients by the principal investigator. Of those 14 patients, 7 were selected from among those treated at a private clinic in the city of Goiânia (Clínica do Aparelho Respiratório) and 7 were selected from among those treated at a public outpatient clinic (Hospital Alberto Rassi-Hospital Geral de Goiânia Pulmonology Outpatient Clinic), also in the city of Goiânia. During medical visits at each facility, patients were invited to participate in the study, and, for each facility, a decision was made to include the first 7 patients who agreed to participate. Based on the principles of good practice for the translation and cross-cultural adaptation of such instruments established by Wild et al.,(17) according to whom cognitive debriefing is satisfactory when 5-8 individuals are involved, we decided to include 7 patients from each facility, a total of 14 patients having therefore participated in the cognitive debriefing step of the protocol. Patients were eligible to participate in the cognitive debriefing step of the cross-cultural adaptation protocol if they were 18 years of age or older and had clinical complaints suggestive of OSA, including excessive daytime sleepiness, nonrestorative sleep, fatigue, insomnia, gasping or choking during sleep, snoring, and witnessed apneas.(20) Patients were excluded if they were unable to read, sign, or understand the informed consent form. Questions related to categorical data were read and answered by the participants, whereas numerical data (i.e., age, weight, and height for calculating the BMI and neck circumference) were recorded by the examiner after measurement. All items were read by all participants so that they were able to determine how clear each item was. Body weight (in kg) was measured with a digital scale (Welmy S.A., Santa Bárbara do Oeste, Brazil), the capacity and precision of which were 200 kg and 100 g, respectively. Height (in m) was measured with a stadiometer attached to the scale (capacity of 2 m, graduated in cm). Participants stood erect, barefoot and wearing light clothing, with J Bras Pneumol. 2016;42(4):266-272

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STOP-Bang questionnaire

Preparation

Translation (performed by two pulmonologists fluent in English)

Reconciliation (carried out by the review committee)

Version 1 of the STOP-Bang questionnaire for use in Brazil

Back-translation (performed by two English teachers)

Review of the back-translation (performed by the review committee)

Harmonization (carried out by the review committee)

Version 2 of the STOP-Bang questionnaire for use in Brazil

Review and approval of the Brazilian Portuguese version of the STOP-Bang questionnaire by the lead author of the original questionnaire

Cognitive debriefing (involving 14 patients)

Analysis of the results

Review

Version 3 of the STOP-Bang questionnaire for use in Brazil

Final report

Final version of the STOP-Bang questionnaire for use in Brazil Figure 1. Flowchart of the translation and cross-cultural adaptation of the STOP-Bang questionnaire for use in Brazil.

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their arms relaxed at their sides and their heels together. The BMI was calculated as weight in kilograms divided by height in meters squared.(21) Neck circumference was measured to the nearest 0.01 cm with an inelastic tape measure of 150 cm in length. Neck circumference was measured at the laryngeal prominence level. The laryngeal prominence is popularly known as “Adam’s apple” and is a protrusion of the thyroid cartilage, which lies below the hyoid bone and nearly encircles the larynx. This was chosen as a point of reference on the basis of the measurements used in the original STOP-Bang questionnaire.(14) A clarity questionnaire was used in order to evaluate patient understanding and acceptance of each question. An interval scale, with scores ranging from 1 to 10, was used in order to assess the clarity of each question. Scores ranging from 1 to 4 indicated that the question was confusing; scores ranging from 5 to 7 indicated that the question was unclear; and scores ranging from 8 to 10 indicated that the question was clear.(22,23) The clarity score was calculated as the arithmetic mean of the scores given by patients. A clarity score of < 4 indicated that the question had to be replaced; a clarity score of < 8 indicated that the question had to be reworded; and a clarity score ≥ 8 indicated that the question was sufficiently clear.(23,24) Participants were allowed to write, below each question, a comment on the interpretation and clarity of the question if they so wished.(23) The clarity scores and comments from patients showed that there was no need to modify the questionnaire. Cronbach’s alpha coefficient was used in order to assess the reliability of the Brazilian Portuguese version of the STOP-Bang questionnaire.(25) 9. Analysis of the results of cognitive debriefing and conclusion: Patient interpretation was compared with the original version of the questionnaire to determine whether there were any discrepancies. The analysis showed that no modifications were required. The project coordinator performed the analysis. Data analysis was performed with the Stata statistical software package, version 12.0 (StataCorp LP, College Station, TX, USA). The distribution of continuous variables was expressed as mean and standard deviation. For categorical variables, absolute and relative frequencies were calculated. 10. Review: The review step consisted of a final evaluation of the translated questionnaire. The translated questionnaire was carefully reviewed by two of the pulmonologists in the review committee and a Portuguese teacher, their objectives being to perform a final evaluation of the translation and correct any misspellings or grammatical errors. Version 3 of the STOP-Bang questionnaire for use in Brazil was thus arrived at. 11. Final report: A final report was written in order to document the process of translation and cross-cultural adaptation of the STOP-Bang questionnaire and disseminate the final version of the questionnaire for use in Brazil. The present article originated from that document.

RESULTS In the reconciliation step of the translation of the STOP-Bang questionnaire, the review committee decided to make two adjustments. Although the word “Tired” in the second question in the original questionnaire was translated as “cansado” by both translators, the review committee decided to use the term “faTigado” instead, which also appears in the question. This allowed us to maintain the acronym STOP-Bang, by which the questionnaire is known worldwide. For the same reason, a decision was made to use the term “circuNferência de pescoço” instead of “tamanho grande de pescoço” in the seventh question, the former also being deemed more appropriate than the latter. The same was true for the term “circunferência cervical”, which appears in the seventh question as well and was deemed more appropriate than “colarinho de camisa”. In the harmonization step of the protocol, the review committee reached a consensus that it would be clearer for patients if response options “yes” and “no” appeared after rather than before the question (i.e., at the end of the sentence rather than at the beginning). The lead author of the STOP-Bang questionnaire, who represented the group of authors of the original questionnaire, made no objections and fully approved the aforementioned adaptations. In the cognitive debriefing step of the protocol, 14 patients were interviewed. Of those, 7 were selected from among those treated at a public pulmonology outpatient clinic and 7 were selected from among those treated at a private pulmonology clinic. All patients interviewed were literate. Of those who had been selected from among those treated at a public outpatient clinic, none had a college degree. Of those who had been selected from among those treated at a private clinic, 2 had a college degree (one in advertising and one in nursing). The invitation to participate in the study was standardized. A decision was made to interview the first 14 patients (7 at each clinic) who presented with complaints of OSA and agreed to participate in the study. A total of 2 males and 12 females were interviewed. The mean age of the patients was 46.8 ± 11.2 years (range, 30-71 years). Only 2 were over 65 years of age, and they had good judgment and good cognitive function. The mean BMI was 43.7 ± 8.5 kg/m2 (range, 29.6-60.0 kg/m2), and the mean neck circumference was 41.3 ± 3.6 cm (range, 37-47 cm; Table 1). All patients interviewed completed all evaluation items. Mean clarity scores ranged from 9.1 to 9.8. None of the patients wrote any comments on the interpretation and clarity of the questions; this constitutes evidence that the questions were deemed clear by most of the patients (Table 2). In the final review step of the protocol, the review committee and a Portuguese teacher found some minor grammatical errors, all of which were corrected. J Bras Pneumol. 2016;42(4):266-272

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The final version of the STOP-Bang questionnaire for use in Brazil incorporated all of the aforementioned modifications (Figure 2). Among the 14 patients who completed the STOPBang questionnaire in the cognitive debriefing step of the cross-cultural adaptation process, the highest numbers of affirmative answers were related to the presence of high blood pressure (in 11 patients) and loud snoring (also in 11), followed by observed apnea (in 9) and fatigue (in 8; Table 3). The Cronbach’s alpha coefficient was 0.62, demonstrating the internal consistency of the instrument. Values between 0.60 and 0.80 are considered good for an exploratory study, showing that the data are reliable and that the instrument is of good quality for interpretation.(25) DISCUSSION In the present study, the STOP-Bang questionnaire, an instrument used in order to assess the risk of developing OSA, was translated to Portuguese and adapted for use in Brazil. Table 1. Characteristics of the sample of patients (N = 14) who participated in the cognitive debriefing of the Brazilian Portuguese version of the STOP-Bang questionnaire at a public hospital and a private clinic in the city of Goiânia, Brazil.a

Characteristic Gender Male Female Place of treatment Private clinic Public hospital Level of education Elementary school High school College Age, years Body mass index, kg/m2 Neck circumference, cm

Result 2 (14.3) 12 (85.7) 7 (50.0) 7 (50.0) 7 (50.0) 5 (35.7) 2 (14.3) 46.8 ± 11.2 43.7 ± 8.5 41.3 ± 3.6

Values expressed as n (%) or mean ± SD.

Table 2. Clarity of the questions in the Brazilian Portuguese version of the STOP-Bang questionnaire, according to the study participants (N = 14).a

Question Clear 1 (roncoS) 14 (100.0) 2 (faTigado) 14 (100.0) 3 (Observado) 14 (100.0) 4 (Pressão) 14 (100.0) 5 (oBesidade) 13 (92.9) 6 (idAde) 13 (92.9) 7(circuNferência 14 (100.00) do pescoço) 8 (Gênero) 14 (100.00) Values expressed as n (%).

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Unclear 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.1) 0 (0.0)

Confusing 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.1) 0 (0.0) 0 (0.0)

0 (0.0)

In the present study, we followed the principles of good practice for the translation and cross-cultural adaptation of such instruments. The methodology employed in our study was based on established guidelines. The process of cross-cultural adaptation of an instrument is complex and involves more than just a simple translation.(26) We followed all of the procedures required in order to achieve semantic, experimental, and conceptual equivalence between the original questionnaire and the translated version, thus ensuring that the resulting instrument is fully adapted to the local culture. We thus sought to ensure that the psychometric properties of the questionnaire were maintained for subsequent instrument validation. The process of cross-culturally adapting an existing instrument is faster, cheaper, and more efficient than is that of developing a new instrument. In addition, the data obtained locally can be compared with international data.(27) Because of the relatively high prevalence of undiagnosed OSA and its short- and long-term complications,(5,6) a reliable screening tool is needed for rapid prediction of OSA. The STOP-Bang questionnaire was developed and validated for that purpose, being initially aimed at surgical patients. The STOP-Bang questionnaire was based on the BQ, which, after being condensed and modified, resulted in the STOP questionnaire.(28) The STOP-Bang questionnaire is currently used worldwide in order to screen patients for OSA. It has been translated in several countries, including Portugal,(12) China,(29) Denmark,(30) Iran,(31) and Saudi Arabia.(32) It is known that there are long waiting lists for polysomnography in most sleep medicine clinics in Brazil. Therefore, the use of screening tools, such as the STOP-Bang questionnaire, appears to be an interesting approach to determine which patients should undergo this screening test for OSA on the basis of the probability of a positive result. Analysis of the data obtained by using the STOPBang questionnaire can provide physicians with a set of predictive parameters to determine the severity of OSA, serving as a valuable guide for diagnostic or therapeutic decisions.(12) The STOP-Bang questionnaire for use in Brazil is also important for future clinical studies conducted in the country, allowing comparisons between the results obtained and those of studies conducted in other countries.(33) One of the limitations of the present study is that most of the patients were female; this was due to the fact that there were many preoperative evaluations for bariatric surgery at the two clinics included in the present study. In the present study, the STOP-Bang questionnaire was translated to Portuguese and adapted for use in

Fonseca LBM, Silveira EA, Lima NM, Rabahi MF

Brazil. The Brazilian Portuguese version of the STOPBang questionnaire proved to be easy to understand, clear, and applicable, the original instrument and the translated version being consistently equivalent. It is therefore recommended that the Brazilian Portuguese version of the STOP-Bang questionnaire be used in order to screen patients for OSA so as to optimize diagnosis and reduce waiting lists for polysomnography. After this initial step, the Brazilian Portuguese version of the STOP-Bang questionnaire can be validated and be quite useful in public health care facilities and private clinics, as well as contributing to clinical research into OSA.

ACKNOWLEDGMENTS We would like to thank Dr. Frances Chung, who developed and validated the STOP-Bang questionnaire, for her kindness and for allowing us to translate the questionnaire to Portuguese and adapt it for use in Brazil. We would also like to thank all colleagues and teachers who participated in the translation, back-translation, and review steps of the cross-cultural adaptation process. Finally, we would like to thank all Clínica do Aparelho Respiratório and Hospital Alberto Rassi-Hospital Geral de Goiânia patients who contributed to the cross-cultural adaptation of the original questionnaire.

QUESTIONÁRIO STOP-Bang

• roncoS? Você ronca alto (alto o bastante para ser ouvido através de portas fechadas ou seu parceiro cutuca você por roncar à noite)? ( ) Sim ( ) Não

• oBesidade com índice de massa corporal (IMC) maior que 35 kg/m2? Índice de massa corporal (IMC) maior que 35 kg/m2? ( ) Sim ( ) Não

• faTigado? Você frequentemente sente-se cansado, fatigado ou sonolento durante o dia (por exemplo, adormecendo enquanto dirige)? ( ) Sim ( ) Não

• IdAde Idade maior que 50 anos? ( ) Sim ( ) Não

• Observado? Alguém já observou você parar de respirar ou engasgando/sufocando durante o sono? ( ) Sim ( ) Não • Pressão? Você tem ou está sendo tratado por pressão alta? ( ) Sim ( ) Não

• circuNferência de Pescoço (medida na altura do "pomo-de-adão") Para homens: circunferência cervical, maior ou igual a 43 cm. Para mulheres: circunferência cervical maior ou igual a 41 cm. ( ) Sim ( ) Não • Gênero Sexo masculino? ( ) Sim ( ) Não

Critérios de pontuação para a população geral: • • •

Baixo risco de apneia obstrutiva do sono (AOS): Sim para 0-2 questões Intermediário risco de AOS: Sim para 3-4 questões Alto risco de AOS: Sim para 5-8 questões

ou “Sim” para 2 ou mais das 4 questões iniciais (STOP) + gênero masculino ou “Sim” para 2 ou mais das 4 questões iniciais (STOP) + IMC > 35 kg/m2 ou “Sim” para 2 ou mais das 4 questões iniciais (STOP) + circunferência cervical ≥ 43 cm para homens ou ≥ 41 cm para mulheres Figure 2. Final version of the STOP-Bang questionnaire for use in Brazil.

Table 3. Affirmative answers to the questions in the Brazilian Portuguese version of the STOP-Bang questionnaire (N = 14).a

Question S: Você ronca alto? T: Você frequentemente sente-se cansado, fatigado ou sonolento durante o dia? O: Alguém já observou você parar de respirar ou engasgando/sufocando durante o sono? P: Você tem, ou está sendo tratado por pressão alta? B: IMC > 35 kg/m2? A: Idade > 50 anos? N: Circunferência cervical ≥ 43 cm em homens ou ≥ 41 cm em mulheres? G: Sexo masculino? IMC: Índice de massa corpórea. aValues expressed as n (%).

Affirmative answers 11 (78.6) 8 (57.1) 9 (64.3) 11 (78.6) 12 (85.7) 3 (21.4) 6 (42.9) 2 (14.3)

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Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: report of the ISPOR Task Force for Translation and Cultural Adaptation. Value Health. 2005;8(2):94-104. http://dx.doi. org/10.1111/j.1524-4733.2005.04054.x 18. Guillemin F, Bombardier C, Beaton D. Cross-cultural adaptation of health-related quality of life measures: literature review and proposed guidelines. J Clin Epidemiol. 1993;46(12):1417-32. http:// dx.doi.org/10.1016/0895-4356(93)90142-N 19. Beaton DE, Bombardier C, Guillemin F, Ferraz MB. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine (Phila Pa 1976). 2000;25(24):3186-91. http://dx.doi. org/10.1097/00007632-200012150-00014 20. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: AASM; 2014. 21. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health. Obes Res. 1998;6 Suppl 2:51S-209S. Erratum in: Obes Res. 1998;6(6):464. 22. Pasquali L. Princípios de elaboração de escalas psicológicas. Rev Psiq Clin. 1998;25(5):206-13. 23. Bonin CD, Santos RZ, Ghisi GL, Vieira AM, Amboni R, Benetti M. Construction and validation of a questionnaire about heart failure patients’ knowledge of their disease. Arq Bras Cardiol. 2014;102(4):364-73. http://dx.doi.org/10.5935/abc.20140032 24. Paine P, Pasquali L, Paulo Ede S, Bianchi AL, Solha AC. Psychometric properties of the Brazilian Health Locus of Control Scale. Psychol Rep. 1994;75(1 Pt 1):91-4. 25. Cronbach J. Fundamentos da Testagem Psicológica. 6th edition. Porto Alegre: Artes Médicas; 1996. 26. Koller M, West K. Linguistic Validation Manual for Patient-Reported Outcomes (PRO) Instruments, By C. Acquadro, K. Conway, C. Girourdet & I. Mear, MAPI ResearchTrust, Lyon, France, 2004,184 pp, ISBN: 2-9522021-0-9, price €70/$90. Qual Life Res. 2005;14(7):17912. http://dx.doi.org/10.1007/s11136-005-5367-1 27. Felisbino MB, Steidle LJ, Gonçalves-Tavares M, Pizzichini MM, Pizzichini E. Leicester Cough Questionnaire: translation to Portuguese and cross-cultural adaptation for use in Brazil. J Bras Pneumol. 2014;40(3):213-21. http://dx.doi.org/10.1590/S180637132014000300003 28. Yang Y, Chung F. A screening tool of obstructive sleep apnea: STOPBang questionnaire. Sleep Med Clinics. 2013;8(1):65-72. http:// dx.doi.org/10.1016/j.jsmc.2012.11.004 29. Luo J, Huang R, Zhong X, Xiao Y, Zhou J. Value of STOP-Bang questionnaire in screening patients with obstructive sleep apnea hypopnea syndrome in sleep disordered breathing clinic. Chin Med J (Engl). 2014;127(10):1843-8. 30. Bille DJ, Bille-Hasselstrøm C, Petersen CG. Translation and validation of the Stop-Bang Questionnaire for obstructive sleep apnoea into Danish. Dan Med J. 2015;62(12):A5158. 31. Sadeghniiat-Haghighi K, Montazeri A, Khajeh-Mehrizi A, Ghajarzadeh M, Alemohammad ZB, Aminian O, et al. The STOP-BANG questionnaire: reliability and validity of the Persian version in sleep clinic population. Qual Life Res. 2015;24(8):2025-30. http://dx.doi. org/10.1007/s11136-015-0923-9 32. Alhouqani S, Al Manhali M, Al Essa A, Al-Houqani M. Evaluation of the Arabic version of STOP-Bang questionnaire as a screening tool for obstructive sleep apnea. Sleep Breath. 2015;19(4);1235-40. http:// dx.doi.org/10.1007/s11325-015-1150-x 33. Tavares MG, Pizzichini MM, Steidle LJ, Nazario NO, Rocha CC, Perraro MC, et al. The Asthma Control Scoring System: translation and cross-cultural adaptation for use in Brazil. J Bras Pneumol. 2010;36(6):683-92.

J Bras Pneumol. 2016;42(4):273-278 http://dx.doi.org/10.1590/S1806-37562015000000290

ORIGINAL ARTICLE

Influence of heart failure on resting lung volumes in patients with COPD Aline Soares de Souza1,2, Priscila Abreu Sperandio1,2, Adriana Mazzuco1,3, Maria Clara Alencar1, Flávio Ferlin Arbex1, Mayron Faria de Oliveira1,2, Denis Eunan O’Donnell4, José Alberto Neder1,5 1. Setor de Função Pulmonar e Fisiologia Clínica do Exercício – SEFICE – Disciplina de Pneumologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo – UNIFESP – São Paulo (SP) Brasil. 2. Instituto Dante Pazzanese de Cardiologia, São Paulo (SP) Brasil. 3. Departamento de Fisioterapia, Universidade Federal de São Carlos – UFSCAR – São Carlos (SP) Brasil. 4. Respiratory Investigation Unit, Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston (ON) Canada. 5. Laboratory of Clinical Exercise Physiology, Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen’s University, Kingston (ON) Canada. Submitted: 9 November 2015. Accepted: 9 May 2016. Study carried out in the Setor de Função Pulmonar e Fisiologia Clínica do Exercício – SEFICE – Disciplina de Pneumologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo – UNIFESP – São Paulo, Brazil.

ABSTRACT Objective: To evaluate the influence of chronic heart failure (CHF) on resting lung volumes in patients with COPD, i.e., inspiratory fraction—inspiratory capacity (IC)/TLC— and relative inspiratory reserve—[1 − (end-inspiratory lung volume/TLC)]. Methods: This was a prospective study involving 56 patients with COPD—24 (23 males/1 female) with COPD+CHF and 32 (28 males/4 females) with COPD only—who, after careful clinical stabilization, underwent spirometry (with forced and slow maneuvers) and whole-body plethysmography. Results: Although FEV1, as well as the FEV1/FVC and FEV1/slow vital capacity ratios, were higher in the COPD+CHF group than in the COPD group, all major “static” volumes—RV, functional residual capacity (FRC), and TLC—were lower in the former group (p < 0.05). There was a greater reduction in FRC than in RV, resulting in the expiratory reserve volume being lower in the COPD+CHF group than in the COPD group. There were relatively proportional reductions in FRC and TLC in the two groups; therefore, IC was also comparable. Consequently, the inspiratory fraction was higher in the COPD+CHF group than in the COPD group (0.42 ± 0.10 vs. 0.36 ± 0.10; p < 0.05). Although the tidal volume/IC ratio was higher in the COPD+CHF group, the relative inspiratory reserve was remarkably similar between the two groups (0.35 ± 0.09 vs. 0.44 ± 0.14; p < 0.05). Conclusions: Despite the restrictive effects of CHF, patients with COPD+CHF have relatively higher inspiratory limits (a greater inspiratory fraction). However, those patients use only a part of those limits, probably in order to avoid critical reductions in inspiratory reserve and increases in elastic recoil. Keywords: Respiratory function tests; Pulmonary disease, chronic obstructive; Heart failure; Spirometry.

INTRODUCTION The pathophysiological mechanisms of COPD are largely expiratory and obstructive. However, their consequences are inspiratory and elastic.(1) In other words, expiratory flow limitation and the resulting air trapping/lung hyperinflation tend to increase operating lung volumes, thus reducing inspiratory reserve volume (IRV).(2) Pulmonary function tests show lower inspiratory fraction—inspiratory capacity (IC)/TLC(3,4)—and relative inspiratory reserve—[1 – (end-inspiratory lung volume (EILV)/TLC)](5)—in patients with the aforementioned abnormalities than in normal individuals. Given that the consequent reduction in dynamic compliance increases operating lung volumes—thus worsening neuromechanical dissociation and dyspnea(6)—it is clinically important to measure inspiratory fraction and relative inspiratory reserve in patients with COPD. In this context, COPD is associated with several comorbidities that can affect lung volumes and their complex interrelationships. Because of its high prevalence and impact on morbidity and mortality, chronic heart failure

(CHF) with reduced ejection fraction is chief among them. (7-9) Several studies have shown that chronic pulmonary congestion, septal thickening, inspiratory muscle weakness, and the compressive effects of cardiomegaly often reduce IC in patients with CHF.(10-12) However, because TLC and tidal volume (VT) changes are variable,(13-16) the way in which inspiratory fraction and relative inspiratory reserve are affected can vary across patients. Therefore, if the aforementioned consequences of CHF are also observed in patients with COPD+CHF and if end-expiratory lung volume (EELV) and EILV remain stable,(17) inspiratory fraction and relative inspiratory reserve might be more affected in patients with COPD+CHF than in those with COPD only. Alternatively, reductions in EELV (induced by recruitment of abdominal expiratory muscles or increased elastic recoil, for example) and EILV (reduced EELV with or without reduced VT)(15) might preserve inspiratory fraction and relative inspiratory reserve despite a lower TLC in patients with COPD+CHF. Given that no previous studies have addressed these issues, there is still a substantial knowledge gap regarding the mechanical

Correspondence to:

Priscila A. Sperandio. Rua Francisco de Castro, 54, CEP 04020-050, São Paulo, SP, Brasil. Tel.: 55 11 5082-4420. E-mail: prissperandio@gmail.com Financial support: Aline S. de Souza is the recipient of a grant from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development). © 2016 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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interactions between COPD and CHF and their effects on the volumes available for inspiratory expansion in patients with COPD+CHF. The objective of the present study was to compare inspiratory fraction and relative inspiratory reserve (and their determinants) between a carefully selected group of patients with COPD+CHF and a group of patients with COPD only. It was hypothesized that the characterization of the effect of CHF on these key physiological markers of COPD would advance the understanding of the mechanical and ventilatory constraints(10) faced by patients with COPD+CHF. METHODS

Sample In the present cross-sectional study with consecutive data collection, we included all consecutive patients who underwent whole-body plethysmography between February of 2012 and March of 2014 at the COPD+CHF outpatient clinic of the Universidade Federal de São Paulo (UNIFESP, Federal University of São Paulo) Department of Pulmonary Function and Exercise Physiology, located in the city of São Paulo, Brazil, and who presented with FEV1/FVC < 0.7 and left ventricular ejection fraction (LVEF) ≤ 45%. All patients had previously been selected from among those treated at the Myocardial Infarction Outpatient Clinic of the aforementioned institution or at the Left Ventricular Dysfunction Outpatient Clinic of the Instituto Dante Pazzanese de Cardiologia (IDPC, Dante Pazzanese Institute of Cardiology), also in the city of São Paulo, Brazil. The patients in the COPD group (FEV1/FVC < 0.7 and LVEF > 45%) were selected from among those treated at the UNIFESP COPD Outpatient Clinic. Patients over 45 years of age with a smoking history of more than 10 pack-years were included. All patients were monitored by the same cardiologist and pulmonologist, undergoing standardized clinical assessment and receiving optimal treatment regimens for both diseases. Patients presenting with COPD exacerbation, decompensated CHF, or both in the month prior to study entry were excluded, as were those with unstable angina. The study was approved by the Research Ethics Committees of UNIFESP (Protocol no. 19595) and IDPC (Protocol no. 68612).

Measurements Spirometry (with forced and slow maneuvers) and whole-body plethysmography were performed with a Platinum Elite™ body plethysmograph (Medical Graphics Corp., St. Paul, MN, USA), in accordance with current recommendations.(18,19) The following variables were assessed: FEV1; FVC; slow vital capacity (SVC); TLC; RV; thoracic gas volume, which was considered to be equivalent to functional residual capacity (FRC) in the present study; VT (the mean of three breaths taken before the inhalation preceding the SVC maneuver); and IC. All variables were expressed in liters. On the basis of the aforementioned variables, EILV (EILV = FRC + VT), IRV (IRV = TLC − EILV), and expiratory 274

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reserve volume (ERV = FRC − RV) were calculated.(19) The reference values were those obtained in a sample of Brazilian adults.(20,21) The values that were analyzed in the present study were those obtained 20 min after the administration of 400 µg of inhaled albuterol.

Data analysis Statistical analysis was performed with the IBM SPSS Statistics software package, version 21.0 (IBM Corporation, Armonk, NY, USA). The Kolmogorov-Smirnov test was used in order to verify the normality of the data. Data were presented as mean and standard deviation. The independent sample t-test was used in order to compare the results between the groups. For qualitative variables, the chi-square test was used in order to assess differences between the groups. The level of statistical significance was set at p < 0.05 for all tests. RESULTS A total of 86 patients (41 patients in the COPD+CHF group and 45 patients in the COPD group) were initially considered eligible for the present study. After exclusion of patients who were clinically unstable, those who were unable to perform advanced pulmonary function tests, and those whose tests were technically inadequate, 24 patients with COPD+CHF (23 of whom were male) and 32 patients with COPD only (28 of whom were male) were included. The COPD+CHF and COPD groups were similar in terms of age (66 ± 9 vs. 64 ± 6 years), body mass index (26.5 ± 3.7 vs. 24.9 ± 4.1 kg/m2), and smoking history (51.7 ± 26.4 vs. 54.3 ± 38.2 pack-years). As expected, LVEF was significantly lower in the COPD+CHF group than in the COPD group (33 ± 7% vs. 68 ± 4%; p < 0.01). The most common cause of CHF was ischemic cardiomyopathy (n = 13), followed by idiopathic etiology (n = 6). Most of the patients in the COPD+CHF group were under treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (n = 21), diuretics (n = 20), or beta blockers (n = 18). There were no significant differences between the two groups regarding the frequency of use of long-acting bronchodilators, inhaled corticosteroids, or both (p > 0.05). Although FEV1 was higher in the COPD+CHF group than in the COPD group, FVC and SVC were similar between the two groups (Table 1). Therefore, FEV1/FVC and FEV1/SVC were higher in the COPD+CHF group (p < 0.05). In contrast, all major “static” lung volumes (RV, FRC, and TLC) were lower in the COPD+CHF group than in the COPD group. In the COPD group, there was a greater reduction in FRC than in RV, ERV therefore being lower in the COPD+CHF group. There were relatively proportional reductions in FRC and TLC in the two groups; therefore, IC was also comparable (p > 0.05; Table 1 and Figure 1A). A similar IC and a lower TLC resulted in a higher inspiratory fraction (IC/TLC) in the COPD+CHF group (p < 0.05; Table

Souza AS, Sperandio PA, Mazzuco A, Alencar MC, Arbex FF, Oliveira MF, O’Donnell DE, Neder JA

Table 1. Functional characteristics of the patients with COPD only and of those with COPD and chronic heart failure.a

Variable

Spirometry (with forced and slow maneuvers) FEV1, L FEV1, % predicted FVC, L FEV1/FVC SVC, L FEV1/SVC VT, L IC, L FEF25-75%, L/s Whole-body plethysmography TLC, L TLC, % predicted FRC, L FRC, % predicted RV, L RV, % predicted EILV, L IRV, L ERV, L sRaw, cmH2O/s Ratios EILV/TLC VT/IC IC/TLC RV/TLC FEF25-75%/FVC FEF25-75%/TLC

Group COPD (n = 32)

COPD+CHF

1.33 ± 0.55 48.5 ± 18.2 2.81 ± 0.67 0.46 ± 0.12 3.05 ± 0.70 0.43 ± 0.14 0.81 ± 0.20 2.27 ± 0.52 0.61 ± 0.44

1.78 ± 0.53* 58.4 ± 16.0* 2.90 ± 0.57 0.60 ± 0.10* 3.12 ± 0.53 0.57 ± 0.10* 1.04 ± 0.34* 2.34 ± 0.55 1.00 ± 0.51*

6.71 ± 1.10 108.9 ± 16.6 4.42 ± 1.10 132.4 ± 28.5 3.36 ± 0.80 165.4 ± 44.8 5.13 ± 1.25 1.60 ± 0.61 0.99 ± 0.58 19.17 ± 14.80

5.91 ± 0.84* 89.3 ± 15.5* 3.45 ± 0.79* 104.4 ± 35.2* 2.78 ± 0.79* 131.6 ± 42.6* 4.52 ± 0.99 1.43 ± 0.51 0.68 ± 0.43* 11.02 ± 10.52*

0.75 ± 0.10 0.35 ± 0.12 0.36 ± 0.10 0.50 ± 0.08 0.22 ± 0.11 0.11 ± 0.07

0.75 ± 0.09 0.44 ± 0.14* 0.43 ± 0.10* 0.46 ± 0.08 0.34 ± 0.14* 0.18 ± 0.07*

(n = 24)

CHF: chronic heart failure; SVC: slow vital capacity; VT: tidal volume; IC: inspiratory capacity; TLC: total lung capacity; FRC: functional residual capacity; RV: residual volume; EILV: end-inspiratory lung volume; IRV: inspiratory reserve volume; ERV: expiratory reserve volume; sRaw: specific airway resistance. aValues expressed as mean ± SD. *p < 0.05 (independent sample t-test).

1 and Figure 1B). It is of note that the patients in the COPD+CHF group used only part of the higher inspiratory fraction available. Therefore, despite a higher VT/IC ratio in the COPD+CHF group, IRV and relative inspiratory reserve—[1 − (EILV/TLC)]—were similar between the two groups (p < 0.05; Table 1 and Figure 1B). DISCUSSION To our knowledge, this is the first cross-sectional study with prospective data collection to compare inspiratory fraction and relative inspiratory reserve—(IC/TLC) and [1 − (EILV/TLC)], respectively(3-5)—as well as their determinants, between patients with COPD+CHF and those with COPD only. The main findings of the present study were that a) in comparison with the patients with COPD only, those with COPD+CHF showed a relatively greater reduction in FRC than in TLC and RV; b) consequently, there was no difference between the two groups regarding IC, but there was an increase in inspiratory fraction (IC/TLC); c) the patients with

COPD+CHF used only part of the higher inspiratory fraction available, given that relative inspiratory reserve—[1 − (EILV/TLC)]—was similar between the two groups. Therefore, our results indicate that, despite the restrictive effects of CHF, there was not only a relative increase in inspiratory limits (a higher inspiratory fraction)(3,4) but also an admirably judicious use of those limits, given that a “critical” IRV was preserved,(2,22) i.e., a similar relative inspiratory reserve. Over the last two decades, there have been considerable advances in the understanding of the crucial role that a precise regulation of operating lung volumes plays in reducing the metabolic demands associated with ventilation and the sensation of dyspnea in patients with COPD.(2) The present study adds to this line of reasoning by showing that, even in the presence of comorbidities associated with reduced static lung volumes (i.e., CHF),(13-16) the precise regulation of a “safe end-inspiratory reserve volume” for mechanical operation of the system at maximum capacity (i.e., TLC) appears to remain intact.(23,24) Although our patients J Bras Pneumol. 2016;42(4):273-278

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TLC 7

Volume (L)

TLC*

IRV VT

EILV* FRC*

ERV

IRV* IC VT* ERV*

3 2

RV*

1 0 B

100

Volume (%TLC)

IRV VT

EILV FRC*

ERV

IRV IC* VT* ERV*

40 20

0 COPD

COPD + CHF

Figure 1. Lung volumes and capacities expressed as absolute values (in A) and corrected for differences in total lung capacity (in B) in patients with COPD only and in those with COPD and chronic heart failure (CHF). TLC: total lung capacity; RV: residual volume; ERV: expiratory reserve volume; VT: tidal volume; IRV: inspiratory reserve volume; FRC: functional residual capacity; EILV: endinspiratory lung volume; and IC: inspiratory capacity. *p < 0.05 (independent sample t-test).

were not evaluated during exercise, the aforementioned strategy suggests that both groups had the same IRV available for consumption at higher ventilatory demands.(2,23,24) However, because we did not directly measure the work of breathing in the present study, we cannot guarantee that the lower operating lung volumes observed in the COPD+CHF group would be enough to overcome the likely increase in elastic recoil associated with CHF.(10) The physiological mechanisms underlying the precise adjustment of IRV in patients with COPD remain largely unknown. However, the relative (i.e., fractional) nature of this adjustment is noteworthy; VT increases only enough to maintain a “critical” IRV,(2,23,24) even if there is still room for further increases. In fact, Faisal et al. have recently demonstrated that this adjustment remains precise in physiologically and structurally opposite diseases (COPD and interstitial lung disease).(25) The way in which the respiratory system precisely defines this threshold appears to involve an awareness (either acquired by experience or innate) of the maximum capacity available. The price of excessive elastic recoil 276

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is clearly avoided.(24) Although we do not know the extent to which the combination of COPD and CHF effectively increases dead space volume, this is a plausible hypothesis, given that lung perfusion might be reduced in areas in which ventilation is relatively preserved.(26) Therefore, it makes sense that, in such patients, VT is somewhat higher in order to reduce the dead space to tidal volume ratio (VD/VT). It is therefore possible that the limits to increases in VT (with concomitant reduction in VD/VT) are also determined by humoral factors, i.e., the VT required in order to reduce VD/VT, thus allowing minute PaCO2 variations that are close to its set point.(27) In fact, given that PaCO2 can be set at slightly lower values in patients with COPD+CHF, the dynamic regulation of VD/VT appears to be of particular relevance for such patients. The fact that there was a reduction in FRC is of crucial importance for the understanding of our findings. Given that the reduction in FRC overcame the decrements in RV, there was a significant decrease in ERV. This confirmed the premise that, in order to maintain VT and IRV, patients with COPD choose to pay the price of nearly reaching maximal expiratory volumes, despite the fact that this can affect the efficiency of pulmonary gas exchange and reduce flow reserves. However, it is of note that CHF probably increases lung elastic recoil and mean expiratory flow (the latter particularly during exercise).(10) Therefore, at least in stable patients, reduced flow reserves might not necessarily be associated with increased expiratory flow limitation in COPD+CHF. The underlying reasons for a relatively greater reduction in FRC remain unclear and include the following: a) increased tonic activity of abdominal expiratory muscles(28,29); b) reduced small airway obstruction, the small airways being particularly relevant for determining volume balance in COPD patients(28); and c) increased rate of lung emptying in units with higher time constants, i.e., those particularly affecting “lower” lung volumes (near RV), as a result of a higher expiratory flow rate and cardiomegaly.(30) Given that there was no difference in body mass index between the two groups (and given that none of the patients had ascites), the hypothesis that TLC was lower in the COPD+CHF group because overweight and obesity were more common in that group does not seem plausible.(31) In addition, lung volumes were nearly normal in the COPD+CHF group, whereas, in the COPD group, they were increased, as expected. Therefore, if we assume that the incidence of CHF is higher than its prevalence,(32) CHF is likely to lead to a “pseudonormalization” of static lung volumes in COPD. However, longitudinal studies are needed in order to test this hypothesis. What is the clinical applicability of our results? The remarkable maintenance of IRV in the COPD+CHF group demonstrates that it is particularly critical to maintain an adequate IC from a lower EELV in such patients. Therefore, although the patients with COPD+CHF were less hyperinflated (had a lower TLC) than those with COPD only, a reduction in air trapping appears to be fundamental to a downward shift in operating lung

Souza AS, Sperandio PA, Mazzuco A, Alencar MC, Arbex FF, Oliveira MF, O’Donnell DE, Neder JA

volumes. In other words, only optimal bronchodilator therapy can effectively increase IC and reduce the EELV/TLC ratio in patients with COPD+CHF. In addition, supplemental mechanisms reducing TLC (pleural effusion, congestion, inspiratory muscle weakness, and morbid obesity)(10-12) should be minimized in order to restore maximum inspiratory thresholds. The present study has some important limitations that should be noted. Our sample of patients was relatively small in comparison with those of large retrospective epidemiological studies. However, before undergoing pulmonary function testing, all of the participants in the present study were carefully optimized from a clinical standpoint by the coordinated efforts of and consensus between a cardiologist and a pulmonologist. Several confounders were thus avoided, including airway obstruction and air trapping secondary to pulmonary edema and small airway compression in unstable patients with CHF. In addition, the results presented here refer to post-bronchodilator plethysmography. Therefore, our results probably provide a picture of the best possible lung function in those patients. Another possible criticism is that FEV1 and FEV1/FVC were higher in the patients in the COPD+CHF group than in those in the COPD group, meaning that the former were less “obstructed” than the latter. Indeed, we cannot rule out the possibility of a selection bias toward less severely ill patients who were able to perform whole-body plethysmography adequately. However, it is extremely difficult to match such patients by FEV1. Guder et al. argued that CHF tends to overestimate the severity of

COPD (as determined by FEV1) because of reduced lung volumes.(17) However, the increased airflow resulting from the increased elastic recoil induced by CHF(33-35) tends to increase FEV1. Another complicating factor is that the functional effects of CHF can be influenced by the relative predominance of emphysema or airway disease (chronic bronchitis). In the present study, the fact that there was no difference between the two groups in terms of the RV/TLC ratio suggests that they were somewhat comparable despite the differences in FEV1. Further studies are needed in order to define the best approach to the functional pairing of patients with COPD+CHF and those with COPD only. In conclusion, despite the significant restrictive effects of CHF (reduced TLC), reductions in FRC and ERV preserve IC and increase inspiratory fraction (IC/TLC) in patients with COPD+CHF. However, in order to preserve a “critical” IRV, such patients use only part of this higher inspiratory fraction, possibly in order to reduce elastic recoil and, consequently, the sensation of dyspnea. The present study lays the foundation for future studies comparing our findings regarding resting lung volumes with mechanical, ventilatory, and sensory responses during exercise in patients with COPD+CHF. ACKNOWLEDGMENTS We would like to thank the IDPC, as well as the UNIFESP Departments of Pulmonology and Cardiology, for making the present study possible.

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ejhf.183 10. Cross TJ, Sabapathy S, Beck KC, Morris NR, Johnson BD. The resistive and elastic work of breathing during exercise in patients with chronic heart failure. Eur Respir J. 2012;39(6):1449-57. http:// dx.doi.org/10.1183/09031936.00125011 11. Apostolo A, Giusti G, Gargiulo P, Bussotti M, Agostoni P. Lungs in heart failure. Pulm Med. 2012;2012:952741. http://dx.doi. org/10.1155/2012/952741 12. Apostolo A, Laveneziana P, Palange P, Agalbato C, Molle R, Popovic D, et al. Impact of chronic obstructive pulmonary disease on exercise ventilatory efficiency in heart failure. Int J Cardiol. 2015;189:134-40. http://dx.doi.org/10.1016/j.ijcard.2015.03.422 13. Faggiano P. Abnormalities of pulmonary function in congestive heart failure. Int J Cardiol. 1994;44(1):1-8. http://dx.doi.org/10.1016/01675273(94)90060-4 14. Dimopoulou I, Daganou M, Tsintzas OK, Tzelepis GE. Effects of severity of long-standing congestive heart failure on pulmonary function. Respir Med. 1998;92(12):1321-5. http://dx.doi.org/10.1016/ S0954-6111(98)90136-6 15. Lalande S, Johnson BD. Breathing strategy to preserve exercising cardiac function in patients with heart failure. Med Hypotheses. 2010;74(3):416-21. http://dx.doi.org/10.1016/j.mehy.2009.09.030 16. Olson TP, Denzer DL, Sinnett WL, Wilson T, Johnson BD. Prognostic value of resting pulmonary function in heart failure. Clin Med Insights Circ Respir Pulm Med. 2013;7:35-43. http://dx.doi.org/10.4137/ ccrpm.s12525 17. Güder G, Rutten FH, Brenner S, Angermann CE, Berliner D, Ertl G, et al. The impact of heart failure on the classification of COPD severity. J Card Fail. 2012;18(8):637-44. http://dx.doi.org/10.1016/j. cardfail.2012.05.008 18. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38. J Bras Pneumol. 2016;42(4):273-278

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http://dx.doi.org/10.1183/09031936.05.00034805 19. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511-22. http://dx.doi.org/10.1183/09031936.05 .00035005 20. Neder JA, Andreoni S, Castelo-Filho A, Nery LE. Reference values for lung function tests. I. Static volumes. Braz J Med Biol Res. 1999;32(6):703-17. http://dx.doi.org/10.1590/s0100879x1999000600006 21. Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in white adults in Brazil. J Bras Pneumol. 2007;33(4):397406. http://dx.doi.org/10.1590/S1806-37132007000400008 22. O’Donnell DE, Webb KA. The major limitation to exercise performance in COPD is dynamic hyperinflation. J Appl Physiol (1985). 2008;105(2):753-5; discussion 755-7. 23. O’Donnell DE, Guenette JA, Maltais F, Webb KA. Decline of resting inspiratory capacity in COPD: the impact on breathing pattern, dyspnea, and ventilatory capacity during exercise. Chest. 2012;141(3):753–62. http://dx.doi.org/10.1378/chest.11-0787 24. Casaburi R, Rennard SI. Exercise limitation in chronic obstructive pulmonary disease. The O’Donnell threshold. Am J Respir Crit Care Med. 2015 Apr 15;191(8):873-5. http://dx.doi.org/10.1164/ rccm.201501-0084ED 25. Faisal A, Alghamdi BJ, Ciavaglia CE, Elbehairy AF, Webb KA, Ora J, et al. Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders. Am J Respir Crit Care Med. 2016;193(3):299-309. http://dx.doi.org/10.1164/rccm.2015040841OC 26. Neder JA, Arbex FF, Alencar MC, O’Donnell CD, Cory J, Webb KA, et al. Exercise ventilatory inefficiency in mild to endstage COPD. Eur Respir J. 2015;45(2):377-87. http://dx.doi.

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org/10.1183/09031936.00135514 27. Whipp BJ, Ward SA, Wasserman K. Ventilatory responses to exercise and their control in man. Am Rev Respir Dis. 1984;129(2 Pt 2):S17-20. http://dx.doi.org/10.1164/arrd.1984.129.2P2.S17 28. Macklem PT. Respiratory mechanics. Annu Rev Physiol. 1978;40:15784. http://dx.doi.org/10.1146/annurev.ph.40.030178.001105 29. Aliverti A, Cala SJ, Duranti R, Ferrigno G, Kenyon CM, Pedotti A, et al. Human respiratory muscle actions and control during exercise. J Appl Physiol (1985). 1997;83(4):1256-69. 30. Olson TP, Beck KC, Johnson BD. Pulmonary function changes associated with cardiomegaly in chronic heart failure. J Card Fail. 2007;13(2):100-7. http://dx.doi.org/10.1016/j.cardfail.2006.10.018 31. O’Donnell DE, Deesomchok A, Lam YM, Guenette JA, Amornputtisathaporn N, Forkert L, et al. Effects of BMI on static lung volumes in patients with airway obstruction. Chest. 2011;140(2):4618. http://dx.doi.org/10.1378/chest.10-2582 32. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail. 2009;11(2):130-9. http://dx.doi.org/10.1093/eurjhf/hfn013 33. Gazetopoulos N, Davies H, Oliver C, Deuchar D. Ventilation and haemodynamics in heart disease. Br Heart J. 1966;28(1):1-15. http:// dx.doi.org/10.1136/hrt.28.1.1 34. Ingram R Jr, McFadden ER Jr. Respiratory changes during exercise in patients with pulmonary venous hypertension. Prog Cardiovasc Dis. 1976;19(2):109-15. http://dx.doi.org/10.1016/0033-0620(76)90019-0 35. Johnson BD, Beck KC, Olson LJ, O’Malley KA, Allison TG, Squires RW, et al. Ventilatory constraints during exercise in patients with chronic heart failure. Chest. 2000;117(2):321-32. http://dx.doi. org/10.1378/chest.117.2.321

J Bras Pneumol. 2016;42(4):279-285 http://dx.doi.org/10.1590/S1806-37562015000000221

ORIGINAL ARTICLE

Evaluation of pulmonary function and respiratory symptoms in pyrochlore mine workers Ritta de Cássia Canedo Oliveira Borges1, José Cerqueira Barros Júnior2, Fabrício Borges Oliveira1, Marisa Andrade Brunherotti3, Paulo Roberto Veiga Quemelo3 1. Curso de Fisioterapia, Centro Universitário do Planalto de Araxá – UNIARAXÁ – Araxá (MG) Brasil. 2. Companhia de Mineração do Pirocloro de Araxá – COMIPA – Araxá (MG) Brasil. 3. Programa de Pós-Graduação em Promoção de Saúde, Universidade de Franca – UNIFRAN – Franca (SP) Brasil. Submitted: 10 September 2015. Accepted: 31 May 2016. Study carried out at the Centro Universitário do Planalto de Araxá – UNIARAXÁ – and at the Companhia de Mineração do Pirocloro de Araxá – COMIPA – Araxá (MG) Brasil.

ABSTRACT Objective: To identify respiratory symptoms and evaluate lung function in mine workers. Methods: This was a cross-sectional observational study involving production sector workers of a pyrochlore mining company. The subjects completed the British Medical Research Council questionnaire, which is designed to evaluate respiratory symptoms, occupational exposure factors, and smoking status. In addition, they underwent pulmonary function tests with a portable spirometer. Results: The study involved 147 workers (all male). The mean age was 41.37 ± 8.71 years, and the mean duration of occupational exposure was 12.26 ± 7.09 years. We found that 33 (22.44%) of the workers had respiratory symptoms and that 26 (17.69%) showed abnormalities in the spirometry results. However, we found that the spirometry results did not correlate significantly with the presence of respiratory symptoms or with the duration of occupational exposure. Conclusions: The frequencies of respiratory symptoms and spirometric changes were low when compared with those reported in other studies involving occupational exposure to dust. No significant associations were observed between respiratory symptoms and spirometry results. Keywords: Spirometry; Mining; Niobium; Occupational exposure.

INTRODUCTION Mining has historically been associated with health problems caused by occupational and environmental exposure to mine waste, particularly in developing countries.(1) Occupational and environmental pollution in the form of dusts, fumes, vapors, and toxic gases are risk factors for respiratory disorders.(2) The prevalence and severity of mining-related occupational lung diseases are a function of the commodities mined, the duration of occupational exposure, and the levels of occupational exposure, as well as of concomitant diseases, environmental conditions, and lifestyle.(3) There are few epidemiological data on pneumoconiosis in Brazil, and such data refer to some branches of mining and focal situations.(4) Exposure to mineral dust is known to be one of the precipitating causes for the development of pneumoconiosis, although there are other factors that may participate in its pathogenesis.(5) Among the lung diseases that are prominent in miners are silicosis, asbestosis, and coal worker’s pneumoconiosis.(6) The average expected time to the onset of pneumoconiosis and its diagnosis is approximately 10 years of working in mining(5); however, depending on the function performed by the worker, the time to disease onset may be less than 5 years.(7) Occupational lung diseases are considered a public health problem that poses potential risks to the country’s economy, because the country will have to support a proportion of patients who are unfit to work.

Therefore, the aim of understanding the pathophysiological mechanisms resulting from this type of exposure is to reduce the incidence of these diseases.(6,7) The state of Minas Gerais, Brazil, accounts for 75% of the entire worldwide production of pyrochlore. The state exports approximately 62,000 tons of ferroniobium (FeNb) annually, and it is estimated that this type of mining can be operated for a further 400 years.(8) Pyrochlore is part of a group of minerals that are of great economic interest, particularly as a source of niobium,(9) having many useful functions and applications in various economic branches, such as the aerospace, armament, and nuclear industries, as well as numerous other applications, such as optical lenses, high intensity lights, and electronic goods.(10) Niobium is considered an inert metal that causes low pulmonary reactivity.(11,12) However, we found no studies focusing on pulmonary function impairment and respiratory symptoms in workers exposed to niobium (pyrochlore). In view of these facts and because of the paucity of studies of workers exposed to pyrochlore, it is important to assess the effects that exposure to pollutants associated with pyrochlore have on the respiratory symptoms and pulmonary function of such workers, in order to establish parameters for intervention, prevention, and health promotion. In this context, the objective of the present study was to evaluate pulmonary function and identify respiratory symptoms in such miners, as well as to assess correlations among the study variables.

Correspondence to:

Ritta de Cássia Oliveira Borges. Avenida Ministro Olavo Drumond, 5, CEP 38180-129, Araxá, MG, Brasil. Tel.: 55 34 3669-2000 or 55 34 3669-2310. E-mail: rittadecassia@yahoo.com.br or rittaoliveira@uniaraxa.edu.br Financial support: None. © 2016 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Evaluation of pulmonary function and respiratory symptoms in pyrochlore mine workers

METHODS

Study subjects and study site This was a cross-sectional observational study involving production sector workers of one of the major open-pit producers of FeNb in the world. In order to produce FeNb, pyrochlore is first mechanically extracted from the ground. Subsequently, the pyrochlore concentrate is transformed into niobium concentrate, which is then mixed with iron oxide and aluminum, originating the final product: FeNb. Particulate matter is measured annually through sample monitoring, being considered respirable low-toxicity dust. It contains no silica or asbestos. The mining company conducts occupational risk assessments annually, in accordance with the Regulatory Guidelines of the Brazilian Ministry of Labor. The assessments are focused on each worker, targeting the environment, safety, and health, and are monitored by legal programs, such as the Occupational Health Medical Control Program, which includes chest X-ray, and the Respiratory Protection Program. The company provides personal protective equipment (PPE) and supervises its use, maintaining strict document control, with a controlled periodicity, and the use of PPE is monitored through ongoing on-site inspections. All workers use a FFP2 valved respirator providing protection against fine particles, fumes, and toxic mists (maximum filter penetration: 6%), and dust control is accomplished by wetting the site. On the basis of the total number of workers in the sector studied (N = 237), we used a convenience sample, consisting of 147 workers, corresponding to a margin of error of 5% and a 95% confidence interval. The inclusion criteria for participant selection were having a weekly workload ≥ 30 hours and having worked in mining for at least one year. We excluded subjects with severe cardiovascular disease, those with chronic lung disease and/or experiencing an exacerbation, and those with (rheumatologic, orthopedic, or neurologic) pathological conditions that prevented data collection. The workers evaluated were operational sector employees: machinery operators (n = 69); drivers (n = 53); controllers (n = 17); samplers (n = 9); and employees engaged in the heavy machinery repair and maintenance sector (n = 11). These workers could be involved in more than one function (e.g.: machinery operation and driving). Machinery operators and drivers perform activities involving the operation of bulldozers, excavators and rollers; drivers are those who are meant for trucks that hold approximately 12 tons and transport the extracted material to the material delivery points. Controllers are support workers in truck loading logistics and machinery logistics at the working fronts. Samplers are responsible for collecting material for mineralogical sampling. Mechanics perform general repair and maintenance of machinery. The present study was approved by the Research Ethics Committee of the University of Franca (Protocol no. 20973213.0.0000.5495), in accordance with Brazilian National Health Council Resolution 466/12. 280

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Data collection instruments Data were collected by means of a questionnaire eliciting sociodemographic, anthropometric, and occupational information. Respiratory symptoms, occupational exposure factors, and smoking status were assessed using the British Medical Research Council questionnaire (MRCQ). This questionnaire addressing respiratory symptoms and occupational exposure to inhaled pollutants is used by the Jorge Duprat Figueiredo Foundation for Occupational Safety and Medicine, located in the city of São Paulo, Brazil.(13) The MRCQ comprises questions on respiratory symptoms (cough, phlegm, wheezing, and dyspnea), history of illness in the past 2 years, and smoking history, as well as a checklist for previous illness. The question responses are dichotomous, and the questionnaire is administered in the workplace, always by the same investigator. After the questionnaire was administered, pulmonary function was assessed with a hand-held spirometer (Spirobank G; MIR, Rome, Italy), which can make direct graphic recordings, in accordance with the American Thoracic Society criteria.(14) Spirometry technical procedures, as well as acceptability and reproducibility criteria for spirometry, were in accordance with the standards adopted by Brazilian Consensus Guidelines for Spirometry.(15,16) The highest FVC value achieved was selected, and, for FEV1, the highest value obtained from the curves with PEF values within the acceptability criteria was taken into account.(15,16) All measurements were performed by the same investigator.

Data analysis and statistical treatment Workers were classified as symptomatic if they presented with at least one of four following respiratory symptoms: cough and phlegm for at least three months a year; wheezing (only when associated with breathlessness); and dyspnea (self-report of being unable to keep pace with another person of the same age, walking on level ground, or self-report of the need to stop and rest when walking on the flat at one’s own pace). Spirometry results were expressed as percentage of predicted.(16) To that end, reference values for FVC and FEV1 were calculated using reference equations for the Brazilian population.(17) Lung disease and severity of disease were classified in accordance with the Brazilian Spirometry Guidelines.(15) Body mass index (BMI) was classified as normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), class I obesity (30.0-34.9 kg/m2), class II obesity (35.0-39.9 kg/m2), and class III obesity (≥ 40.0 kg/m2).(18) Participants were categorized by smoking status as smokers, former smokers, or nonsmokers, and smoking history was quantified in pack-years. Every worker who reported smoking one or more cigarettes a day for more than one year and who continued smoking at the time of the interview was considered a smoker. Workers who reported quitting smoking more than one year prior were classified as former

Borges RCCO, Barros Júnior JC, Oliveira FB, Brunherotti MA, Quemelo PRV

smokers. Workers who had never experimented with cigarettes were considered nonsmokers. Pack-years were calculated by dividing the number of cigarettes smoked per day by 20 and multiplying that value by the number of years smoked.(19) The study population characteristics are given in tables, in which data are expressed as frequencies, proportions, means, standard deviations, and medians. The data were tabulated and analyzed with Microsoft Excel and GraphPad Prisma, version 6.0 (GraphPad Software, San Diego, CA, USA). Normality was tested with the Kolmogorov-Smirnov test, which revealed that the data were nonparametric in nature. The association between respiratory symptoms and spirometry results was assessed with the chi-square test, and, for contingency tables with at least one expected value of less than 5, we used Fisher’s exact test. The correlation between duration of working in mining and spirometric indices was assessed with Spearman’s correlation coefficient. For this correlation analysis, the worker data were divided into two sets: (1) workers who had never smoked; and (2) workers who smoked or were former smokers. The level of significance for all statistical tests was set at 5%. RESULTS All participants were males in the 23- to 61-year age group. The mean age was 41.37 ± 8.71 years.

Age group categorization revealed that 72.78% of the workers were between 30 and 50 years of age. Of the 147 workers, most were married (76.87%) and had completed high school (80.27%). Most workers were classified as overweight (48.97%). The mean duration of occupational exposure to dust was 12.26 ± 7.09 years, and 61.20% of the workers were nonsmokers (Table 1). Respiratory symptoms were reported by 33 workers (22.44%), some of whom reported more than one symptom; it is of note that, of those who were classified as symptomatic, 20 (35.08%) had a history of smoking or a history of former smoking (Table 2). Evaluation of pulmonary function revealed that most workers (n = 121; 82.31%) had normal spirometry results (Table 3). Of the workers who had normal spirometry results, 44 (36.4%) were smokers or former smokers. In addition, of the workers who were classified as having spirometric changes, 13 (22.8%) had a history of smoking or a history of former smoking. Figure 1 shows the scatter plots of the correlation between spirometry results and duration of working in mining for nonsmokers (Figures A) and for smokers and former smokers (Figures B). In both cases, the variables analyzed were found to correlate poorly. As for the association between respiratory symptoms and spirometric indices in the study participants, no significant values were observed (Table 4).

Table 1. General characteristics of the sample (N = 147).

Characteristic Age group, years < 30 30-50 > 50 BMI, kg/m2 Normal weight Overweight Obesity Class I Class II Class III Duration of mining exposure, years < 10 10-20 > 20 Smoking status Nonsmoker Former smoker Smoker Smoking history, pack-years Pulmonary function test FVC, % of predicted FEV1 , % of predicted FEV1/FVC, % of predicted FEF25-75%, % of predicted

9 107 31

6.12 72.78 21.10

33 72 42 35 6 1

22.44 48.97 28.59 83.33 14.28 2.39

88 57 2

59.86 38.77 1.36

90 35 22

61.20 23.80 15.00

Mean ± SD 41.37 ± 8.71

Median 42

27.83 ± 3.83

12.26 ± 7.09

23.67 ± 17.32

94.17 ± 14.45 95.24 ± 15.17 98.63 ± 7.18 101.26 ± 28.60

91 93 100 97

BMI: body mass index.

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DISCUSSION The respiratory symptom results found for the workers classified as symptomatic (22.4%) on the basis of the respiratory changes (cough, phlegm, wheezing, and dyspnea) in the present study do not corroborate the findings of a study in which a similar respiratory symptom questionnaire was used and 78% of the workers interviewed were found to have respiratory symptoms, 35% of whom had severe respiratory symptoms.(13) The difference between the findings may be due to the different mining activities the workers were engaged in and the mineral dust types they were exposed to, since silica is more aggressive than pyrochlore. A similar study showed that the most common symptoms, in order of frequency, were phlegm (41.7%), wheezing (33.0%), cough (31.9%), and dyspnea (9.7%)(20); in the present study, the results were similar, but the percentages were lower. Phlegm has also been found to be the most prevalent respiratory symptom in coal miners (36.4%).(21) The presence of respiratory symptoms may be associated with severity of disease and indicate cause for ongoing concern about the health status of workers.(22) However, the present study shows that the most common symptoms were phlegm and wheezing (in 10.2% of the sample for both); these rates do not suggest significant disease on the basis of the respiratory changes, as has been observed in studies of occupational disease.(20,23) The low frequency of respiratory symptoms in the present study can be explained by the specificity of the extracted mineral (pyrochlore) and by the institutional adoption of preventive measures, such as the Respiratory Protection Program, which includes several measures, from monitoring of dust levels to full provision of PPE to all workers and control regarding PPE use. Although the MRCQ has been used in other studies and investigations, it is important to emphasize that we found no studies describing the process of translation and validation of this instrument, and this should be considered a limiting factor of the present study. In the present study, we found that 15% of the workers were smokers and 23.8% were former smokers. Tobacco smoking is considered the greatest single avoidable cause of morbidity and mortality worldwide.(23) The relative importance of smoking in the respiratory health of occupational groups has previously been analyzed, with it being found that, in coal miners, the contribution of smoking to respiratory morbidity and mortality was more important than was occupational exposure, and that, in cases of exposure to silica or asbestos, the effects of those minerals on pulmonary function were similar in magnitude.(24) For occupational respiratory diseases, this cause-and-effect interaction seems unquestionable; tobacco smoking is the major confounding bias that should be taken into account in the analysis of the risk factor involved in the genesis of respiratory symptoms.(23) Smoking cessation leads to regression of bronchitic symptoms and to a trend toward a delayed decline in pulmonary function.(25) Little 282

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is known about the effects of occupational exposure cessation on symptoms and on pulmonary function; however, on the basis of knowledge of pathogenesis, it is assumed that the effects of occupational exposure cessation on symptoms are similar to those of smoking cessation.(23) The proportion of workers with normal spirometry results in the present study (82.3%) is consistent with that reported in a study of a group of workers involved in the production of fertilizers and exposed to different occupational products, conducted in the state of Rio Grande do Sul, Brazil,(26) as well as with that reported in studies in the area of occupational lung diseases.(21,23) A study conducted in the coal region in southernmost Santa Catarina, Brazil, found that most coal miners had normal spirometry results. Those findings were attributed to improvements in working conditions, to the use of PPE, and to the adoption of dust reduction measures in the workplace.(7) The lack of correlation between spirometric variables and duration of mining exposure is consistent with reports from other studies that also found no significant differences between duration of occupational exposure to dust and pulmonary function.(23,27) The findings are similar to those of a study of phosphate rock miners in Canada in which no reductions due to that occupational exposure were observed in the spirometric indices.Â (28) The workers studied had serial annual spirometry over 3 to 7 years, and no evidence was found of a sharp decline in FEV1 that could be attributed to the occupational exposure.(28) In contrast, a recently published study showed a correlation between duration of exposure to air pollutants that are present in the ceramics production process and pulmonary function abnormalities; however, such a correlation was found for workers who did not use PPE.(29) In the present study, no significant associations were observed between respiratory symptoms and Table 2. Worker distribution by respiratory symptom and smoking status (N = 147).a

Symptom

Cough Phlegm Wheezing Dyspnea

Smokers/former smokers (n = 57; 38.8%) 5 (8.77) 9 (15.78) 5 (8.77) 1 (5.75)

Nonsmokers (n = 90; 61.2%) 7 (7.77) 6 (6.66) 10 (11.11) 2 (2.22)

Values expressed as n (%).

Table 3. Worker distribution by spirometric classification and smoking status (N = 147).a

Classification (pattern) Normal Obstructive Restrictive Mixed

Overall

Smokers/ former smokers 121 (82.31) 44 (36.4) 13 (8.84) 6 (46.2) 12 (8.17) 6 (50.0) 1 (0.68) 1 (100.0)

Values expressed as n (%).

Nonsmokers

77 (63.6) 7 (53.8) 6 (50.0) 0 (0.0)

Borges RCCO, Barros JĂşnior JC, Oliveira FB, Brunherotti MA, Quemelo PRV

150

r = -0,1338 p= 0,2140

FVC, % of predicted

100

120 100 80 60

FEV1/FVC, % of predicted

FEF25-75%, % of predicted

120

10 20 30 Duration of working in mining

r = -0,3166 p= 0,0027

100 90 80 0

200

10 20 30 Duration of working in mining

r = -0,3312 p= 0,0016

100 50

10 20 30 Duration of working in mining

r = -0,0303 p= 0,8194

150 100 80

10 20 30 Duration of working in mining

r = -0,0150 p= 0,9102

120 110 100 90 80 70

200

150

110

r = -0,0885 p= 0,4119

FEV1, % of predicted

140

100

FEV1/FVC, % of predicted

FEV1, % of predicted

10 20 30 Duration of working in mining

FEF25-75%, % of predicted

r = -0,0441 p= 0,7398

150

10 20 30 Duration of working in mining

r = -0,1443 p= 0,2756

250 200 150 100 50 0

10 20 30 Duration of working in mining

Figure 1. Scatter plots of the correlation between spirometry results and duration of working in mining for nonsmokers (in A) and for smokers and former smokers (in B).

spirometric changes, similar to what was reported by De Capitani in his study of workers exposed to phosphate rock.(30) In contrast, in marble workers, a statistically significant difference has been found between dyspnea and spirometry results.(23) In another study, symptoms were associated only with a history of respiratory disease and with smoking.(20) It is important to point out that the findings of the present study were compared

with those of studies involving workers exposed to other mineral dusts with potentially different effects. In addition, chest X-rays were not performed in the present study, which makes it impossible to confirm the presence of pneumoconiosis. Company information indicates that, to date, there have been no recorded cases of pneumoconiosis in the workers exposed to mineral dust. J Bras Pneumol. 2016;42(4):279-285

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Evaluation of pulmonary function and respiratory symptoms in pyrochlore mine workers

Table 4. Association between respiratory symptoms and spirometry results (N = 147).a

Respiratory symptoms Cough No Yes

Spirometry results Normal

Abnormal

112 9 121

23 3 26

110 11 117

22 4 26

111 10 121

21 5 26

86 35 121

16 10 26

p 0.446*

Total Phlegm No Yes Total Wheezing No Yes Total Dyspnea No Yes Total

0.306*

0.144*

0.470**

Values expressed as n. *Fisher’s exact test. **Chisquare test.

It is well known how important it is to adopt measures for promoting worker health in the processes of improvement of quality of life, functionality, and productivity, whether on an occupational or personal level. These assumptions were confirmed in the present study, since the company has worker-targeted care programs that are based on ongoing activities to continuously monitor the workers and the workplace, encouragement of good health practices, and regular follow-ups with specialists. This study presents itself as an important guide to evaluating pulmonary function in workers involved in pyrochlore extraction activities, given that there are few studies in the literature evaluating possible respiratory diseases in workers with this type of exposure. It is possible that the low frequency of respiratory symptoms and spirometric changes in the pyrochlore miners, the poor correlation between respiratory symptoms and spirometry results, and the poor correlation between respiratory symptoms and duration of exposure to dust indicate good working conditions and the prevention of diseases in this sector, combined with the low toxicity of pyrochlore.

REFERENCES 1. Plumlee GS, Morman SA. Mine Wastes and Human Health. Elements. 2011;7(6):399-404. http://dx.doi.org/10.2113/gselements.7.6.399 2. Fernandes AL, Stelmach R, Algranti E. Occupacional asthma [Article in Portuguese]. J Bras Pneumol. 2006;32(Suppl 1):S27-S34. http:// dx.doi.org/10.1590/S1806-37132006000800006 3. Ross MH, Murray J. Occupational respiratory disease in mining. Occup Med (Lond). 2004;54(5):304-10. http://dx.doi.org/10.1093/ occmed/kqh073 4. Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde Departamento de Ações Programáticas Estratégicas. Saúde do trabalhador, protocolos de complexidade diferenciada. Série A. Brasília: Ministério da Saúde; 2006. 5. Souza Filho AJ, Alice SH, Luca V. Pneumoconiosis of coal mine workers [Article in Portuguese]. J Pneumol. 1981;7(2):57-66. 6. de Capitani EM, Algranti E. Other pneumoconioses [Article in Portuguese]. J Bras Pneumol. 2006;32(Suppl 2):S54-S59. http:// dx.doi.org/10.1590/S1806-37132006000800010 7. Souza FJ, Gallas MG, Souza Filho AJ. Documental analysis of the epidemiological profile of a group of coal miners in the southernmost region of Santa Catarina in 2006 [Article in Portuguese. Arq Catarin Med. 2013;42(4):73-8. 8. Instituto Brasileiro de Mineração - IBRAM [homepage na Internet]. Brasília: IBRAM [cited 2014 Oct 17]. Informações sobre a Economia Mineral do Estado de Minas Gerais. [Adobe Acrobat document, 14p.]. Available from: http://www.ibram.org.br/sites/1300/1382/00004355. pdf 9. Wall F, Williams CT, Wooley AR. Pyrochlore from weathered carbonatite at Lueshe, Zaire. Mineralog Mag. 1996;60:731-50. http:// dx.doi.org/10.1180/minmag.1996.060.402.03 10. Beynon H. Protesto Ambiental e Mudança Social no Reino Unido. Mana. 1999;5(1):7-28. http://dx.doi.org/10.1590/S010493131999000100001 11. Bagatin E, Pereira CA, Afiune JB. Granulomatous diseases of occupational etiology [Article in Portuguese]. J Bras Pneumol. 2006;32(Suppl 1):S69-S84. http://dx.doi.org/10.1590/S180637132006000800012 12. Dias da Cunha K, Lipztein JL, Azeredo AM, Melo D, Julião LM, Lamego FF, et al. Study of workers exposure to thorium, uranium and niobium mineral dust. Water Air Soil Pollut. 2002;137(1):45-61. http://dx.doi.org/10.1023/A:1015599406550 13. Rondon EN, Silva RM, Botelho C. Respiratory symptoms as health status indicators in workers at ceramics manufacturing facilities. J

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Bras Pneumol. 2011;37(1):36-45. http://dx.doi.org/10.1590/S180637132011000100007 14. Lung function testing: selection of reference values and interpretative strategies. American Thoracic Society. Am Rev Respir Dis. 1991;144(5):1202-18. http://dx.doi.org/10.1164/ajrccm/144.5.1202 15. Pereira CA. Espirometria. J Pneumol. 2002;28(Suppl 3):S1-S82. 16. Pereira CA. I Consenso Brasileiro sobre Espirometria. J Pneumol. 1996:22(3):105-64. 17. Pereira CA, Barreto SP, Simões JG, Pereira FW, Gerstler JG, Nakatani J. Valores de Referência para Espirometria em uma amostra da população brasileira adulta. J Pneumol. 1992;18(1):10-22. 18. Associação Brasileira para o Estudo da Obesidade e da Síndrome Metabólica (ABESO). Diretrizes brasileiras de obesidade 2009/2010. 3rd ed, Itapevi: AC Farmacêutica; 2009. 19. Almeida TA, Wiermann AL, Wiermann AL, Camargo JF,Johnsson RR, Martinelli FA, et al. Análise retrospectiva epidemiológica e de resultados de tratamento de pacientes portadores de câncer de pulmão metastático em instituição no Sul do Brasil. Rev Bras Oncol Clin. 2010;22(7):92-8. 20. Lemle A, Araújo AJ, Lapa e Silva JR, Lima FP, Santiago AC, Cardoso AP, et al. Sintomas respiratórios e testes espirográficos dos funcionários de uma pedreira do Rio de Janeiro. Rev Assoc Med Bras. 1994;40(1):23-35. 21. Algranti E. Métodos de investigação em doenças ocupacionais pulmonares. J Pneumol 1994;20:165-73. 22. Bagatin E, Jardim JR, Nery LE, Capitani EM, Marchi E, Sabino MO, et al. Ocorrência de silicose pulmonar na região de Campinas - SP. J Pneumol. 1995;21(1):17-26. 23. Pivetta AB, Botelho C. Prevalência de sintomas respiratórios e avaliação espirométrica em trabalhadores de marmorarias. J Pneumol. 1997;23(4):179-88. 24. Elmes PC. Relative importance of cigarette smoking in occupational lung disease. Br J Ind Med. 1981;38(1):1-13. http://dx.doi. org/10.1136/oem.38.1.1 25. Dockery DW, Speizer FE, Ferris BJ Jr, Ware JH, Louis TA, Spiro A 3rd. Cumulative and reversible effects of lifetime smoking on simple tests of lung function in adults. Am Rev Respir Dis. 1988;137(2):28692. http://dx.doi.org/10.1164/ajrccm/137.2.286 26. Hüttner MD, Moreira JS. Environmental and epidemiological evaluation of workers of the fertilizer industry of Rio Grande, RS [Article in Portuguese]. J Pneumol. 2000;26(5):245-53. http://dx.doi.

Borges RCCO, Barros JĂşnior JC, Oliveira FB, Brunherotti MA, Quemelo PRV

org/10.1590/S0102-35862000000500005 27. Hertzberg VS, Rosenman KD, Reilly MJ, Rice CH. Effect of occupational silica exposure on pulmonary function. Chest. 2002;122(2):721-8. http://dx.doi.org/10.1378/chest.122.2.721 28. Dutton CB, Pigeon MJ, Renzi PM, Feustel PJ, Dutton RE, Renzi GD. Lung function in workers refining phosphorus rock to obtain elementary phosphorus. J Occup Med. 1993;35(10):1028-33.

29. Salicio VA, Botelho C, Silva AM, Salicio MA. Factors associated with alterations in lung function among workers in the ceramics industry [Article in Portuguese]. Cienc Saude Colet. 2013;18(5):1353-60. http://dx.doi.org/10.1590/S1413-81232013000500020 30. De Capitani EM. Prevalence of pneumoconiosis among workers exposed to phosphate rock. Rev Saude Publica. 1989;23(2):98-106. http://dx.doi.org/10.1590/S0034-89101989000200003

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BRIEF COMMUNICATION

Recent transmission of drug-resistant Mycobacterium tuberculosis in a prison population in southern Brazil Ana Julia Reis1, Simone Maria Martini de David2, Luciana de Souza Nunes3, Andreia Rosane de Moura Valim3, Lia Gonçalves Possuelo3 1. Universidade Federal do Rio Grande, Rio Grande, Rio Grande do Sul, Brasil. 2. Laboratório Central do Estado do Rio Grande do Sul (IPB-LACEN/RS), Rio Grande do Sul, Brasil. 3. Programa de Pós-Graduação em Promoção da Saúde, Centro de Pesquisa e Treinamento em Biotecnologia – CPTBio – Universidade de Santa Cruz do Sul, Santa Cruz do Sul, Rio Grande do Sul, Brasil. Submitted: 21 January 2016. Accepted: 19 April 2016. Study carried out at the Universidade Federal do Rio Grande, Rio Grande, and at the Universidade de Santa Cruz do Sul, Santa Cruz do Sul (RS) Brasil.

ABSTRACT We conducted a cross-sectional, retrospective study, characterized by classical and molecular epidemiology, involving M. tuberculosis isolates from a regional prison in southern Brazil. Between January of 2011 and August of 2014, 379 prisoners underwent sputum smear microscopy and culture; 53 (13.9%) were diagnosed with active tuberculosis. Of those, 8 (22.9%) presented with isoniazid-resistant tuberculosis. Strain genotyping was carried out by 15-locus mycobacterial interspersed repetitive unitvariable-number tandem-repeat analysis; 68.6% of the patients were distributed into five clusters, and 87.5% of the resistant cases were in the same cluster. The frequency of drug-resistant tuberculosis cases and the rate of recent transmission were high. Our data suggest the need to implement an effective tuberculosis control program within the prison system. Keywords: Tuberculosis; Prisons; Molecular epidemiology.

Chief among the factors contributing to the increasing incidence of tuberculosis in prison populations are: male gender; a low level of education; coming from a disadvantaged community; illicit drug use; a high prevalence of HIV infection; limited access to health care; overcrowded, poorly lit, and poorly ventilated cells; and a lack of information on tuberculosis.(1,2) In addition, studies have shown that both a higher frequency of prior arrests and length of incarceration are directly associated with a higher incidence of this disease.(3,4) In recent years, the incidence of tuberculosis has decreased worldwide, with a 45% reduction in the number of cases between 1990 and 2012. According to the World Health Organization, Brazil ranks 19th among the 22 countries that collectively account for 80% of all cases of tuberculosis worldwide.(5) However, the incidence rates of the disease in Brazil and in the Brazilian state of Rio Grande do Sul have remained unchanged. In 2013, a total of 78,628 cases were reported in Brazil, and, of those, 6,378 (8.1%) were reported for the prison population. In the state of Rio Grande do Sul, 6,917 cases were reported in 2014, with 9.4% of those cases being reported for the prison population.(6) In the prison population, it is possible to determine recent transmission of tuberculosis, characterized by the identification of genetically similar strains, within the prison facilities. Through active surveillance and the aid of molecular biology methods, the clonal relationship among strains can be determined, which is useful for epidemiological investigations, as well as for identification

of genetically related strains and their spread among the prison population.(7) The increasing incidence of cases of tuberculosis caused by drug-resistant strains of Mycobacterium tuberculosis is directly associated with inappropriate treatment or treatment nonadherence. Delayed detection of the disease, in patients with resistance, allows continuing transmission of these strains in a given population.(8,9) M. tuberculosis genotyping is a useful tool for epidemiological studies, as well as for identifying clonal spread, any highly prevalent strains, and outbreaks. Among the current genotyping techniques, mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) has been used because it has similar discriminatory power to that of RFLP and because it employs PCR, which results in reduced completion time and reduced complexity when compared with RFLP.(10) The objective of the present study was to determine the epidemiological profile of cases of tuberculosis in a prison in southern Brazil, by using classical and molecular epidemiology. We conducted a cross-sectional, retrospective study of M. tuberculosis isolates from patients diagnosed with tuberculosis in the Santa Cruz do Sul Regional Prison, in the city of Santa Cruz do Sul, Rio Grande do Sul, Brazil, between January of 2011 and August of 2014. This is a medium-sized prison with health care staff. During the study period, 873 sputum smears were performed, accounting for 379 convicts; of those, 53 were diagnosed with tuberculosis in prison, indicating a prevalence of 80

Correspondence to:

Lia Gonçalves Possuelo. Universidade de Santa Cruz do Sul, Avenida Independência, 2293, Universitário, CEP 96815-900, Santa Cruz do Sul, RS, Brasil. Tel.: 55 51 8471-3720. E-mail: liapossuelo@unisc.br Financial support: This study received financial support from the Brazilian Ministério da Ciência, Tecnologia e Inovação/Conselho Nacional de Desenvolvimento Científico e Tecnológico (MCTI/CNPq, National Ministry of Science, Technology, and Innovation/National Council for Scientific and Technological Development; Grant no. MCTI/CNPq/ UNIVERSAL 14/2014) and the Programa de Capacitação e Difusão Tecnológica/Fundação Estadual de Produção e Pesquisa em Saúde (PADCT/FEPPS, Education and Technology Diffusion Program/[Rio Grande do Sul] State Foundation for Health Science Research; Grant no. PADCT/FEPPS/2014).

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Reis AJ, David SMM, Nunes LS, Valim ARM, Possuele LG

cases per 100,000 population. M. tuberculosis isolates were obtained from 35 different patients (66%). The clinical isolates from those patients, which were subcultured in Ogawa-Kudoh medium and incubated at 37°C for 4-8 weeks, were derived from a sample bank maintained by the Institute of Biological Research, Rio Grande do Sul State Central Laboratory. The 35 isolates were tested for susceptibility to isoniazid, ethambutol, rifampin, and pyrazinamide by the method of proportions(11) and were genotyped by a PCR-based method using 15-locus MIRU-VNTR analysis.(12) Demographic and prison-related data were obtained from the Integrated System of Penitentiary Information, which is regularly updated by prison officers, who provide data such as length of incarceration, history of incarceration, visits, number of inmates per cell, and changes of cells. The clinical and laboratory data of the patients were collected from the Rio Grande do Sul State Central Laboratory and the Santa Cruz do Sul municipal tuberculosis outpatient clinic. The epidemiological variables analyzed included age, gender, level of education, HIV infection, cell block, length of incarceration, history of incarceration, total length of incarceration, and number of changes of cells. The degree of relatedness among strains (genotype numbers) was compared by constructing a dendrogram. (13) The epidemiological, clinical, and prison-related data were evaluated with the IBM SPSS Statistics software package, version 20.0 (IBM Corp.,

Armonk, NY, USA). Values are presented as means and standard deviations or as absolute numbers and proportions. Means were compared by the Student’s t-test, and categorical variables were compared by Pearson’s chi-square test. Values of p ≤ 0.05 were considered significant. The research project was approved by the Research Ethics Committee of the Rio Grande do Sul State Foundation for Health Science Research (Ruling no. 984.264). Of the 35 individuals included in the study, all were male (100%), with a mean age of 33.2 years; 31 (88.6%) had had 9 years of schooling (Table 1). A total of 28 (80.0%) had been in prison for more than 3 years, and all (100%) had been arrested more than once, with the mean number of times arrested being 8.9 ± 5.2. Data regarding changes of cell were obtained for 34 individuals, all of whom had changed cells more than once during their incarceration period. In terms of the spatial distribution of the tuberculosis cases within the prison facility, we found that 10 individuals (27.8%) had remained longer in cell block C than in the other cell blocks. With regard to clinical characteristics, HIV test results were available for 19 patients (52.8%), 1 (5.3%) of whom tested positive. There were 21 patients (58.3%) with a positive AFB-smear and 35 (100%) with a positive culture, and culture resulted in a 41.7% increase in sensitivity for the diagnosis of tuberculosis.

Table 1. Patient clinical, demographic, and prison-related characteristics by classification as cluster or non-cluster cases.a

Variable Cluster Age, years 34.10 ± 11.85 Level of education 9 years of schooling 20 (64.5) High school 3 (100.0) Illiterate 1 (100.0) Cell block A 7 (77.8) B 5 (100.0) C 8 (80.0) D 2 (33.3) Length of incarceration Up to 3 years 3 (42.9) More than 3 years 21 (75.0) Number of times arrested Up to 10 times 18 (72.0) More than 10 times 6 (60.0) Number of inmates per cell Up to 6 5 (100.0) More than 6 17 (68.0) Visits Yes 13 (72.2) No 11 (64.7) Conjugal visits Yes 10 (83.3) No 14 (60.9) a Values expressed as n (%) or as mean ± SD.

Non-cluster 31.40 ± 7.75

Total 33.20 ± 10.70

11 (35.5) 0 (0.0) 0 (0.0)

21 (88.6) 3 (8.6) 1 (2.9)

2 (22.2) 0 (0.0) 2 (20.0) 4 (66.7)

9 (25.7) 5 (14.3) 10 (28.6) 6 (17.1)

4 (57.1) 7 (25.0)

7 (20.0) 28 (80.0)

0.17

7 (28.0) 4 (40.0)

25 (71.4) 10 (28.6)

0.68

0 (0.0) 8 (32.0)

5 (16.7) 25 (83.3)

0.28

5 (27.8) 6 (35.3)

18 (51.4) 17 (48.6)

0.72

2 (16.7) 9 (39.1)

12 (34.3) 23 (65.7)

0.25

0.49

0.35

0.07

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Recent transmission of drug-resistant Mycobacterium tuberculosis in a prison population in southern Brazil

Of the 35 isolates undergoing genotyping, 24 (68.6%) were found to be grouped into five clusters, named from A to E, each containing 3 to 7 individuals (FigureÂ 1). Patient clinical, demographic, and prison-related data, by classification as cluster or non-cluster cases, are presented in Table 1.

41.7% increase in sensitivity achieved by culture, when compared with smear microscopy, emphasizes the need to perform culture in order to increase the tuberculosis case detection rate.(14) Although HIV testing is mandatory for patients with tuberculosis, HIV test results were available for only 52.8%, with one case of HIV-tuberculosis coinfection being identified (5.3%), a value that is lower than that reported in studies conducted in southern Brazil.(15,16)

Of the 35 isolates assessed regarding their drug susceptibility profile, 8 (22.9%) were isoniazid mono-resistant. A total of 87.5% of the resistant isolates were in the same cluster (D), with patients being distributed between cell blocks A and B, which are located on the prison same wing. The two largest clusters, B and D, accounted for 52.0% of the strains and contained all cases of drug resistance.

Of the isolated strains, 24 (68.6%) were found to be grouped into five clusters. In a study conducted in another prison in Rio Grande do Sul, 58.3% of the isolates had an identical genetic profile.(14) Although this high rate of clustering suggests recent transmission, which might have occurred within the prison facility, the lack of studies of isolates obtained from the local extramural population is a limiting factor for the present analysis.(17,18)

Of the 35 patients whose isolates were tested for antimicrobial susceptibility, 28 (80.0%) had been in prison for more than 3 years and all (100%) had been arrested more than once, with the mean number of times arrested being 8.9 Âą 5.2, a mean that is higher than that reported in a study conducted in southern Brazil.(14)

Isoniazid mono-resistance was identified in 8 isolates (22.9%), 7 (87.5%) of which were in the same cluster (p < 0.05), supporting the hypothesis of recent transmission of the bacilli.(19,20) The high resistance rate

One of the major obstacles to tuberculosis control is the accurate and early detection of cases. The 10 2 20 27 7 28 37 4 43 44 45 15 17 8 16 21 35 26 25 5 11 18 23 29 30 34 39 14 22 42 9 19 32 41 38

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4 4 4 3 3 3 4

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 1 1 1 1 1 1 1 1 1 1 6 6 7 8

4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 4 4 4 4 4 4 4 3 3 3 3 4 4 4 4

2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 1 1 1 1 1 1 1 1 1 1 1 4 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 2 2 2

5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

4 4 4 4 4 4 4 4 4 4 4 4 4 4 2 2 2 2 2 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 5 3 3 3 3 3 3 3 4 4 4 4 5 5 5 5

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 3 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

7 7 7 7 7 7 7 7 7 7 7 7 7 7 5 5 5 5 5 7 7 7 7 7 7 7 7 8 8 8 8 7 7 7 7

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 3 3 3 2

SUSCEPTIBLE

RESISTANT

SUSCEPTIBLE

CLUSTER B

SUSCEPTIBLE

CLUSTER C

RESISTANT

CLUSTER D

SUSCEPTIBLE

CLUSTER E

0.1 Figure 1. Dendrogram showing the clustering patterns associated with the drug susceptibility profile.

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CLUSTER A

Reis AJ, David SMM, Nunes LS, Valim ARM, Possuele LG

observed in our study is higher than that reported in other studies.(7,14) Drug resistance is considered to be a major problem in closed institutions, where outbreaks can reach epidemic proportions.(14) Cluster D, consisting of 7 patients who had resistance to isoniazid, was distributed between cell blocks A and B (both of which are located on the same prison wing and have a common exercise yard); although the individuals were not in the same cell, it should be taken into account that contact among inmates can take place in the exercise yard and that changes of cells and cell blocks are common. The present study showed that the percentage of isoniazid-resistant isolates and the frequency of isolates sharing the same genotype were high. These data support the possibility that transmission of the

bacillus occurred predominantly within the prison facility. Tuberculosis control in prison facilities depends on an effective disease control program, including active search for individuals with respiratory symptoms, prompt diagnosis, and directly observed treatment, within the prison system. In addition, providing continuing education for prison system workers and discussing the topic “prison health care” in other forums, such as community councils, can bring numerous benefits to tuberculosis control in prisons. ACKNOWLEDGMENTS We would like to thank Daniela Becker, Eloete tahlecker, Vanda Hermes, Pedro Almeida da Silva, S Augusto Weber, Graziela Hamann de Freitas, and João L. Scaini for their assistance in the various stages of the study.

REFERENCES 1. Brasil. Ministério da Saúde. Manual de Recomendações para o Controle da Tuberculose no Brasil. Brasília: Ministério da Saúde; 2011. 2. Moreira TR, Fávero JL, Maciel EL. Tuberculose no sistema prisional capixaba. Rev Bras Pesq Saude. 2010;12(1):26-33. 3. Carbone Ada S, Paião DS, Sgarbi RV, Lemos EF, Cazanti RF, Ota MM, et al. Active and latent tuberculosis in Brazilian correctional facilities: a cross-sectional study. BMC Infect Dis. 2015;15:24. http:// dx.doi.org/10.1186/s12879-015-0764-8 4. Urrego J, Ko AI, da Silva Santos Carbone A, Paião DS, Sgarbi RV, Yeckel CW, et al. The Impact of Ventilation and Early Diagnosis on Tuberculosis Transmission in Brazilian Prisons. Am J Trop Med Hyg. 2015;93(4):739-46. http://dx.doi.org/10.4269/ajtmh.15-0166 5. World Health Organization. Global Tuberculosis Report 2014. Geneva: World Health Organization; 2014. 6. Brasil. Ministério da Saúde. Sistema de Informação de Agravos de Notificação [homepage on the Internet]. Brasília: Ministério da Saúde [updated 2015 Nov 16; cited 2015 Nov 28]. Banco de dados sobre tuberculose do DATASUS Available from: http://dtr2004.saude.gov. br/sinanweb/tabnet/dh?sinannet/tuberculose/bases/tubercbrnet.def 7. Kuhleis D, Ribeiro AW, Costa ER, Cafrune PI, Schmid KB, Costa LL, et al. Tuberculosis in a southern Brazilian prison. Mem Inst Oswaldo Cruz. 2012;107(7):909-15. http://dx.doi.org/10.1590/S007402762012000700012 8. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis Geneva: World Health Organization; 2011. 9. Valim AR, Possuelo LG, Cafrune PI, Borges M, Ribeiro MO, Rossetti ML, et al. Evaluation and Genotyping of Multidrug-Resistant Cases of Tuberculosis in Southern Brazil. Microb Drug Resist. 2006;12(3):18691. http://dx.doi.org/10.1089/mdr.2006.12.186 10. Pereira AM, Santos LC, Fernandes HB, Alves SL, Junqueira-Kipnis AP, Kipnis A. Análise molecular de Mycobacterium tuberculosis isolados de pacientes atendidos em Goiânia, Goiás, por meio do RFLP-IS6110 e do 15 loci MIRU-VNTR. Rev Patol Trop. 2013;42(3):275-88. http:// dx.doi.org/10.5216/rpt.v42i3.26925 11. Brasil. Ministério da Saúde. Manual Nacional de Vigilância Laboratorial da Tuberculose e outras Micobactérias. Brasília: Ministério da Saúde; 2008. 12. Supply P. Multilocus Variable Number Tandem Repeat Genotyping

of Mycobacterium tuberculosis: Technical Guide [monograph on the internet]. Lille: Institut de Biologie/Institut Pasteur de Lille; 2005 [updated 2015 Sep 10; cited 2015 Set 25]. [Adobe Acrobat document, 74p.]. Available from: http://www.miru-vntrplus.org/ MIRU/files/MIRU-VNTRtypingmanualv6.pdf 13. MIRU-VNTRplus [homepage on the Internet]. Münster: MIRUVNTRplus [updated 2015 Jun 16; cited 2015 Jun 30]. Available from: http://www.miru-vntrplus.org/MIRU/index.faces 14. Valença MS, Scaini JL, Abileira FS, Gonçalves CV, von Groll A, Silva PE. Prevalence of tuberculosis in prison: risk factors and molecular epidemiology. Int J Tuberc Lung Dis. 2015;19(10):1182-7. http:// dx.doi.org/10.5588/ijtld.15.0126 15. Valença MS, da Rocha JZ, Ramis IB, Carrion LL, Madruga C, de Macedo MB, et al. Improving tuberculosis control through the partnership between university and the health system. Rev Soc Bras Med Trop. 2012;45(4):491-5. http://dx.doi.org/10.1590/S003786822012005000004 16. Noguti EN, Leite CQ, Malaspina AC, Santos AC, Hirata RD, Hirata MH, et al. Genotyping of Mycobacterium tuberculosis isolates from a low-endemic setting in northwestern state of Paraná in Southern Brazil. Mem Inst Oswaldo Cruz. 2010;105(6):779-85. http://dx.doi. org/10.1590/S0074-02762010000600008 17. Ibrayeva A, Kozhamkulov U, Raiymbek D, Alenova A, Igilikova S, Zholdybayeva E, et al. Molecular epidemiology of Mycobacterium tuberculosis strains circulating in the penitentiary system of Kazakhstan. Int J Tuberc Lung Dis. 2014;18(3):298-301. http://dx.doi. org/10.5588/ijtld.13.0558 18. Scholante Silva AB, Von Groll A, Félix C, Conceição FR, Spies FS, Scaini CJ, et al. Clonal diversity of M. tuberculosis isolated in a sea port city in Brazil. Tuberculosis (Edinb). 2009;89(6):443-7. http:// dx.doi.org/10.1016/j.tube.2009.05.009 19. Toungoussova OS, Mariandyshev A, Bjune G, Sandven P, Caugant DA. Molecular epidemiology and drug resistance of Mycobacterium tuberculosis isolates in the Archangel prison in Russia: predominance of the W-Beijing clone family. Clin Infect Dis. 2003;37(5):665-72. http://dx.doi.org/10.1086/377205 20. Portugal I, Barreiro L, Vultos T, Macedo R, Furtado C, Fonseca Antunes A, et al. Molecular epidemiology of Mycobacterium tuberculosis in Lisbon. Rev Port Pneumol. 2008;14(2):239-59. http:// dx.doi.org/10.1016/S0873-2159(15)30233-6

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Smoking control: challenges and achievements Luiz Carlos Corrêa da Silva1, Alberto José de Araújo2, Ângela Maria Dias de Queiroz3, Maria da Penha Uchoa Sales4, Maria Vera Cruz de Oliveira Castellano5; Comissão de Tabagismo da SBPT 1. Pavilhão Pereira Filho, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre (RS) Brasil. 2. Núcleo de Estudos e Tratamento do Tabagismo, Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 3. Hospital São Julião, Campo Grande (MS) Brasil. 4. Hospital de Messejana, Fortaleza (CE) Brasil. 5. Hospital do Servidor Público Estadual de São Paulo, São Paulo (SP) Brasil. Submitted: 8 May 2016. Accepted: 7 July 2016. Study carried out by the Comissão de Tabagismo, Sociedade Brasileira de Pneumologia e Tisiologia – SBPT – Brasília (DF) Brasil.

ABSTRACT Smoking is the most preventable and controllable health risk. Therefore, all health care professionals should give their utmost attention to and be more focused on the problem of smoking. Tobacco is a highly profitable product, because of its large-scale production and great number of consumers. Smoking control policies and treatment resources for smoking cessation have advanced in recent years, showing highly satisfactory results, particularly in Brazil. However, there is yet a long way to go before smoking can be considered a controlled disease from a public health standpoint. We can already perceive that the behavior of our society regarding smoking is changing, albeit slowly. Therefore, pulmonologists have a very promising area in which to work with their patients and the general population. We must act with greater impetus in support of health care policies and social living standards that directly contribute to improving health and quality of life. In this respect, pulmonologists can play a greater role as they get more involved in treating smokers, strengthening anti-smoking laws, and demanding health care policies related to lung diseases. Keywords: Tobacco products; Smoking; Health policy; Smoking cessation; Health personnel.

INTRODUCTION The primary objective of the present article was to offer, particularly to pulmonologists, smoking-related information that can aid in the daily practice of delivering care to smoking patients at the medical office. Since the middle of last century in Brazil, some pulmonologists have called attention to the health hazards of smoking, and this at a time when pro-tobacco media messages were overt and the scientific evidence on the causes of such hazards was inconsistent. They devoted themselves to the cause of smoking cessation as true champions of health, hacking their way through a jungle infested with ignorance, commercial interests, tax greed, pro-tobacco media messages, and also the social acceptability of smoking. In honoring José Rosemberg and Mario Rigatto, we pay tribute to all. The Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association) Commission on Smoking started its representative activities in 2000 and, thanks to the work of its members, has made the SBPT one of the most active and respected Brazilian institutions in this sector. It participated in the major initiatives that resulted in the enactment of the Anti-Smoking Law (Brazilian Federal Law no. 12,546/2011),(1) in partnership with governmental and non-governmental entities: the Brazilian National Ministry of Health Instituto Nacional do Câncer (INCA, National Cancer Institute); the Comissão Nacional para Implementação da Convenção-Quadro para o Controle do Tabaco (CONICQ, Brazilian National

Commission for Implementation of the Framework Convention on Tobacco Control); the Aliança de Controle do Tabagismo + Saúde (ACT+, Alliance for the Control of Smoking + Health); the Associação Médica Brasileira (AMB, Brazilian Medical Association); and the Brazilian Federal Medical Council. Through the “Letter from Gramado”, issued during the Brazilian Pulmonology Conference held in that Brazilian city in 2014, the position of the SBPT regarding smoking became more strongly consolidated.(2) Differential characteristics of the SBPT regarding smoking include its active leadership, pulmonologist training programs in treating smokers, the dissemination of the concept that “smoking is a treatable disease”, and ongoing initiatives for the development of policies for the control of this pandemic. Some important facts have underpinned the successive initiatives undertaken in recent decades to control smoking. The large study by Doll et al.,(3) involving a cohort of 35,000 British physicians, followed for more than five decades, effectively showed the hazards caused by smoking, particularly the remarkable increase in the prevalence of lung cancer. In addition, there is the huge set of information that has been obtained in recent decades and that invariably points to unequivocal evidence on the risks and hazards of smoking. In the USA, a ruling by Judge Gladys Kessler,(4) who compiled a large dossier on the consequences of smoking and the fraudulent strategies employed by the tobacco industry (TI), resulted in US tobacco companies being sentenced to pay billions of dollars. The development of the Framework

Correspondence to:

Luiz Carlos Corrêa da Silva. Rua Pedro Ivo, 532/302, Mont’Serrat, CEP 90450-210, Porto Alegre, RS, Brasil. Tel.: 55 51 9991-0974 or 55 51 3221-8522. E-mail: lccsilva@yahoo.com.br Financial support: None.

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Convention on Tobacco Control (FCTC),(5) the first and largest international public health treaty negotiated by the World Health Organization (WHO), in 2005, was a milestone in the control of this pandemic with devastating consequences. In Brazil, the key role of the initiatives and interventions of the INCA,(6) the CONICQ,(7) and the ACT+(8) is of note, as is that of medical organizations. Since tobacco production and sales, mainly in the form of cigarettes, remain a component of the State’s economic policy and tobacco consumption remains a component of society’s everyday life, bringing huge economic gains to the industry and its shareholders, there remains an enormous power that ensures the survival of this sector. Analysis of such a scenario leads to the conclusion that there will be little progress beyond our current state, at least within the desired time frame, if serious initiatives are not undertaken to fight the TI, especially regarding its interference in the implementation of the health policies recommended by the FCTC. The health argument will not be strong enough to ban tobacco, a drug that is produced and distributed legally, and, therefore, smoking will still continue in this century and will probably reach the 22nd century. In addition to tobacco control and education policies, there is a need for other ways to act and strengthen the network, which will make it possible for future generations to wipe this pest off the face of the earth. It will be indispensable to tax the leaf export prices and the sales of other tobacco products exemplary. In addition, taxes should be established by law in order to meet the public health system and social security expenditures for tobacco-related diseases. Furthermore, it is urgent that all those involved, from an economic standpoint, in the tobacco supply chain be punished by justice for the harm they have caused to tobacco victims, an event rarely seen in Brazil. Let us analyze some issues from the standpoint of the TI. The major motivation and strength of the TI, which is also its Achilles’ heel, are its positive financial results. The TI buys political support by providing funds and resources to election campaigns, by covering the needs of opportunist people and groups, and by exchanging benefits with other sectors. The TI very well knows how to maneuver the so-called fragile sectors, such as the family agriculture sector, which still is highly dependent on tobacco cultivation. In addition, the TI relies on the vulnerability of smokers, who, because they are dependent, cannot deal rationally with this risk factor for their health and life. If legal readings are up to date, correct, and impartial and the TI has to pay millions of dollars in compensation for harm caused to tobacco users, the TI certainly will not be able to stay in business. Let us consider the standpoint of activists and governmental and non-governmental groups and organizations devoted to tobacco and smoking control. The government support has been feeble, although there has been a state

policy (embodied in law) ratifying the FCTC since 2005. Unfortunately, as a rule, the government only thinks of the immediate revenues generated by taxes, revenues that in fact are much lower than the expenditures for tobacco-related diseases. In addition, the TI, through effective lobbying strategies, has secured support from distinguished representatives of various spheres of government, all of whom defend its corporate rights. Rarely do political leaders take a firm stand and affirm their decisions regarding the implementation of laws that are more restrictive of tobacco consumption or regarding diversification of tobacco cultivation. Some exceptions include Uruguay’s President Tabaré Vázquez, an oncologist, in 2003; former New York Mayor Michael Bloomberg, a philanthropist, in 2005; and former São Paulo State Governor José Serra, an economist, in 2009. Although there have been many anti-tobacco achievements, they often become fragmented and discontinuous, and maintaining them is difficult and laborious given the fire power of the TI, which is always on the alert and relies on many lobbyists and other pressure groups, usually linked to trade associations of bars, restaurants, hotels, and bakeries, that act as “façade groups” defending the interests of the TI. Networking has been very efficient and important for the continuity of initiatives and should be encouraged and increased, despite the fact that maintaining it is very exhausting. For the purpose of networking, partnerships should be established with institutions that are interested in the topic and have members with ability to foster teamwork, in order to devise strategies that are stronger and will attract more followers and more leaders, particularly those working with civil society and those with political influence. Everything that has been achieved should be maintained—and there have been no few advances in Brazil—however, compensation claims for harm suffered by citizens should be particularly encouraged as consistently as possible. To that end, there is now an instrument devised by the AMB, the ACT+, and other institutions, among which is the SBPT: an AMB guideline called “Evidências Científicas sobre Tabagismo para Subsídio ao Poder Judiciário” (Scientific Evidence on Smoking for Use by the Judiciary).(9) This guideline needs to be incorporated into practice and used as a reference by the justice sector in the analysis of such claims. Below, we address some topics considered of particular importance, with which pulmonologists need to be familiar and which they need to explore further with a view to their practice and to their contribution to smoking control. CONCEPTS For over two decades, smoking has been considered to be a neurobehavioral disorder caused by nicotine dependence.(10) In addition, there are numerous other factors, especially behavioral and psychological ones, J Bras Pneumol. 2016;42(4):290-298

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that induce smoking and therefore hinder smoking cessation. Anxiety, depression, disorders of various natures, psychiatric problems, low self-esteem, automatisms, triggers, and customs, as well as psychosocial, cultural, and genetic factors, are inducers. In contrast, reproaches, restrictive pressures, anti-smoking laws, etc. are smoking control measures. It is necessary to understand that people smoke because they are dependent and not just because they want to.(9) Smoking, in addition to being a chronic disease caused by nicotine dependence, is one of the major risk factors for diseases and high mortality. Contrary to what was advertised for years, smoking is not a lifestyle choice, a sign of charm, a sociability factor, or an expression of choice or free will, nor does it bring economic advantages to the government or to society.(11) CONSEQUENCES OF SMOKING According to data from the WHO,(12) the major causes of human mortality, accounting for more than 68% of deaths, are chronic noncommunicable diseases, many of which are tobacco-related: cardiovascular disease (particularly acute myocardial infarction); cancer (in the lung and in other sites); stroke, and COPD. By not smoking or by quitting smoking, you can reduce the risk of developing these diseases by more than 30%, with reductions being as high as 90% for lung cancer and for COPD. Nonsmokers have a better quality of life and live 10 to 15 years longer.(13) One of the consequences of passive smoking, that is, cardiovascular damage, was studied by Lightwood & Glantz, who found that, after the implementation of smoke-free environments in several countries, there was a nearly 30% reduction in acute cardiac events in the short term.(14) It has recently been shown that the harmful effects of tobacco are transmitted across generations, increasing the risk of asthma intergenerationally, that is, from mother to son, and transgenerationally, that is, from grandparents to grandchildren, even if the mother does not have asthma and does not smoke. There is evidence that the smoking of the maternal grandmother while pregnant with the mother increases the risk of asthma development in the grandchild by two to three times, even if the mother did not smoke during pregnancy and does not have asthma.(15) The American Cancer Society has released a report on smokers who are dying from diseases hitherto considered unrelated to tobacco.(16) Fourteen additional diseases were associated with smoking: breast cancer; prostate cancer; renal failure; intestinal ischemia; arterial hypertension; and infections; as well as several other respiratory diseases in addition to COPD. This resulted in an increase of 17% in mortality. SMOKING TREND In developed countries and in some developing countries, a marked reduction in the prevalence of 292

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smoking has been achieved. However, in the world as a whole, this prevalence is increasing, particularly in countries with low economic resources and in poorer and less educated populations. In 2014, there were six million deaths from tobacco-related diseases, and, by 2030, this figure could reach eight million if nothing of great impact is done to control the pandemic.(17) Since the 1980s, Brazil has been noteworthy for developing progressively more effective control policies, which has reduced the prevalence of smoking in the adult population from 35% in 1989(18) to 14.7% in 2013.(19) Although there are more than 26 million former smokers in Brazil, since many people have quit smoking on their own or with treatment, there are still 22 million smokers who need treatment. These “residual smokers” may have more difficulty in quitting smoking, whether because they have greater nicotine dependence, behavioral disorders, or psychiatric disorders or because of other factors hindering cessation, among which are genetic, social, and environmental factors. This large group has yet to be properly studied. The TI, in turn, always develops new strategies and tricks to sell its products. Electronic cigarettes, waterpipe tobacco smoking, smokeless tobacco (snus), and new nicotine delivery devices need to be controlled and contained, under penalty of losing the ground gained in smoking control. The TI and its shareholders have great expectations for this new vein of the market, since these products have led most users to believe—by misinformation and manipulation through strong advertising campaigns—that they are harmless and do not cause the health hazards known to be associated with the traditional forms of smoking (cigarettes, cigars, and pipes). Forecasts by insurance entities indicate such an exponential growth with the explosion in electronic cigarette sales that these sales may surpass conventional cigarette sales in a few decades. Initiation of the use of these electronic nicotine delivery devices has reached a reasonable portion of the population. The total volume of conventional cigarettes sold, accounting for US$85 billion in retail sales, has been declining at an annual rate of 3-4%.(20) In recent years, the decline has accelerated, mainly because of the ban on indoor smoking, health concerns, pricing policies, and other government regulations resulting from the WHO FCTC.(6) It is estimated that electronic cigarette sales will grow exponentially between 2015 and 2023, and that, by 2022, electronic cigarette sales will surpass conventional cigarette sales and will continue on a upward curve.(21) Therefore, after 140 years of dominance of paper-wrapped cigarettes, which began with the invention of the Bonsack cigarette rolling machine, in 1880, electronic cigarettes will take the role of villain in the 21st century. ANTI-SMOKING LAW Brazilian Federal Law no. 12,546/2011,(1) which has been in effect since December of 2014, must be known

CorrĂŞa da Silva LC, AraĂşjo AJ, Queiroz AMD, Sales MPU, Castellano VCO

and respected by all and must be properly enforced by the entitled authority, particularly the health oversight sector. This law contains items of practical relevance, such as a ban on smoking indoors (with indoors being defined as covered areas, side walled areas, places with awnings, outdoor decks at bars and restaurants, bus stops, etc.), a ban on designated smoking areas, price increase policies, a ban on advertising at sales points, and warning labels covering one third of the face of the cigarette pack. The back of the cigarette pack will continue to display the usual warnings. SMOKING CONTROL STRATEGIES

Prevention It is essential to prevent youths from experimenting with cigarettes, because, if they do experiment, they will have a greater than 50% chance of becoming dependent. What should be done? Education; family control and school control; and enforcement of anti-smoking laws, particularly a ban on the sale of tobacco products to minors and other initiatives aimed at youths.(21)

Protection The population should be protected from the effects of environmental tobacco smoke and from the influences that lead to smoking, particularly those related to the circle of family, friends, and colleagues. Anti-smoking laws, which, among other rules, ban smoking in public places, should be rigorously enforced.(21)

Treatment Treatment should be offered to all smokers who are unable to quit smoking on their own initiative and wish to quit smoking. The cost-effectiveness of treatment is highly favorable, because, when people quit smoking, they live 10-15 years longer and have a better quality of life and there is a 30-90% reduction in the occurrence of chronic, tobacco-related noncommunicable diseases. In addition, former smokers serve as an example and stimulus for those who still smoke.(21) The coverage and scope of such interventions can vary, but it is known that, among the population of smokers in Brazil, which comprises 22 million people, less than 5% receive treatment provided by the Brazilian National Ministry of Health. In contrast, the Anti-Smoking Law, in one way or another, reaches the entire population and therefore, directly or indirectly, has a coverage of 100%. Establishing environments free of tobacco smoke is the most effective measure for controlling smoking in the community. Increasing prices also achieves significant results, since a 10% increase in prices leads to a 4% decrease in consumption.(22) MULTIPLYING NETWORKS The only way to fight and overcome this pandemic that affects 1.3 billion people worldwide is to create a large network that can bring together as many

institutions and people as possible. The WHO, given its experience, its political status, and its worldwide leadership role advocating for the FCTC, formally unites this global network through the conference of the parties. In Brazil, the National Ministry of Health (through the INCA), nongovernmental organizations (such as the ACT+), medical organizations (such as the SBPT), and other local state and municipal institutions develop their control programs based on the FCTC guidelines. It is of note that the FCTC has recently celebrated its 10th anniversary, and the results show that its smoking control goals have been achieved in the 180 countries that have ratified the treaty and that are adapting or formulating their policies and laws according to national characteristics. SMOKING TREATMENT PROGRAM This topic is based on several references.(11,23-26) The initial planning of treatment should always take into account the reality of the patientsâ&#x20AC;&#x2122; world, their sociocultural profile, behavioral aspects, beliefs, taboos, other types of dependence, and, especially, their level of motivation to quit smoking and their level of nicotine dependence. It should be defined whether an individual program, a group program, or a mixed program is the most appropriate. Treatment duration should be no less than three months, but it can vary greatly depending on the individual situation and the physician-patient relationship.

First phase of the program (intensive, aimed at cessation) Consultations should occur weekly in the first month. In the first consultation, personal aspects, history of smoking, level of motivation, and level of dependence should be assessed, as should respiratory symptoms and other types of symptoms. Assessment tests (e.g., chest X-ray and spirometry) should be requested as necessary, if possible. The whole program should be explained to patients, with emphasis on the four basic steps: (1) wanting to (having desire and motivation); (2) preparing oneself (with technical support, cognitive behavioral therapy [CBT], and, if necessary, medications); (3) setting D-Day (the cessation day; this will create an objective commitment); and (4) maintaining abstinence (relapse prevention). In the second consultation, the test results should be assessed, the required data should be collected, and the program should be explained in more detail. The CBT items that apply to individual cases, particular those related to motivation and to the necessary behavioral changes, should be emphasized. The other CBT items that should be addressed are smoking cessation objectives, smoking cessation benefits, triggers, frustrations, automatic mechanisms, reward mechanisms, ambivalence, and how to cope with the most common causes of relapse (a coping plan). J Bras Pneumol. 2016;42(4):290-298

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The need for medication prescription should be assessed, and, that being the case, the most appropriate treatment regimen should be chosen. D-Day should be set. It can be the day preferred by the patient: his or her own birthday; the birthday of a family member or friend; or any other relevant date. It is important that D-Day be within the next three weeks, in order to prevent a delay in decision that would discourage the patient from pursuing the set goal. The primary objective of the program is that D-Day will happen. Drug therapy is aimed at reducing the symptoms of smoking withdrawal syndrome. CBT is aimed at aspects that greatly affect smoking cessation and maintenance of abstinence: psychological dependence; anxiety; depression; psychosocial aspects; low self-esteem; automatisms; and triggers.

Second phase of the program (maintenance, aimed at preventing relapse) After cessation, treatment should focus on preparing patients for challenges that often arise and frequently lead to lapses and relapses. Although it is thought that, after a year of abstinence, the worst has passed, patients should be constantly on their guard, since, even after many years, they may feel the urge to smoke and may relapse. It should be emphasized to patients that, when faced with any difficulty, they should maintain abstinence and, as soon as possible, have a consultation with or contact their physician or someone in the team in order not to affect treatment negatively. RELAPSE Fear of relapse or relapse itself needs to be handled objectively. Patients need to know that many smokers only manage to quit smoking successfully after the umpteenth attempt. On average, five quit attempts are needed. If patients relapse, they should return to the program and, with technical support, review and correct what went wrong. Persistence is what matters. Retreatment may require previously unused resources, such as a combination of several medications, CBT reinforcement, and, obviously, greater attention and commitment of patients and physicians. REMOTE AID FOR SMOKERS Information and communication technologies can potentially be combined with the advantages of intensive treatments, which are more individualized, and with far-reaching interventions, through incorporation of interactive responses, by adapting personal contact strategies. Studies have highlighted the considerable potential of social networks for promoting the adoption of healthier behaviors, including smoking cessation. Web-based projects that enable social support through forums, e-mails, and chat rooms have resulted in a three-fold increase in the chance of success of motivated smokers struggling to overcome smoking in the first three months.(27-30) 294

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In Brazil, there is a computer application called TratBem,(28) which has been developed to assist patients in the different stages of changing habits, by providing social, informative, and psychological support through automatic or individualized messages. Different messages can be sent to different patients depending on the number of days left to D-Day or after the quit date. During cravings, patients can send messages and receive support directly from the application, through messaging from a support team professional or their own support network. It is important to emphasize that low-income people can benefit from this application, using only text messages. This support resource for smokers going through the cessation process has been presented and demonstrated in events in the fields of computer science, medical informatics and health. This application enables interaction among patients, family members, friends, and health professionals in a collaborative effort to overcome the smoking addiction.(30) SMOKING AND COPD Smoking is the major factor associated with COPD, and its mechanism of action is through an inflammatory cascade involving epithelial cells, macrophages, fibroblasts, and cytokines, such as IL-4, IL-5, TNF-Îą, etc., which, together with neutrophils and the action of neutrophil elastase, results in alveolar wall destruction, fibrosis of the small airways, and hypersecretion of mucus. This triad is the basis of the major symptoms of COPD: dyspnea; cough; and expectoration. These symptoms cause significant progressive disability, with a rapid deterioration in quality of life and in life expectancy. In their study, Fletcher & Peto(31) showed that the rate of lung function loss slows after smoking cessation, even if the cessation occurs at age 65. Anthonisen et al.,(32) after an 11-year follow-up period, concluded that the patients who continued to smoke had a lower FEV1 than did those who quit smoking. In an interesting meta-analysis of phase III randomized studies that assessed the effects of bronchodilators and inhaled corticosteroids in COPD patients, conducted by Tonnesen,(33) the prevalence of active smokers ranged from 38% to 77%. Spirometry is mandatory for patients over 40 years of age who seek smoking cessation treatment. Godoy et al.(34) reported that 30% of the patients enrolled in a smoking cessation program had COPD. The calculation of lung age, which, in COPD patients, gives higher values than the chronological age values, can be a motivator for smoking cessation.(35) Patients must be motivated and must have overcome ambivalent feelings about smoking cessation before starting the medication treatment. The same medication protocols used for the general population should be used for smoking patients with COPD. Smoking cessation results in decreased dyspnea,

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slowing of COPD progression, and reduced frequency of exacerbations.(11,35,36) ADVOCACY The word advocacy does not have a one-word translation into Portuguese. It could be translated as “the process of positive persuasion of people who have significant decision-making influence in a given sector” or something similar. However, the best definition seems to be “a set of activities that is planned to transform certain conditions with a view to achieving better circumstances and may involve efforts to change perceptions, attitudes, and/or policies, whether written or not”. Leaders of governmental institutions need to be informed with updated objective data on tobacco and smoking. They need to be aware that the days of tobacco leaf exports worth billions are numbered and that the sectors associated with this trade, particularly small farmers, need to be prepared for migration to other crops and for other necessary changes. In addition, they need to know that, of the measures already imposed by the Anti-smoking Law, increasing prices and implementing 100 percent smoke-free environments are the most effective and have the most immediate results. PULMONOLOGISTS AND THE SBPT IN SMOKING CONTROL These considerations extend to all physicians and other health care professionals. Everything begins with personal attitude: they should not smoke; they should be a model of healthy behavior; they should tirelessly advocate 100 percent smoke-free environments; they should take a firm stand against smoking; they should always advise patients not to smoke; and, finally, they should continuously encourage the practice of a healthy lifestyle, which includes smoking prevention and smoking cessation. In consultations and interactions with patients, the following questions should be asked, at least at the first contact: “Do you smoke?”; “Do you want to quit?”; “How do you intent to do it?”; and “Do you want help?”. A smoking cessation plan should always be proposed to smoking patients, and they should be told with conviction “If you want to quit smoking, you will. Let’s find the way together.” The many ways to quit smoking should be taken into account: • Personal initiative, without specific professional guidance • A brief intervention, with counseling and monitoring by a physician or another health care professional • Treatment in accordance with guidelines recommended by referral institutions (INCA, SBPT, American Thoracic Society, and European Respiratory Society), using resources such as CBT and medications (nicotine replacement therapy,

nicotine, bupropion, varenicline, etc.), always under medical supervision • A structured, multidisciplinary treatment program, with the participation of professionals from various fields, using the same resources as the previous modality but relying on the experience of the professionals in their respective areas The SBPT, through its successive Boards of Directors and the direct involvement of the Commission on Smoking, has been promoting a debate regarding the need for approval of a “Field of Interest”, or simply a “Certification in Smoking Cessation”, since its First Brazilian Conference on Smoking in 2005. This certification would assist a large number of pulmonologists who work in the treatment of smoking, as well as making it possible for other specialists, such as cardiologists, general practitioners, psychiatrists, and pediatricians, to work in the prevention and treatment of smoking as a certified professional. Therefore, the SBT has been offering training courses in interventions for smokers during its national, regional and state conferences, as well as in its continuing education programs. This proposal meets the definition of mode of organization of medical work, performed by professionals trained to perform specific medical activities, being derived from and related to one or more specialties. The approval of the proposal is warranted because smoking is the leading preventable cause of disease, disability, and death worldwide and in Brazil. In our country, there are approximately 22 million smokers, who generate public expenditures of 21 billion Brazilian reals per year solely on the treatment of diseases related to tobacco consumption.(37) In the latest SBPT proposal submitted to the AMB, there is a basic protocol for an intensive 12-week intervention for smokers, including outpatient clinical assessments and individual and/or group follow-up. The intervention frequency can be weekly or fortnightly, and a limit of seven consultations should not be exceeded. The procedural codes, according to the AMB table, would be as follows: outpatient medical consultation (code 2B); and inpatient medical visit to a smoker who presents with withdrawal syndrome (code 2A). The intensive intervention for smoking patients will be a procedure identified with a specific code and does not include consultations for other clinical complications. Since smoking is a disease susceptible to relapse, we must consider for this procedure the need to promote the return of smoking patients to the intensive intervention for a new quit attempt, on the basis of medical reasons. In the proposal sent by the SBPT, measurement of exhaled carbon monoxide (eCO) was also included, being categorized as code 1A (similar to noninvasive oximetry). Once the creation of a “Certification in Smoking Cessation” is approved, a training and certification program endorsed by the AMB should be put into J Bras Pneumol. 2016;42(4):290-298

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practice so that certified medical professionals can be accredited to work with private and supplemental health insurance plans. The SBPT, which has already been developing courses for pulmonologists, has presented to the AMB a proposal with basic requirements and contents for the training and certification of physicians. INITIATIVES OF REGIONAL SOCIETIES Pulmonologists play an important role in motivating smokers to quit smoking, in guiding therapy, and in the follow-up of patients. Regional societies, as is to be expected, locally reinforce national smoking control campaigns. In order to encourage pulmonologists to act more effectively, regional societies should help them implement interventions for smokers in their private practices, in hospitals, at public health care facilities, and at universities, by establishing partnerships with public and private sectors to organize centers for the prevention and treatment of smoking. In addition, regional societies should work on the front lines to advise lay public of the harmful effects of smoking, addressing this issue on special dates related to tobacco (World No Tobacco Day, National Day against Tobacco, World COPD Day, World Asthma Day, National Cancer Awareness Day, etc.) through various media vehicles. Events, such as sports competitions and educational activities in shopping centers and supermarkets, should be promoted for lay people in the community. Active participation of regional societies in scientific meetings at symposiums, conferences, and forums is another form of encouragement, given that such meetings set the stage for fruitful discussions regarding smoking, as a way to educate more people, increasing the impact of campaigns focused on gaining the support of opinion leaders for these initiatives. Furthermore, partnerships should be sought with primary and secondary schools, undergraduate medical schools, and residency medical programs. Last but not least, regional societies should work in conjunction with the various primary care programs in their various areas of complexity (programs to control arterial hypertension, diabetes mellitus, tuberculosis, and leprosy; programs for adolescents; and programs for children), promoting in those areas the behaviors and practices of the smoking cessation intervention, with the aim of providing comprehensive care to the community. DIAGNOSTIC PROCEDURES THAT CAN BE USEFUL FOR SMOKING CESSATION The basic routine recommended in the SBPT Guidelines for Smoking Cessation(26) is to request chest X-ray, pre- and post-bronchodilator spirometry, electrocardiography, a complete blood count, and serum and urine biochemistry. Measurement of eCO and measurement of cotinine (in serum, saliva, or urine) are useful in the assessment and follow-up of smokers and should be used when available. The tests serve as motivators for smoking cessation. 296

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Chest X-ray, depending on the conditions available, can be useful in the smoker protocol, especially for early detection of tobacco-related diseases, such as lung cancer, COPD, and respiratory bronchiolitis. In a randomized clinical trial conducted in Denmark, 4,104 smokers motivated to quit, who were enrolled in a smoking cessation program, were divided into two groups: those undergoing and those not undergoing CT screening for lung cancer.(38) At 1-year follow-up, smoking cessation and relapse rates were similar between the two groups. However, the subgroup of those with initial CT findings requiring a repeat chest CT scan three months later had higher smoking cessation rates and lower relapse rates than did the other subjects. Chest CT is found to have a favorable cost-benefit ratio in the screening of high-risk patients when it is performed using low doses of radiation. In countries with scarce logistics and/or financial resources, low-dose CT screening referrals will be subject to available resources.(39) It should be taken into account that, when a patient undergoes chest CT, this might mean that there is a health concern, which is a motivator and an opportunity for smoking cessation.(40) Spirometry should be performed whenever possible, because it enables early diagnosis of COPD. In addition, it can aid in determining the patient’s “functional age”, which can be used to encourage smoking cessation. For instance, after being assessed, the smoking patient can be told the following: “Your lung function should correspond to that expected for your age group, but, on the basis of the observed spirometric values, it is equivalent to that predicted for those 20 years older than you.” Measurement of eCO can be useful primarily to show patients that results above 6 ppm indicate that they are still smoking. During the smoking cessation process, a decrease in eCO levels can greatly influence smokers. A random high measurement can be a means to catch their attention and motivate them to quit smoking.(25,26) ELECTRONIC CIGARETTES AND WATERPIPE TOBACCO SMOKING The position of the SBPT on electronic cigarettes is as follows: until robust studies are performed that demonstrate the safety and efficacy of the proposed indications for use, the sale of electronic cigarettes cannot be authorized and they should be subject to the same control regulations as those applied to conventional cigarettes and other smoking products. Likewise, the same control regulations should be applied to waterpipe tobacco smoking and to any other form of smoking that might emerge, given their risks. There are hundreds of “brands” of electronic cigarettes, which have the most varied characteristics and compositions and which have not been submitted to oversight. Therefore, their regulation will be impossible! Forms of exposure emerge all the time and proliferate: now there are electronic cigarettes and waterpipe

Corrêa da Silva LC, Araújo AJ, Queiroz AMD, Sales MPU, Castellano VCO

tobacco smoking. Both are taking up where conventional cigarettes left off and may undermine the achievements already made in smoking control. They should be seen in the same light as that in which we now view conventional cigarettes. The tobacco companies have already dominated this sector. We wonder why. The loss of profit caused by the reduction in conventional cigarette sales is projected to be replaced by the profit gain from electronic cigarette sales. FINAL CONSIDERATIONS Pulmonologists and all health care professionals need to give maximum attention to smoking patients and to youths who have not yet started smoking, since primary and secondary prevention are priorities. Providing a brief intervention, no matter how short, will already be a significant contribution, since this type of intervention is the most cost-effective one. At the opposite end of the spectrum are pulmonologists with a more focused dedication to smoking cessation, that is,

tobacco treatment specialists, who take care of smokers individually or in group, in a multidisciplinary team. Currently, there are very effective resources for the treatment of smokers, and pulmonologists need to be informed and trained for this purpose. The SBPT Commission on Smoking will always be available to help. ACKNOWLEDGMENTS The authors would like to thank all of those who always collaborate with the SBPT Commission on Smoking, particularly its former coordinators, for their work, and all of those who, even anonymously, contribute to smoking control. We are also grateful to the SBPT directors, who always support and encourage the continuation of the fight against smoking, which is endless. We are especially grateful to the SBPT staff members, who go to great lengths to make it possible for our projects and initiatives to be carried out as promptly as possible and with the highest quality possible.

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22. Brecher E, van Walbeek C. An Analysis of Cigarette Affordability [monograph on the Internet]. Paris: International Union Against Tuberculosis and Lung Disease; 2008 [cited 2016 May 8]. [Adobe Acrobat document, 36p.]. Available from: http://global. tobaccofreekids.org/files/pdfs/en/TAX_Cigarette_affordability_ report_en.pdf 23. Fiore MC, Jaén CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ, et al. Clinical practice guideline. Treating tobacco use and dependence: 2008 update [monograph on the Internet]. Rockville: US Department of Health and Human Services; 2008. [cited 2016 May 8]. [Adobe Acrobat document, 276p.]. Available from: http://bphc.hrsa.gov/ buckets/treatingtobacco.pdf 24. Viegas CAA, editor. Tabagismo: do diagnóstico à Saúde Pública. São Paulo: Atheneu; 2007. 25. Sociedade Brasileira de Pneumologia e Tisiologia (SBPT); Araújo AJ, editors. Manual de Condutas e Práticas em Tabagismo. São Paulo: Gen/AC Farmacêutica; 2012. 26. Reichert J, Araújo AJ, Gonçalves CM, Godoy I, Chatkin JM, Sales MP, et al. Diretrizes para cessação do tabagismo da SBPT: 2008. J Bras Pneumol. 2008;34(10):845-80. http://dx.doi.org/10.1590/S180637132008001000014 27. Cassell M, Jackson C, Cheuvront B. Health communication on the Internet: an effective channel for health behavior change? J Health Commun. 1998;3(1):71-9. http://dx.doi. org/10.1080/108107398127517 28. Oliveira F, Sales MP, Fonteles J, Silva N, Pereira F, Melo J, et al. Apresentando o TratBem: Suporte Social, Informacional e Psicológico ao Tabagista. Proceedings of the 15th Workshop de Informática Médica, XXXV Congresso da Sociedade Brasileira de Computação; 2015 Jul 20-23; Recife, Brasil. 29. Oliveira F. From quitlines to smartphones: a new paradigm? Anales del 4º Congreso Latinoamericano y del Caribe Tabaco o Salud; 2014 Mar 26-28; San José, Republica Dominicana. 30. Sales MP, Oliveira FM. Melo JF. Promoting social, informational and social support 24/7, uniting patients, family, friends and health professionals to fight tobacco addiction. Anales del 4º Congreso Latinoamericano y del Caribe Tabaco o Salud; 2014 Mar 26-28; San José, Republica Dominicana. 31. Fletcher C, Peto R. The natural history of chronic airflow obstruction.

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LETTER TO THE EDITOR

Resistance profile of strains of Mycobacterium fortuitum isolated from clinical specimens Debora Ribeiro de Souza Santos1,2, Maria Cristina Silva Lourenço3, Fábrice Santana Coelho4, Fernanda Carvalho Queiroz Mello5, Rafael Silva Duarte6 TO THE EDITOR: The Mycobacterium fortuitum group is associated with lung diseases in humans. This group is also responsible for most (60-80%) cases of post-surgical and catheter-related infections caused by rapidly growing mycobacteria.(1) In the present study, we evaluated 75 strains of the M. fortuitum group isolated from human clinical specimens, predominantly in the state of Rio de Janeiro, Brazil, and previously identified as M. fortuitum by hsp65 PCR-restriction enzyme analysis (PRA) in routine laboratories. (2,3) These strains were isolated from patients between 2000 and 2010, various types of samples having been collected: sputum (n = 49) from patients with respiratory symptoms, probable cases with clinical and radiological signs and one M. fortuitum isolation, 24% of the strains coming from confirmed cases of infection with more than one M. fortuitum isolation associated with the clinical and radiological profile; biopsies of nodules (n = 8); mammary secretions (n = 8), skin abscesses (n = 3), breast implant (n = 1), bronchial secretion (n = 1); bronchoalveolar lavage (n = 1); bone marrow aspirate (n = 1); urine (n = 2); and surgical wound secretion (n = 1). Only 1 strain from each patient was included in the study. Antimicrobial susceptibility testing was performed as recommended by the Clinical and Laboratory Standards Institute.(4) Ofloxacin susceptibility was tested based on the study conducted by Wallace et al.(5) There was significant variation among the 75 strains in terms of the in vitro response to the eight antimicrobial agents tested (Table 1). Approximately 86.6% of the strains of the M. fortuitum group (n = 65) exhibited susceptibility to amikacin with a minimum inhibitory concentration (MIC) of 1-16 µg/mL. For cefoxitin, the proportion of resistant strains was quite high, 96% (n = 72), considering the categories “resistant” and “intermediate”, with an MIC of 32-256 µg/mL. The same was observed for clarithromycin, to which the resistance rate was 94.6% (n = 71), with an MIC of 8-32 µg/mL. For the fluoroquinolone group, susceptibility rates and MIC values for ciprofloxacin, moxifloxacin, and ofloxacin were, respectively, 88% (n = 66) and ≤ 1 µg/mL; 94.6% (n = 71) and ≤ 1 µg/mL; and 78.6% (n = 59) and ≤ 2 µg/mL. For doxycycline, we found a resistance rate of 68% (n = 51) and an MIC ≥ 1 µg/mL. Trimethoprim/

sulfamethoxazole, in contrast with data in the literature, provided a resistance rate of 100% (n = 75) with an MIC ≥ 4/76 µg/mL in all of the strains tested. For each of the antimicrobial agents evaluated, we determined the MIC at which 50% of the isolates are inhibited (MIC50), the MIC at which 90% of the isolates are inhibited (MIC90), and the mode (Table 2). It is of great importance to identify effective drug therapies for the various subspecies of the M. fortuitum group.(6) In comparison with data in the literature on susceptibility profiles, some of our results were significantly different. According to one study,(1) the M. fortuitum group exhibits susceptibility to the sulfonamides, represented by trimethoprim/sulfamethoxazole, 100% of the strains tested being sulfonamide-susceptible. In contrast, we observed a rate of resistance to trimethoprim/sulfamethoxazole of 100%, with very high MIC values (> 8/152 µg/mL). Our results were obtained in strict accordance with the Clinical and Laboratory Standards Institute recommendations(4) and underwent interlaboratory quality control assessment (data not shown). According to a statement published by the American Thoracic Society/Infectious Disease Society of America,(7) 80% of the M. fortuitum group is clarithromycin-susceptible and 50% of it is doxycycline-susceptible. However, despite the observed in vitro susceptibility, macrolides should be used with caution, because of the presence of the erythromycin-inducible methylase (erm) gene, which confers resistance to macrolides.(7,8) One of the hypotheses that could explain the high rates of resistance to some antimicrobial agents in M. fortuitum is the widespread empiric use, in recent decades, of antibiotics for the treatment of nonspecific respiratory infections and of urinary tract infections, facilitated by patient access to these medications at no cost through the Brazilian Unified Health Care System and by convenient dosing schedules, which could exert a selective pressure on the samples. This is similar to what happens to M. tuberculosis strains following exposure to quinolones, as reported in two studies.(9,10) According to the study conducted by Brown-Elliott et al.,(1) only rarely in cases of pretreatment with quinolones will strains of the M. fortuitum group be resistant to quinolones, including

1. Programa de Pós-Graduação em Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 2. Departamento de Ciências Biológicas, Escola Nacional de Saúde Pública Sérgio Arouca, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 3. Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 4. Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 5. Instituto de Doenças do Tórax, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil 6. Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. © 2016 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Table 1. Minimum inhibitory concentration of antimicrobial agents for the 75 strains of the Mycobacterium fortuitum group.

Antimicrobial agent 128 7

32 3

16 5

2 42

7 42 1

1 26

Amikacin Cefoxitin Ciprofloxacin Clarithromycin Doxycycline

Moxifloxacin Ofloxacin

Trimethoprim/ sulfamethoxazole

MIC, µg/mL 8 4 10 15

256

16/304 66

8/152 8

2 24

0.5

0.25

0.125

17 3 2

29 6

2 1

16 9 MIC, µg/mL 4/76 2/38 1

1/19

0.5/9.5

MIC: minimum inhibitory concentration.

Table 2. Minimum inhibitory concentration (at which 50% and 90% of the isolates are inhibited) of antimicrobial agents for the 75 strains of the Mycobacterium fortuitum group.

Antimicrobial agent Range Mode MIC50, µg/mL MIC90, µg/mL Susceptibility, % Amikacin 128-1 2 4 < 32 86.6 Cefoxitin 256-2 64 64 256 4.0 Ciprofloxacin 16-0.125 0.5 0.5 4 88.0 Clarithromycin 64-0.5 16 16 16 5.4 Doxycycline 32-0.25 32 32 32 32.0 Moxifloxacin 16-0.125 1 1 16 94.6 Ofloxacin 4-0.125 4 1 4 78.6 Trimethoprim/sulfamethoxazole 16/304-0.5/9.5 16/304 16/304 16/304 0.0 MIC: minimum inhibitory concentration; MIC50: MIC at which 50% of the isolates are inhibited; and MIC90: MIC at which 90% of the isolates are inhibited. ciprofloxacin and moxifloxacin. Such exposure could explain the identification of some quinolone-resistant isolates. The role of empiric fluoroquinolone therapy for community-acquired pneumonia remains controversial in countries with a high incidence of tuberculosis, because of the possibility of delay in the diagnosis and treatment of tuberculosis, as well as of emergence of fluoroquinolone-resistant strains of M. tuberculosis.(10) According to Singh,(9) the guidelines on the management of community-acquired pneumonia in adults published by Mandell et al.(11) are very useful in developed countries, where the prevalence of tuberculosis is very low; however, they should not be applied in developing countries where the rate of tuberculosis is high. The guideline recommendations advocate the use of novel fluoroquinolones, such as gemifloxacin, levofloxacin,

or moxifloxacin, to treat almost all categories of patients with community-acquired pneumonia. Because fluoroquinolones are broad-spectrum antimicrobial agents, their widespread, indiscriminate use, especially at subtherapeutic doses, is likely to increase quinolone resistance in microorganisms, including nontuberculous mycobacteria.(9) In the present study, we found high resistance to quinolones and full resistance to trimethoprim/ sulfamethoxazole in the strains evaluated, the rates being significantly different from those reported previously.(1,7,8) These data indicate the need to perform broth microdilution testing to determine susceptibility to antimicrobial agents and the need to enable the implementation of this method in the routine workflow of mycobacteriology laboratories, so that an effective and appropriate therapeutic approach can be developed.

REFERENCES 1. Brown-Elliott BA, Nash KA, Wallace RJ Jr. Antimicrobial susceptibility testing, drug resistance mechanisms, and therapy of infections with nontuberculous mycobacteria. Clin Microbiol Rev. 2012;25(3):54582. http://dx.doi.org/10.1128/CMR.05030-11 2. Ringuet H, Akoua-Koffi C, Honore S, Varnerot A, Vicent V, Berche P, et al. hsp65 sequencing for identification of rapidly growing mycobacteria. J Clin Microbiol. 1999;37(3):852-7. 3. Telenti A, Marchesi F, Balz M, Bally F, Böttger EC, Bodmer T. Rapid identification of mycobacteria to the species level by polymerase

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chain reaction and restriction enzyme analysis. J Clin Microbiol. 1993;31(2):175-8. 4. Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard—Second Edition. Wayne (PA): CLSI; 2011 Mar. Standard No. M24-A2. 2011;31(5). 5. Wallace RJ Jr, Silcox VA, Tsukamura M, Brown BA, Kilburn JO, Butler WR, et al. Clinical significance, biochemical features, and susceptibility patterns of sporadic isolates of the Mycobacterium

Santos DRS, Lourenรงo MCS, Coelho FS, Mello FCQ, Duarte RS

chelonae-like organism J Clin Microbiol. 1993;31(12):3231-9. 6. Kirschner P, Kiekenbeck M, Meissner D, Wolters J, Bรถttger EC. Genetic heterogeneity within Mycobacterium fortuitum complex species: genotypic criteria for identification. J Clin Microbiol. 1992;30(11):2772-5. 7. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416. http://dx.doi.org/10.1164/ rccm.200604-571ST 8. Daley CL, Griffith DE. Pulmonary non-tuberculous mycobacterial infections. Int J Tuberc Lung Dis. 2010;14(6):665-71. 9. Singh A. Fluoroquinolones should not be the first-line antibiotics

to treat community-acquired pneumonia in areas of tuberculosis endemicity. Clin Infect Dis. 2007;45(1):133; author reply 134-5. http:// dx.doi.org/10.1086/518702 10. Shen GH, Tsao TC, Kao SJ, Lee JJ, Chen YH, Hsteh WC, et al. Does empirical treatment of community-acquired pneumonia with fluoroquinolones delay tuberculosis treatment and result in fluoroquinolone resistance in Mycobacterium tuberculosis? Controversies and solutions. Int J Antimicrob Agents. 2012;39(3):2015. http://dx.doi.org/10.1016/j.ijantimicag.2011.11.014 11. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-72 http://dx.doi.org/10.1086/511159

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LETTER TO THE EDITOR

Management of pericardial cyst in the mediastinum: a single-port approach Dario Amore1, Antonio Mazzella1, Alessandro Izzo2, Antonio Cennamo2, Fabio Perrotta2 TO THE EDITOR: Pleuropericardial cysts are relatively infrequent lesions, benign in most cases, representing 7% of all mediastinal tumors.(1) The diagnosis is incidental on chest X-rays in more than 50% of the cases, since clinical symptoms are scarce.(2) Pericardial cysts are usually identified in the fourth or fifth decade of life, and they are more frequently located at the right costophrenic angle (in 70% of the cases); the left costophrenic angle (in 10-40%); and the vascular hila, superior mediastinum, or left heart border (in 5-10%).(3) The gold standard treatment for the management of those cysts is surgical resection and video-assisted thoracic surgery (VATS), the latter being the best option for these patients.

We report the case of a 55-year-old male admitted to our hospital with an incidental radiological diagnosis of a mass in the anteroinferior mediastinum, measuring 45 mm and developing on the right side. The clinical history of the patient was totally negative, and he referred no clinical symptoms linked to the cyst. In order to diagnose the mass and prevent the risk of complications, the patient underwent complete surgical resection of the cyst by single-port VATS (Figure 1). Under general anesthesia and single-lung ventilation, he the patient was placed in semi-supine position, with a long gel roll placed under the right shoulder. Internal intercostal nerve blocks and continuous elastomeric pump infusion loaded with morphine were used to achieve optimal analgesia.

Figure 1. In A, a CT scan revealing anterior mediastinal collection. In B, a photograph of the specimen. In C, a photograph showing the dissection of the cyst with the electronic device. In D, a photograph showing the suspension of the cyst with a ring clamp. In E, a photograph showing the removal of the cyst with the endobag. In F, a photograph showing the 4-cm skin incision with the chest tube inserted. 1. Divisione di Chirurgia Toracica, A.O. dei Colli ‘Ospedale Monaldi’, Napoli, Italia. 2. Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Seconda Università degli Studi di Napoli, Napoli, Italia.

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Amore D, Mazzella A, Izzo A, Cennamo A, Perrotta F

A 4-cm incision in the sixth intercostal space, on the mid-axillary line, was performed on the right side. A 10-mm, 30° thoracoscope was introduced into the pleural cavity. The complete resection of the cyst and the surrounding mediastinal fat was carried out thanks to the endoscopic instruments and electronic surgical device. The specimen was completely retrieved using an endobag and a 20 Fr chest tube placed at the level of the incision wound (Figure 1); surgical time was 35 minutes. The chest tube was removed on the second postoperative day, and the patient was discharged on the following day. Macroscopically, the pathological examination revealed a pericardial cyst, measuring 45 × 35 mm. Pericardial cysts are caused by an incomplete coalescence of fetal lacunae during the development of the pericardium; they might also be acquired after cardiothoracic surgery.(4) They are usually solitary and adjacent to the pericardium, communicating with it in 20% of the cases. The best treatment is surgical resection, and VATS should be considered as a major method of treatment. Single-port VATS is gaining more and more importance in thoracic surgery practice. This approach has been described in the literature for the management of primary pneumothorax, as well as for performing wedges, lobectomies, or more invasive procedures, such as sleeve lobectomies.(5) A recent study demonstrated, in a cohort of 29 patients, the safety of this technique in the management of anterior mediastinal masses.(6)

In our case, the single-port approach allowed perfect control of mediastinal structures, as well as of the right lung, followed by the cyst excision. A ring clamp permitted the suspension of the cyst for its dissection and entire removal, avoiding damage to the capsule, which subsequently might cause fluid spilling into the thorax. The minimal invasiveness of this technique, together with the precise endoscopic dissection, avoided postoperative pleural collection, as well as allowing immediate chest tube removal, and fast discharge of the patient. When compared with other types of approach, the benefits of uniportal VATS include various aspects: the involvement of only one intercostal space, no spreading of ribs, less postoperative pain, and better aesthetic results.(5,7,8) The 4-cm skin incision allowed easy introduction and mobilization of all instruments (30° thoracoscope, ring clamp ring, and electronic dissection device). The absence of intraoperative and postoperative complications, as well as of intraoperative blood loss, together with less pain in the early postoperative period, less pulmonary function impairment, and better cosmetic result demonstrate the safety and the superiority of the single-port approach for the treatment of such diseases. However, the correct choice of the approach (thoracotomy, three-port thoracoscopy, or single-port thoracoscopy) depends on the experience of the surgeon and their being comfortable with the technique. In conclusion, single-port VATS might represent the best therapeutic option in the management of pericardial cysts in the mediastinum.

REFERENCES 1. Patel J, Park C, Michaels J, Rosen S, Kort S. Pericardial cyst: case reports and a literature review. Echocardiography. 2004;21(3):26972. http://dx.doi.org/10.1111/j.0742-2822.2004.03097.x 2. Nina VJ, Manzano NC, Mendes VG, Salgado Filho N. Giant pericardial cyst: case report. Rev Bras Cir Cardiovasc. 2007;22(3):349-51. http:// dx.doi.org/10.1590/S0102-76382007000300013 3. Yuncu G, Cakan A, Ors Kaya S, Sevinc S, Ucvet A, Ermete S. Atypically located pericardial cysts. J Cardiovasc Surg (Torino). 2001;42(2):275-8. 4. Satur CM, Hsin MK, Dussek JE. Giant pericardial cysts. Ann Thorac Surg. 1996;61(1):208-10. http://dx.doi.org/10.1016/00034975(95)00720-2 5. Gonzalez-Rivas D, Fieira E, Delgado M, de la Torre M, Mendez

L, Fernandez R: Uniportal video-assisted thoracoscopic sleeve lobectomy and other complex resections. J Thorac Dis, 2014;6(Suppl 6):S674-81. 6. Wu CF, Gonzalez-Rivas D, Wen CT, Liu YH, Wu YC, Chao YK, et al. Single-port video-assisted thoracoscopic mediastinal tumour resection. Interact Cardiovasc Thorac Surg. 2015;21(5):644-9. http:// dx.doi.org/10.1093/icvts/ivv224 7. Mazzella A, Izzo A, Amore D, Cerqua FS, Perrotta F. A new perspective on the treatment of complicated giant emphysematous bulla. A case report. Ann Ital Chir. 2016;87(ePub). pii: S2239253X16024816. 8. Mazzella A, Izzo A, Amore D, Cennamo A, Cerqua FS, Perrotta F. Single port VATS resection of a sessile solitary fibrous tumour of the visceral pleura. A case report. Ann Ital Chir. 2015;86(ePub). pii: S2239253X15024457.

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LETTER TO THE EDITOR

Not every irreversible airflow obstruction is COPD José Baddini-Martinez1

TO THE EDITOR: The incorporation of clear concepts and the use of precise terminology are fundamental requirements to ensure good communication among health professionals as well as proper care of patients. Airway diseases have always been fertile ground for the use of incorrect terms and the proliferation of nebulous ideas. Although it was to be expected that these problems would be reduced over time, conceptual vices remain, especially among physicians who are unfamiliar with our specialty. A few years ago, I mentioned the risk of interpreting all wheezing as being due to bronchial asthma.(1) Now I want to discuss a phenomenon seen particularly among general practitioners, residents in clinical medicine, and medical students: the belief that all irreversible airflow obstruction on spirometry implies the diagnosis of COPD. The term COPD was coined more than five decades ago as being a pathophysiological change associated with chronic tobacco use. At that same time, emphysema was defined as a pathological concept involving destruction of distal airspaces. In contrast, chronic bronchitis was defined as a clinical change associated with having had cough and expectoration for a certain period of time. As a consequence, the current definition recommended by the Global Initiative for Chronic Obstructive Lung Disease states that “COPD is a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with enhanced chronic inflammatory responses in the airways and the lungs to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.”(3)

exposure. In addition, it is important to emphasize that the expression “noxious particles or gases” refers to inert environmental exposures rather than to infectious agents. Therefore, obstructive lung disease due to sequelae of tuberculosis is not COPD. In contrast, the diagnosis of asthma is based on the presence of dyspnea, wheezing, chest tightness, and cough.(4) These symptoms vary in intensity over time, as does the degree of expiratory airflow obstruction. Similar to what happens in COPD, what determines the symptoms and the variable airflow obstruction is the presence of airway inflammation. However, this inflammation is distinct in character, being generally eosinophilic in nature, as opposed to that of COPD, which is usually neutrophilic. In addition, what causes asthma, at least at onset, are mechanisms of atopy and hypersensitivity to inhaled agents. Being primarily immunoallergic in nature, these reactions do not have a close relationship with the duration of exposure or with the concentration of inhaled material, unlike COPD. Asthma generally begins in childhood, has a strong genetic influence, and is usually accompanied by other signs of atopy. In addition to the fact that COPD is a disease whose symptoms appear later in life, the exposures related to the development of COPD do not involve sensitization mechanisms and are distinct from those associated with the development of asthma: wood stove smoke vs. cockroach antigens, for example.

Therefore, the diagnosis of COPD necessarily requires findings of persistent airway obstruction on spirometry. Persistent or irreversible airflow obstruction is defined as obstruction that does not disappear or completely resolve after inhaled bronchodilator use. In this context, many patients with COPD can certainly respond to inhaled bronchodilators, but without a complete normalization of the FEV1/FVC ratio.

The crucial point that I want to raise here is the following: in the same way that confirming the diagnosis of COPD requires findings of irreversible airflow obstruction on spirometry, raising the diagnostic possibility of COPD requires the identification in the patient’s history of environmental exposure of findings suggestive of, for example, smoking or exposure to smoke from biomass burning for home heating and cooking purposes. The only exception to this rule would be emphysema caused by alpha-1 antitrypsin deficiency. However, this is a rare condition, in which exposure to environmental smoke often also occurs. For this reason, in every patient under 45 years of age who is suspected of having COPD, serum levels of alpha-1 antitrypsin should be determined.

The second necessary element for the diagnosis of COPD is disease development in response to prolonged inhalation of noxious particles or gases. Although smoking is still the most important toxic element, it has been found in recent decades that other environmental exposures, especially to biomass burning, can also cause this disease. Thus, it is not acceptable to consider a diagnosis of COPD in patients without a consistent history of environmental

Obviously, when faced with any lung disease, anamnesis takes on importance for characterizing not only current symptoms and their triggering agents but also the occurrence of previous respiratory symptoms, occupational history, family history, etc. These data, together with physical examination and standard anteroposterior and lateral X-rays of the chest, provide the foundation for the differential diagnosis of various lung diseases.

1. Divisão de Pneumologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto (SP) Brasil.

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Baddini-Martinez J.

Chart 1 lists various clinical conditions that can result in persistent airflow obstruction on simple spirometry but do not meet the diagnosis of COPD because of the lack of appropriate environmental exposure as a factor associated with their development. It is important to emphasize that all of the listed conditions can, more or less frequently, produce an isolated airflow obstruction pattern on spirometry. That is, more complex issues involving a reduced or very reduced FVC on spirometry, which can be classified as a nonspecific or mixed pattern, are not being discussed here. Certainly, in these two last conditions, complete pulmonary function studies, involving measurements of TLC and RV, are ideal for the proper characterization of the functional diagnosis and, consequently, of the underlying lung disease itself. In fact, the finding of a nonspecific mixed pattern in patients in whom COPD is strongly suspected usually means the occurrence of some other superimposed comorbid condition.(5) In summary, although COPD is a very common condition, whenever patients have a persistent airflow

Chart 1. Some causes of persistent pulmonary obstruction other than COPD.

Severe asthma Bronchiectasis Tracheal stenosis or airway stenosis: after intubation; presence of tumors or foreign bodies; infectious stenosis; or postinfectious stenosis (tuberculosis, paracoccidioidomycosis, etc.) Sarcoidosis Lymphangioleiomyomatosis Langerhans cell histiocytosis Bronchiolitis obliterans

obstruction pattern on spirometry but no consistent history of environmental exposure, they should undergo further testing, particularly flow-volume curves and pulmonary function testing (including measurements of TLC and DLCO), as well as HRCT scanning of the chest. So, in a nutshell, not every irreversible airflow obstruction is COPD!

REFERENCES 1. Martinez JA. Not all that wheezes is asthma! J Bras Pneumol. 2013;39(4):518-20. http://dx.doi.org/10.1590/S1806-37132013000400017 2. Terminology, definitions and classifications of chronic pulmonary emphysema and related conditions: a report of the conclusions of a Ciba Guest Symposium. Thorax. 1959;14(4):286-99. http://dx.doi. org/10.1136/thx.14.4.286 3. Global Initiative for Chronic Obstructive Lung Disease - GOLD [homepage on the Internet]. Bethesda: Global Initiative for Chronic Obstructive Lung Disease [cited 2016 Jun 24]. Global Strategy for the Diagnosis, Management, and Prevention of COPD 2016. Available

from: http://goldcopd.org/global-strategy-diagnosis-managementprevention-copd-2016/ 4. Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, et al. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J. 2015;46(3):622-39. http://dx.doi. org/10.1183/13993003.00853-2015 5. Wan ES, Hokanson JE, Murphy JR, Regan EA, Make BJ, Lynch DA, et al. Clinical and radiographic predictors of GOLD-unclassified smokers in the COPDGene study. Am J Respir Crit Care Med. 2011;184(1):57-63. http://dx.doi.org/10.1164/rccm.201101-0021OC

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CORRESPONDENCE

The rapid shallow breathing index as a predictor of successful mechanical ventilation weaning: clinical utility when calculated from ventilator data Luiz Alberto Forgiarini Junior1, Antonio M. Esquinas2 First, we would like to congratulate Souza et al. for their article entitled “The rapid shallow breathing index as a predictor of successful mechanical ventilation weaning: clinical utility when calculated from ventilator data”, recently published in the JBP.(1) The subject is of great importance for professionals in the intensive care unit, and the article presents a new tool for the evaluation of critically ill patients on mechanical ventilation. In the literature, there are a variety of studies demonstrating the use of rapid shallow breathing index (RSBI) calculated directly from the mechanical ventilator data. However, the poor methodological quality of those studies makes it impossible to implement the RSBI directly in clinical practice or to determine the appropriate cut-off point for the index. The development of new assessment tools that can be adapted for use in daily practice is extremely important to the efficiency of care provided by a multidisciplinary team. Improvements in the use of predictive factors for weaning have been reported in the literature. For example, Takaki et al.(2) conducted a study designed to evaluate the best predictors of successful extubation in the cardiac intensive care unit by correcting the RSBI values for the anthropometric characteristics of the patients. Those authors demonstrated that the modified RSBI adjusted for the current body weight or body mass index has greater predictive power than does the conventional RSBI.

One interesting finding presented by Souza et al.(1) is that even if there is significant difference in the direct comparison of the RSBI obtained by spirometry or directly from the ventilator, the two are very similar in terms of accuracy, which justifies the use of either method. Although we observed a statistically significant difference in the direct comparison of measurement methods, the values obtained in both groups were below 105, which is indicative of successful weaning. We believe that research related to an index or tools for assessing weaning potential must also take into account the population studied. For example, the RSBI has not proven to be a reliable predictor of successful weaning in patients with neurological damage. This is clear in the study conducted by Kutchak et al.,(3) who evaluated the use of reflex cough PEF as a predictor of successful extubation in neurological patients. Those authors showed that, although all of the patients (those in whom extubation was successful and those in whom it was not) presented an RSBI < 105, reflex cough PEF had an accuracy of 0.81 in predicting successful extubation. Certainly, despite the interesting findings of the Souza et al.(1) study, new research demonstrating the effectiveness of the RSBI in different populations or adjusting its values by clinical factors should be encouraged.

REFERENCES 1. Souza LC, Lugon JR. The rapid shallow breathing index as a predictor of successful mechanical ventilation weaning: clinical utility when calculated from ventilator data. J Bras Pneumol. 2015;41(6):530-5. http://dx.doi.org/10.1590/S1806-37132015000000077 2. Takaki S, Kadiman SB, Tahir SS, Ariff MH, Kurahashi K, Goto T. Modified rapid shallow breathing index adjusted with anthropometric parameters increases predictive power for extubation failure compared with the

unmodified index in postcardiac surgery patients. J Cardiothorac Vasc Anesth. 2015;29(1):64-8. http://dx.doi.org/10.1053/j.jvca.2014.06.022 3. Kutchak FM, Debesaitys AM, Rieder Mde M, Meneguzzi C, Skueresky AS, Forgiarini Junior LA, et al. Reflex cough PEF as a predictor of successful extubation in neurological patients. J Bras Pneumol. 2015;41(4):358-64. http://dx.doi.org/10.1590/S1806-37132015000004453

1. Curso de Fisioterapia, Programa de Pós-Graduação em Biociências e Reabilitação e Programa de Pós-Graduação em Reabilitação e Inclusão, Centro Universitário Metodista, Instituto Porto Alegre, Porto Alegre (RS) Brasil. 2. Unidad de Medicina Intensiva, Hospital Morales Meseguer, Murcia, España.

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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, ISSN-1806-3756), 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 and case reports 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. Case Reports: Case Reports should not exceed 1500 words, excluding title page, abstract, references and illustrations. The text should be composed of: Introduction, Case Report, Discussion and References. It is recommended that any and all information that might identify the patient be withheld, and that only those laboratory exams that are important for the diagnosis and discussion be presented. The total number of illustrations (figures or tables) should not exceed three, and the number of references should be limited to 20. When the number of cases presented exceeds three, the manuscript will be classified as a Case Series, and the same rules applicable to an original article will be applied. Brief Communications: Brief communications should not exceed 1500 words, excluding references and tables. The total number of tables and figures should not exceed two, and the references should be limited to 20. The text should be unstructured. Letters to the Editor: Letters to the Editor should be succinct original contributions, not exceeding 800 words and containing a maximum of 6 references. Comments and suggestions related to previously published materials or to any medical theme of interest will be considered for publication. 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 E TISIOLOGIA DO MATO GROSSO DO SUL

ASSOCIAÇÃO CATARINENSE DE PNEUMOLOGIA E TISIOLOGIA

SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO ESTADO DO RIO DE JANEIRO

Presidente: Secretário: Endereço: CEP: Telefone: Email: 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 | site: www.acapti.org.br

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

Presidente: Secretária: Endereço: CEP: Tel/fax: E-mail:

Angela Maria Dias de Queiroz Lilian Andries Rua Dr. Arthur Jorge n° 2117 - 902, Bairro São Francisco 79010-210 - Campo Grande - MS (67)33252955 / (67)99853782 diasqueiroz@hotmail.com

Gilmar Alves Zonzin Mônica Flores Rick Rua da Lapa, 120 - 3° andar - salas 301/302 - Centro 20.021-180 - Rio de Janeiro – RJ (21) 3852-3677 sopterj@sopterj.com.br | site: www.sopterj.com.br

ASSOCIAÇÃO DE PNEUMOLOGIA E CIRUGIA TORÁCICA DO ESTADO DO RIO GRANDE DO NORTE

SOCIEDADE DE PNEUMOLOGIA E TISIOLOGIA DO RIO GRANDE DO SUL

ASSOCIAÇÃO MARANHENSE DE PNEUMOLOGIA E CIRURGIA TORÁCICA

SOCIEDADE GOIANA DE PNEUMOLOGIA E TISIOLOGIA

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

Carlos Augusto Abreu Albério Márcia Cristina Corrêa Vasconcelos Faculdade de Medicina - Praça Camilo Salga do - 1 - Umarizal 66050-060 - Belém – PA (91)8115-5048 ca.alberio@uol.com.br

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

Evandro de Azevedo Martins Clio da Rocha Monteiro Heidrich 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 – (61)8406-8948 sbdt@ambr.org.br | biancars@superig.com.br

SOCIEDADE CEARENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretária: 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 montal59@hotmail.com

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

SOCIEDADE DE PNEUMOLOGIA DO MATO GROSSO 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) 3052-3002 cfggarcia@yahoo.com.br

Presidente: Vice: Endereço: CEP: Telefone: E-mail: Presidente: Secretária: Endereço: Setor Oeste 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 Karla Cristina de Moraes Arantes Curado Roseliane de Souza Araújo Galeria Pátio 22 - Rua 22, nº 69, Sala 17 –

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:

David Vogel Koza Ana Cristina De Carvalho Fernandez Fonseca Av. João Pinheiro, 161 - sala 203 - Centro 30.130-180 - Belo Horizonte – MG (31)3213-3197 sociedademineiradepneumologia@gmail.com www.smpct.org.br

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

José George Cunha Carneiro Braga José Gerson Gadelha Rua Maria Caetano Fernandes de Lima, 225 - Tambauzinho 58042-050 – João Pessoa - PB (83)93020555 georgecbraga@hotmail.com

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

Lêda Maria Rabelo Daniella Porfírio Nunes Av. Sete de Setembro, 5402 - Conj. 105, 10ª andar Batel 80240-000 - Curitiba – PR (41)3342-8889 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 PIAUIENSE DE PNEUMOLOGIA E TISIOLOGIA Presidente: Secretária: Endereço: CEP: Telefone: E-mail:

Cromwell Barbosa de Carvalho Melo Tatiana Santos Malheiros Nunes Avenida Jose dos Santos e Silva, 1903 Nucleo de Cirurgia Torácica 64001-300- Teresina – PI (86)32215068 cromwellmelo.cirurgiatoracica@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

EVENTS 2016/2017

NACIONAIS

INTERNACIONAIS

VII Curso Nacional de Ventilação Mecânica IV Curso Nacional de Sono Data: 18 a 20 de agosto de 2016 Local: São Paulo/SP Informações: eventos@sbpt.org.br Fone: 0800 61 6218

ERS 2016 Data: 03 a 07 de setembro de 2016 Local: Londres, Reino Unido Informações: www.ersnet.org

XXXVIII Congresso Brasileiro de Pneumologia e Tisiologia XI Congresso Luso-Brasileiro de Pneumologia XIV Congresso Brasileiro de Endoscopia Respiratória Data: 11 a 15 de outubro de 2016 Local: Rio de Janeiro - RJ Informações: eventos@sbpt.org.br Fone: 0800 61 6218 XVII Curso Nacional de Atualização em Pneumologia Data: 20 a 22 de abril de 2017 Local: Othon Palace Copacabana - Rio de Janeiro/RJ Informações: 0800616218 ou eventos@sbpt.org.br

ATS 2017 Data: 19-24 de Maio de 2017 Local: Washington, D.C/USA Informações: www.thoracic.org SEPAR 2017 Data: 2-5 de junho de 2017 Local: Madrid Marriott Auditorium Hotel & Conference Center, Madrid/Espanha Informações: www.separ.es ERS 2017 Data: 09-13 de Setembro de 2017 Local: Milão, Itália Informações: www.ersnet.org CHEST 2017 Data: 28/10 a 01 de novembro de 2017 Local: Toronto/Canadá Informações: www.chestnet.org