JBP - Volume 43, number 5, September/October 2017 by Jornal Brasileiro Pneumologia

ISSN 1806-3713

Volume 43, Number 5

September | October 2017

www.jbp.org.br

Volume 43, Number 5 September | October 2017

HIGHLIGHT

Situation of diagnosis of tuberculosis worldwide

Usual interstitial pneumonia

Effects of CPAP on systemic blood pressure

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Published once every two months J Bras Pneumol. v.43, number 5, p. 327-400 September/October 2017 EDITOR-IN-CHIEF

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

DEPUTY EDITOR

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

Associação Brasileira de Editores Científicos

EXECUTIVE EDITORS

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

ASSOCIATE EDITORS

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

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

EDITORIAL COUNCIL

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

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

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BTS Board of Directors (2017-2018 biennium): President: Fernando Luiz Cavalcanti Lundgren - PE Secretary-General: Benedito Francisco Cabral Júnior - DF CFO: Simone Chaves Fagondes - RS Scientific Director: Ana Luisa Godoy Fernandes - SP Director, Communications: Fernanda Miranda de Oliveira - GO Director, Education and Professional Practice:: Irma de Godoy - SP Director, Professional Advocacy: Marcelo Gervilla Gregório - SP President, BTS Congress 2018: Marcelo Fouad Rabahi - GO President Elect (2019/2020 biennium): José Miguel Chatkin - RS Editor-in-Chief of the Brazilian Journal of Pulmonology: Rogério de Souza - SP AUDIT COMMITTEE: Active Members: Ronaldo Rangel Travassos Júnior - PB, Eduardo Felipe Barbosa Silva - DF, Filadélfia Passos Travassos Martins - CE Alternates: Leandro Genehr Fitscher - RS, Ciléa Aparecida Victória Martins - ES, Eduardo Pamplona Bethlem - RJ COORDINATORS, BTS DEPARTMENTS: Thoracic Surgery – Darcy Ribeiro Pinto Filho -RS Sleep–disordered Breathing – Pedro Rodrigues Genta -SP Respiratory Endoscopy – Mauro Musa Zamboni -RJ Pulmonary Function – Silvia Carla Sousa Rodrigues -SP Imaging – Pablo Rydz Pinheiro Santana -SP Lung Diseases – Vera Luiza Capelozzi -SP Pediatric Pulmonology – Marina Buarque de Almeida -SP COORDINATORS, BTS SCIENTIFIC COMMITTEES: Asthma – Maria Alenita de Oliveira - SP Lung Cancer – Gustavo Faibischew Prado - SP Pulmonary Circulation – Marcelo Basso Gazzana -SP Advanced Lung Disease – Paulo Henrique Ramos Feitosa -DF Interstitial Diseases – José Antônio Baddini Martinez -SP Environmental and Occupational Respiratory Diseases – Carlos Nunes Tietboehl-Filho -RS COPD – Frederico Leon Arrabal Fernandes -SP Epidemiology – Juliana Carvalho Ferreira - SP Cystic Fibrosis – Rodrigo Abensur Athanazio – SP Respiratory Infections and Mycoses – Mônica Corso Pereira - SP Pleura – Roberta Karla Barbosa de Sales -SP Smoking – Maria da Penha Uchoa Sales - CE Intensive Care – Eduardo Leite Vieira Costa -SP Tuberculosis – Denise Rossato Silva -RS ADMINISTRATIVE SECRETARIAT OF THE BRAZILIAN JOURNAL OF PULMONOLOGY Address: SCS Quadra 01, Bloco K, Asa Sul, salas 203/204. Edifício Denasa, CEP 70398-900, Brasília, DF, Brazil. Tel. +55 61 3245-1030/+55 0800 616218. Assistant Managing Editor: Luana Maria Bernardes Campos. E-mail: jpneumo@jornaldepneumologia.com.br Circulation: 4.000 copies Distribution: Free to members of the BTS and libraries Printed on acid-free paper SUPPORT:

ISSN 1806-3713

Published once every two months J Bras Pneumol. v.43, number 5, p. 327-400 September/October 2017

EDITORIAL 327 - Momentum Rogério Souza

CONTINUING EDUCATION: IMAGING 329 - Honeycombing Edson Marchiori, Bruno Hochhegger, Gláucia Zanetti

CONTINUING EDUCATION: SCIENTIFIC METHODOLOGY 330 - Understanding diagnostic tests. Part 1. Juliana Carvalho Ferreira, Cecilia Maria Patino

Contents

ORIGINAL ARTICLE 331 - The Quebec Sleep Questionnaire on quality of life in patients with obstructive sleep apnea: translation into Portuguese and cross-cultural adaptation for use in Brazil José Tavares de Melo Júnior, Rosemeri Maurici, Michelle Gonçalves de Souza Tavares, Marcia Margareth Menezes Pizzichini, Emilio Pizzichini

337 - Factors associated with malnutrition in adolescent and adult patients with cystic fibrosis Gabriela Cristofoli Barni, Gabriele Carra Forte, Luis Felipe Forgiarini, Claudine Lacerda de Oliveira Abrahão, Paulo de Tarso Roth Dalcin

344 - Parapneumonic pleural effusion: early versus late thoracoscopy Rodrigo Romualdo Pereira, Cristina Gonçalves Alvim, Cláudia Ribeiro de Andrade, Cássio da Cunha Ibiapina

351 - Frequency of COPD in health care workers who smoke Ivan Kopitovic, Aleksandar Bokan, Ilija Andrijevic, Miroslav Ilic, Sanja Marinkovic, Dragana Milicic, Marija Vukoja

357 - Quality of Communication Questionnaire for COPD patients receiving palliative care: translation and cross-cultural adaptation for use in Brazil Flávia Del Castanhel, Suely Grosseman

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Published once every two months J Bras Pneumol. v.43, number 5, p. 327-400 September/October 2017

363 - Lung cancer: changes in histology, gender, and age over the last 30 years in Brazil Maria Teresa Ruiz Tsukazan, Álvaro Vigo, Vinícius Duval da Silva, Carlos Henrique Barrios, Jayme de Oliveira Rios, José Antônio de Figueiredo Pinto

368 - Epidemiological trends of allergic diseases in adolescents Silvia de Souza Campos Fernandes, Cláudia Ribeiro de Andrade, Cristina Gonçalves Alvim, Paulo Augusto Moreira Camargos, Cássio da Cunha Ibiapina

META-ANALYSIS 373 - Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a systematic review and metaanalysis of six randomized controlled trials Qiang Lei, Yunhui Lv, Kai Li, Lei Ma, Guodong Du, Yan Xiang, Xuqing Li

Contents

SPECIAL ARTICLE 380 - Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey Massimo Amicosante, Lia D’Ambrosio, Marcela Munoz, Fernanda Carvalho de Queiroz Mello, Marc Tebruegge, Novel Njweipi Chegou, Fouad Seghrouchni, Rosella Centis, Delia Goletti, Graham Bothamley, Giovanni Battista Migliori; TB Diagnostic Survey Working Group

PICTORIAL ESSAY 393 - Usual interstitial pneumonia: typical, possible, and “inconsistent” patterns Pedro Paulo Teixeira e Silva Torres, Marcelo Fouad Rabahi, Maria Auxiliadora Carmo Moreira, Gustavo de Souza Portes Meirelles, Edson Marchiori

IMAGING IN PULMONARY MEDICINE 399 - Liquid silicone injection in the chest wall simulating cysticercosis Luiz Felipe Nobre, Gláucia Zanetti, Edson Marchiori

LETTER TO THE EDITOR 400 - When is the use of contrast media in chest CT indicated? Bruno Hochhegger, Robson Rottenfusser, Edson Marchiori

J Bras Pneumol. 2017;43(5):327-328 http://dx.doi.org/10.1590/S1806-37562017000500001

EDITORIAL

Momentum Rogério Souza1,2

The Portuguese word momento can be translated in a number of ways. It is first and foremost translated as “moment”, which has an eminently temporal connotation, indicating a definite or indeterminate period of time, a secondary meaning (in Portuguese only) being that of a specific circumstance. However, it can also be translated as “momentum”, as the term is used in the field of physics, indicating the force imposed on a rotational system, generating an impulse or change. In the field of medicine, we can recognize the same uses of the terms “moment” (often expressed as “at the time of”) and “momentum”. The development of new diagnostic tools and therapeutic interventions significantly change the landscape of the recognition of and even advancement in the knowledge related to various clinical situations. The development of new techniques of computed tomography angiography of the chest has significantly increased its capacity to identify acute pulmonary thromboembolism; according to some authors, the method has become overly sensitive.(1) Although no causal relationships can be established, new approaches and therapeutic strategies have since been developed.(2) In the area of vascular diseases, the development of specific medications for the treatment of pulmonary arterial hypertension has had an undeniable impact on the development of knowledge related to that particular clinical situation, not only for its identification, in Brazil and elsewhere, but also for establishing treatment strategies and quantifying risks.(3-6) The example of pulmonary arterial hypertension illustrates the fact that this is not an issue related to disease prevalence, because it determines only the “moment” at which the change occurs. Another example is that of interstitial lung disease. Undoubtedly, the advent of HRCT allowed the identification of distinct radiological patterns,(7,8) which, together with clinical and pathological analyses, resulted in the current system of classification. More recently, the development of therapeutic alternatives has brought about a new “moment” of growth,(9) moving us toward another point of change, in which the interpretation of imaging exams is no longer merely visual and tends to have a highly significant mathematical aspect in the aggregate.(10) It is still difficult to know what impact this will have on day-to-day clinical practice and patient management, given the existing therapeutic limitations, although it is not difficult to imagine that, with the development of new drugs, a more precise diagnostic analysis will allow individualized medicine to be used in the approach to

patients with interstitial lung disease. The current issue of the JBP presents a pictorial essay that discusses, in a quite didactic manner, all of the certainties and inconsistencies that involve the diagnosis of usual interstitial pneumonia, the most prevalent form of idiopathic interstitial lung disease.(11) There have long been examples of clinical situations that do not involve a change in “momentum”, either because no new therapeutic or diagnostic approaches have been developed or because there is a lack of studies, even epidemiological studies, in the area. Analyzing the JBP, one can clearly see the growing role that tuberculosis plays in Brazil and around the world. In contrast, it has been quite some time since we published any studies related to pleural diseases. In this issue, we publish a quite interesting study evaluating the best “moment” at which to perform thoracoscopy in the approach to parapneumonic effusion in pediatric patients.(12) In addition to the obvious scientific aspect of the information generated by the study, one can understand that there are opportunities for future studies in the area. So what explains the fact that pleural diseases are so poorly represented in our scientific context? Of course, the development of diagnostic tools and new medications brings financial investments, which certainly further promotes the associated lines of research. However, if this were the only factor, would not that be a perverse inversion of the role of research centers and universities? Or could it be a demonstration that the role of independent funding agencies needs to be rethought? Might it not even be an indication of the need to organize interinstitutional research groups, especially in areas that are poorly represented, regardless of any epidemiological aspects of the clinical situation studied? Here, we should reflect upon not only the researchers but also the entities of scientific dissemination, especially those that are affiliated with scientific societies, as is the JBP, in order to directly stimulate research in areas with less visibility. A direct demonstration of interest by the scientific journals might be needed in order to change this situation. Such a demonstration, however, is not without risk, because it can have a direct impact on bibliometric indicators; the lower the overall number of studies in a given area is, the lower is the potential for the citation of such studies. This underscores the importance of this discussion, which is especially important among medical societies. In view of the considerations discussed above, the JBP is, at the current “moment”, stronger than ever. Dr. Bruno Baldi, associate professor of pulmonology at the University of São Paulo School of Medicine, has now been elected deputy editor. He will perform that

1. Disciplina de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil. 2. Editor-Chefe do JBP - Jornal Brasileiro de Pneumologia, Brasília (DF) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

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function until the end of 2018, when he will assume the role of editor-in-chief. Undoubtedly, this is quite a significant gain for the JBP and, particularly, for its

current management. I would like take advantage of this moment of reflection to wish Bruno an excellent journey forward with our journal.

REFERENCES 1. Wiener RS, Schwartz LM, Woloshin S. When a test is too good: how CT pulmonary angiograms find pulmonary emboli that do not need to be found. BMJ, 2013;347:f3368. https://doi.org/10.1136/bmj.f3368 2. Fernandes CJ, Alves Júnior JL, Gavilanes F, Prada LF, Morinaga LK, Souza R. New anticoagulants for the treatment of venous thromboembolism. J Bras Pneumol. 2016;42(2):146-54. https://doi. org/10.1590/S1806-37562016042020068 3. Alves JL Jr, Gavilanes F, Jardim C, Fernandes CJCDS, Morinaga LTK, Dias B, et al. Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. Chest. 2015;147(2):495-501. https://doi.org/10.1378/chest.14-1036 4. Hoette S, Jardim C, Souza Rd. Diagnosis and treatment of pulmonary hypertension: an update. J Bras Pneumol. 2010;36(6):795-811. https://doi.org/10.1590/S1806-37132010000600018 5. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65(18):197697. https://doi.org/10.1016/j.jacc.2015.03.540 6. Prada LF, Gavilanes F, Souza R. Incidence of spontaneous subdural hematoma in incident cases of pulmonary arterial hypertension: a registry of cases occurring over a five-year period. J Bras Pneumol. 2015;41(1):101-2. https://doi.org/10.1590/S180637132015000100014

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7. Marchiori E, Zanetti G, Hochhegger B. Diffuse lung cysts. J Bras Pneumol. 2015;41(5):484. https://doi.org/10.1590/S180637132015000000160 8. Marchiori E, Zanetti G, Hochhegger B. Small interstitial nodules. J Bras Pneumol. 2015;41(3):250. https://doi.org/10.1590/S180637132015000000059 9. Baddini-Martinez J, Baldi BG, Costa CH, Jezler S, Lima MS, Rufino R. Update on diagnosis and treatment of idiopathic pulmonary fibrosis. J Bras Pneumol. 2015;41(5):454-66. https://doi.org/10.1590/S180637132015000000152 10. Jun S, Park B, Seo JB, Lee S, Kim N. Development of a ComputerAided Differential Diagnosis System to Distinguish Between Usual Interstitial Pneumonia and Non-specific Interstitial Pneumonia Using Texture- and Shape-Based Hierarchical Classifiers on HRCT Images. J Digit Imaging. 2017 Sep 7. [Epub ahead of print]. https://doi. org/10.1007/s10278-017-0018-y 11. Torres PP, Rabahi MF, Moreira MA, Meirelles GS, Marchiori E. Usual interstitial pneumonia: typical, possible, and “inconsistent” patterns. J Bras Pneumol. 2017;43(5):393-8. 12. Pereira RR, Algim CG, Andrade CR, Ibiapina CC. Parapneumonic pleural effusion: early versus late thoracoscopy. J Bras Pneumol. 2017;43(5):344-50. https://doi.org/10.1590/s180637562016000000261

J Bras Pneumol. 2017;43(5):329-329 http://dx.doi.org/10.1590/S1806-37562017000000232

CONTINUING EDUCATION: IMAGING

Honeycombing Edson Marchiori1, Bruno Hochhegger2, Gláucia Zanetti1

A 34-year-old female patient presented with complaints of dry cough, dyspnea, and weight loss. She reported frequent episodes of heartburn and regurgitation. Physical examination revealed bilateral crackles, microstomia, and muscle hypotrophy. A CT scan of the chest showed multiple cysts, predominantly in the inferior and posterior portions of the lungs, as well as dilation of the distal esophagus (Figure 1). CT findings included multiple cysts, located predominantly in the posterior subpleural lung bases, stacked upon one another in layers, and sharing walls, characterizing honeycombing. Dilation of the distal esophagus was also observed. Histologically, honeycombing consists of lung cysts resulting from distal airspace destruction by fibrosis of the lung parenchyma, with loss of acinar and bronchiolar architecture. In summary, honeycombing indicates the presence of pulmonary fibrosis and is an important criterion for the diagnosis of usual interstitial pneumonia. Honeycombing can be idiopathic, therefore indicating idiopathic pulmonary fibrosis (IPF), or secondary to a number of diseases, including hypersensitivity pneumonitis (HP), sarcoidosis, asbestosis, drug reaction, and connective tissue diseases (particularly rheumatoid arthritis and scleroderma). Certain clinical and CT features can assist in narrowing the differential diagnosis. A diagnosis of asbestosis can be made on the basis of occupational history and the

presence of pleural plaques. In cases of sarcoidosis, honeycombing is predominantly found in the upper lobes and perihilar and peribronchovascular regions, being commonly associated with calcified hilar and mediastinal lymph nodes. A diagnosis of IPF is made by excluding other causes of honeycombing, which is typically subpleural and located at the lung bases in cases of IPF. It is difficult to differentiate between IPF and chronic HP. A history of antigen exposure (e.g., being a bird fancier, being exposed to household mold, and using bird feather pillows) associated with CT findings of subacute HP (ground-glass opacities, poorly defined centrilobular nodules, and areas of decreased attenuation because of air trapping) are suggestive of chronic HP. In addition, chronic HP rarely involves the lung bases, typically affecting the upper lobes. In patients presenting with a dilated and atonic esophagus, as was the case in our patient, honeycombing is suggestive of scleroderma. Age is also an important factor; our patient was 34 years old, and most of the patients who are diagnosed with IPF are over 50 years of age. Microstomia and muscle hypotrophy are common findings in patients with scleroderma. In conclusion, interstitial pneumonias are often difficult to diagnose, and, in many cases, a definitive diagnosis can only be made by means of a multidisciplinary approach, with the involvement of pulmonologists, radiologists, and pathologists.

Figure 1. Axial CT scan of the chest at the level of the lower lobes, showing multiple subpleural cysts that share walls and stack upon one another in layers, predominantly in the inferior and posterior portions of the lungs (arrowheads). Note dilation of the distal esophagus (asterisk).

RECOMMENDED READING 1. Muller NL, Silva CI, editors. Imaging of the Chest. Philadelphia: Sauders-Elsevier; 2008. 1. Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. 2. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre (RS) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

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J Bras Pneumol. 2017;43(5):330-330 http://dx.doi.org/10.1590/S1806-37562017000000330

Understanding diagnostic tests. Part 1. Juliana Carvalho Ferreira1,2, Cecilia Maria Patino1,3

PRACTICAL SCENARIO Investigators studied the diagnostic accuracy of serum procalcitonin levels to diagnose parapneumonic pleural effusions (PPE) and differentiate it from other causes of pleural effusions. They found that procalcitonin (with a cut-off value of 0.195 ng/mL) had a sensitivity of 83% and a specificity of 80% to diagnose PPE and accurately diagnosed individuals with PPE.(1) USING DIAGNOSTIC TESTS IN CLINICAL PRACTICE Clinicians are frequently faced with the challenge of diagnosing a disease based on diagnostic test results. Most diagnostic tests used in clinical practice, however, are not perfect and produce false positive results (the test is positive, but the patient does not have the disease) and false negative results (the test is negative, but the patient has the disease). Therefore, learning to interpret the properties of diagnostic tests is a critical competency for clinicians and researchers. In this article, we discuss sensitivity and specificity. In the forthcoming parts, we will discuss positive and negative predictive values, and receiver operating characteristic (ROC) curves. Sensitivity and specificity are important measures of a diagnostic test because they give us an idea of how well a new diagnostic test performs when compared with an existing gold standard test. Sensitivity is defined as the proportion of subjects with the disease who have a positive test. In the example in Table 1, true positives (n = 39) divided by the total number of subjects with disease (n = 47) results in 83%. Specificity is defined as the proportion of subjects without the disease who have a negative test. In the example, true negatives (n = 81) divided by total number of subjects without the disease (n = 101) results in 80%.

When a new diagnostic test is evaluated, the investigator sets a cut-off point which defines whether the test is positive or negative, and there is always a trade-off between sensitivity and specificity. In our example, if the cut-off point for a positive procalcitonin test was decreased from 0.195 ng/mL to 0.095 ng/mL, it might detect more cases of PPE, decreasing the false negative rate and increasing sensitivity, but the test would also be positive in more subjects without PPE, increasing the false positive rate and decreasing specificity. This trade-off between sensitivity and specificity for several possible cut-off points can be used to plot a ROC curve and describe the overall test performance in discriminating between presence and absence of the disease; we can also use sensitivity and specificity to calculate likelihood ratios, as we will see later in this series. Sensitivity and specificity are useful measures to evaluate the performance of a diagnostic test but are not very helpful for personalized clinical decision making.(2) When a clinician is facing a patient with a positive test result, the most important question is: what is the probability that, given that the test is positive, the patient has the disease? The sensitivity of the test does not tell us that; it tells us the probability of a positive test, given that the patient has the disease. We will address more relevant clinical measures of diagnosis in part 2 of this series. Table 1. Diagnostic performance of serum procalcitonin testing for identifying parapneumonic pleural effusion.

Result PCT+ PCT− Total

PPE + a = 39 c=8 47

Total − b = 20 d = 81 101

59 89 148

Data obtained from He et al.(1) PCT: procalcitonin; PPE: parapneumonic pleural effusion. Sensitivity (light grey column) = a/(a + c). Specificity (dark grey column) = b/(b + d).

REFERENCES 1. He C, Wang B, Li D, Xu H, Shen Y. Performance of procalcitonin in diagnosing parapneumonic pleural effusions: A clinical study and meta-analysis. Medicine (Baltimore). 2017;96(33):e7829. https://doi.

org/10.1097/MD.0000000000007829 2. Altman DG, Bland M. Diagnostic tests. 1: Sensitivity and specificity. BMJ. 1994;308(6943):1552. https://doi.org/10.1136/bmj.308.6943.1552

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

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J Bras Pneumol. 2017;43(5):331-336 http://dx.doi.org/10.1590/S1806-37562016000000160

ORIGINAL ARTICLE

The Quebec Sleep Questionnaire on quality of life in patients with obstructive sleep apnea: translation into Portuguese and cross-cultural adaptation for use in Brazil José Tavares de Melo Júnior1, Rosemeri Maurici1,2, Michelle Gonçalves de Souza Tavares3, Marcia Margareth Menezes Pizzichini1,4, Emilio Pizzichini1,2,5 1. Programa de Pós-Graduação em Ciências Médicas, Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil. 2. Núcleo de Pesquisa em Asma e Inflamação das Vias Aéreas – NUPAIVA – Universidade Federal de Santa Catarina, Florianópolis (SC) Brasil. 3. Universidade do Sul de Santa Catarina – Unisul – Florianópolis (SC) Brasil. 4. Departamento de Clínica Médica, Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil. 5. Departamento de Pneumologia, Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil. Submitted: 30 May 2016. Accepted: 26 February 2017. Study carried out at Hospital Universitário Polydoro Ernani de São Thiago, Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil.

ABSTRACT Objective: To translate the Quebec Sleep Questionnaire (QSQ), a specific instrument for the assessment of quality of life in patients with sleep obstructive apnea, into Portuguese and to create a version that is cross-culturally adapted for use in Brazil. Methods: The Portuguese-language version was developed according to a rigorous methodology, which included the following steps: preparation; translation from English into Portuguese in three versions; reconciliation to a single version; back-translation of that version into English; comparison and harmonization of the back-translation with the original version; review of the Portuguese-language version; cognitive debriefing; text review; and arrival at the final version. Results: The Portuguese-language version of the QSQ for use in Brazil had a clarity score, as measured by cognitive debriefing, ranging from 0.81 to 0.99, demonstrating the consistency of translation and cross-cultural adaptation processes. Conclusions: The process of translating the QSQ into Portuguese and creating a version that is cross-culturally adapted for use in Brazil produced a valid instrument to assess the quality of life in patients with obstructive sleep apnea. Keywords: Obstructive sleep apnea, Quality of life; Translations; Validation studies.

INTRODUCTION Obstructive sleep apnea (OSA) can be diagnosed on the basis of 5 or more predominantly obstructive respiratory events per hour during polysomnography. These events should be accompanied by signs and symptoms, such as heavy snoring, daytime sleepiness, sudden awakenings with a feeling of suffocation, and apneas observed by others. Alternatively, the occurrence of more than 15 obstructive respiratory events per hour meets the diagnostic criterion even in the absence of signs and symptoms.(1) OSA represents more than 85% of all causes of sleep-disordered breathing.(2) In a population-based study conducted in the city of São Paulo, Brazil, the prevalence of OSA was 32.8%,(3) bringing the magnitude of this problem to light. With regard to financial impact, in the United States, the annual cost only for treating medical problems caused by OSA is estimated at 3.4 billion dollars.(4) Studies have demonstrated that OSA has a strong relationship with systemic arterial hypertension,(5) changes in glucose metabolism,(6) cardiovascular diseases,(7) and respiratory diseases, such as asthma and COPD.(8) In

addition, excessive daytime sleepiness, fatigue, irritability, and personality changes have also been attributed to intermittent oxyhemoglobin desaturations and to the chronic sleep deprivation caused by sleep fragmentation.(9) All of the above changes can lead to decreased quality of life. While studies overvalue the apnea-hypopnea index (AHI) as an outcome measure, the effect of OSA on quality of life is, curiously, seldom mentioned. However, there is a poor correlation between OSA patient-reported quality of life and the AHI, making it inappropriate to use the AHI as the sole outcome measure.(10) Therefore, it seems reasonable that quality-of-life measurement via a specific questionnaire should be considered, which would allow it to be used in epidemiological studies in different regions and in clinical trials. In addition, administering this type of instrument to patients would enable a more reliable analysis of short-, medium-, and long-term effects of a given treatment. One of the most commonly used generic quality-of-life questionnaires is the Medical Outcomes Study 36-item Short-Form Health Survey, which has been adapted for use in Brazil(11) and has been used in studies of OSA.(12) However, although the use of generic tools facilitates comparisons across chronic diseases, these tools do

Correspondence to:

José Tavares de Melo Júnior. Núcleo de Pesquisa em Asma e Inflamação das Vias Aéreas (NUPAIVA), Hospital Universitário da UFSC, Campus Universitário, Trindade, CEP 88040-970, Florianópolis, SC, Brasil. Tel./Fax: 55 48 3234-7711. E-mail: josetavaresjr@hotmail.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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The Quebec Sleep Questionnaire on quality of life in patients with obstructive sleep apnea: translation into Portuguese and cross-cultural adaptation for use in Brazil

not assess the most important specific aspects of a particular disease to the patient.(13) In addition, generic instruments may not be able to detect the effects of interventions or treatments.(14) To that end, there is a need for specific validated questionnaires, such as the Quebec Sleep Questionnaire (QSQ),(15) which is one of the major instruments for assessing quality of life in OSA patients. Originally designed in French, the QSQ was translated by its authors from French into English and was shown to have excellent psychometric properties.(15) At the time, the minimal clinically important differences for each domain were also determined: 1.8 points for daytime sleepiness; 2.0 points for diurnal symptoms; 1.5 points for nocturnal symptoms; 1.1 points for emotions; and 2.5 points for social interactions. Subsequently, the QSQ was translated into Spanish and adapted for use in Spain,(16) and this Spanish-language version was adequately tested for psychometric properties. (17) In comparison with other instruments that are also specific for OSA, such as the Calgary Sleep Apnea Quality of Life Instrument (SAQLI),(18) the QSQ has some characteristics that should be observed and that make it advantageous. While the SAQLI (56 questions) takes longer to complete, has to be administered by an interviewer, and, in particular, has a “symptoms” domain that is individualized, which may allow interference from the patient,(19) the QSQ is shorter and has standardized items, which makes it more appropriate for large and long-term studies. (20) In contrast, the Maugeri Obstructive Sleep Apnea Syndrome questionnaire was developed to assess the physical and psychological impact of OSA, with an emphasis on adherence to continuous positive airway pressure treatment.(21) It is of note that the questionnaire does not include questions about nocturnal symptoms.(21) Another specific instrument that is widely used in research and clinical practice is the Epworth Sleepiness Scale (ESS).(22,23) However, the ESS is not aimed at measuring quality of life and refers specifically to the “sleepiness” domain. To date in Brazil, no specific instruments for assessing quality of life in OSA patients have been developed, nor have any such instruments been adapted for use in the country. Therefore, the objectives of the present study were to translate the QSQ into Portuguese and to create a version that is cross-culturally adapted for use in Brazil. METHODS

Description of the QSQ • The QSQ is an instrument comprising 32 items that assess the impact of apnea on five distinct domains: daytime sleepiness; diurnal symptoms; nocturnal symptoms; emotions; and social interactions. Each domain consists of 4 to 10 items that are rated on a 1- to 7-point Likert scale. The results are expressed as the mean score for each separate domain. Higher scores indicate milder symptoms. The items within each 332

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• • • •

domain are listed below: Daytime sleepiness: items 7; 16; 20; 27; 31; and 32 Diurnal symptoms: items 1; 10; 11; 14; 17; 18; 19; 23, 26; and 29 Nocturnal symptoms: items 4; 9; 21; 22; 25; 28; and 30 Emotions: items 5; 6; 8; 15; and 24 Social interactions: items 2; 3; 12; and 13

Item 32, which refers to the act of driving an automobile, should be left blank if the patient does not drive, and the mean score for the “daytime sleepiness” domain should be calculated from the remaining five items.

Design This was a methodological study involving the translation of the QSQ into Portuguese and the creation of a version that is cross-culturally adapted for use in Brazil. The steps of the cross-cultural adaptation process, steps that can also be found in other publications,(24-26) were performed in strict accordance with internationally accepted guidelines(27) and are summarized as follows: 1) preparation: researchers’ meeting aimed at planning the study and contacting with the developer of the QSQ to obtain permission to use the instrument; 2) forward translation: three health care professionals carried out three independent forward translations of the QSQ from English into Portuguese; 3) reconciliation: reconciliation of the three forward translations into a single forward translation, performed by the translators; 4) backtranslation: back-translation of the single reconciled version into English; 5) comparison and harmonization: comparison conducted by the authors between the back-translation and the original version of the QSQ in order to detect potential discrepancies; 6) review of the Portuguese-language version of the QSQ by experts; 7) cognitive debriefing: process of testing the translated questionnaire on the target population in order to check understandability of the questions. Twenty-five patients were interviewed, all of whom were literate, were over 18 years of age, had a diagnostic suspicion of OSA—snoring, witnessed apneas, and excessive daytime sleepiness—were treated as outpatients, and had clinical indications for polysomnography. The diagnosis of OSA was subsequently confirmed by baseline overnight polysomnography, which was performed in a certified sleep laboratory, when the AHI was greater than or equal to 15 events/h or when the AHI was greater than or equal to 5 events/h in patients who reported other symptoms, such as awakening due to gasping, daytime sleepiness, fatigue, cognitive changes, and nonrestorative or fragmented sleep.(28) The patients were first asked to complete the translated questionnaire itself. Since the QSQ is a self-administered questionnaire, its translated version was completed by the participants themselves without the assistance of the attending physician. Then, in order to cognitively debrief the translated questionnaire, another instrument was completed. At this point, the participants were told that they should rate their understanding of each of the 32 previously answered questions on a 1- to 10-point Likert scale.

Melo Júnior JT, Maurici R, Tavares MGS, Pizzichini MMM, Pizzichini E

Scores between 1 and 4 were defined as indicating confusing wording; scores between 5 and 7 were defined as indicating unclear wording; and scores between 8 and 10 were defined as indicating clear wording.(29) The clarity score for each item was obtained by calculating the mean of the scores attributed by the patients to each of the items. The items whose means were less than 0.4 should be replaced. The items whose means were less than 0.8 should be reformulated. Finally, the items that had means ≥ 0.8 were considered appropriate in terms of understandability and were maintained; 8) review: full-text review by a Portuguese teacher; and 9) final version: preparation of the final version of the symptom-specific questionnaire for assessing quality of life in OSA patients. The study protocol, including the final version of the written informed consent form, was submitted to and approved by the Human Research Ethics Committee of the Federal University of Santa Catarina. Participation in the present study was voluntary, and all participants, who were recruited at a private clinic in the city of Florianópolis, Brazil, gave written informed consent before answering any questions. Patient demographics and clinical data were characterized with descriptive statistics, and the results were expressed as mean and standard deviation. RESULTS Of the 25 patients interviewed for cognitive debriefing, 3 were excluded because they were lost to follow-up. Of the remaining 22 patients, 16 were male. Patient age ranged from 26 to 65 years. The mean body mass index (BMI) was 28.5 kg/m2, being 29.0 ± 5.0 kg/m2 for males and 27.1 ± 2.3 kg/m2 for females. Table 1. Patient distribution by demographic characteristics and polysomnography data.a

Characteristic Age, years Male gender Level of education ≤ high school Body mass index, kg/m2* Neck circumference, cm AHI, events/h Arousal index, events/h

Result 44.68 ± 10.75 16 (72.7) 5 (22.7) 28.5 ± 4.4 39.3 ± 3.6 23.4 ± 26.7 27.5 ± 13.5

AHI: apnea-hypopnea index. aValues expressed as n (%) or as mean ± SD.

The mean neck circumference for males and females was, respectively, 40.6 ± 3.4 cm and 36.0 ± 1.41 cm. Polysomnography revealed a mean AHI of 23.4 ± 26.7 events/h (range: 0.0-89.7 events/h; Table 1). The results of the Portuguese-language version of the QSQ administered to the participants are summarized in Table 2. In the forward and back-translation steps, no questions or corrections were raised. The review carried out by the expert committee did not point out any grammatical or conceptual errors. Similarly, there were no difficulties in translating or adapting words related to the domains. However, some English idioms and phrases were a matter of review and discussion. For instance, in the step in which the back-translated version was compared with the original version, the author of the QSQ raised two questions regarding differences from the initial concept. The first referred to the fact that item 23 differed between the back-translated version and the original English-language version; however, the author agreed to the cross-cultural adaptation for use in Brazil, because our translation was more faithful to the original French-language version. Therefore, “feeling that you lack energy” read “feeling that you are exhausted (worn-out)” in the back-translation, and, as already said, was accepted by the author of the QSQ. The second question referred to the response choices in the Likert scale for items 10 to 15: the backtranslation of these response choices was “excessively; often/moderately to often; moderately; a little; barely; and not at all”. The author of the QSQ explained that these response choices expressed quantity and time and that he would rather they expressed only quantity (as in the original French-Canadian version). As a result, the response choices in the Likert scale were changed to “quantidade muito grande; quantidade grande; moderada a grande quantidade; moderada quantidade; pequena a moderada quantidade; pequena quantidade; e nada”. After the changed version of the back-translation was approved by the author of the QSQ, an expert committee met to evaluate the Portuguese-language version of the questionnaire in order to detect errors, offer suggestions, and evaluate its content and structure. The review carried out by the expert committee did not point out any grammatical or conceptual errors. Grammatical corrections were made also by the

Table 2. Scores in each domain of the Portuguese-language version of the Quebec Sleep Questionnaire by apneahypopnea index.

Domain

Daytime sleepiness Diurnal symptoms Nocturnal symptoms Emotions Social interactions

Group AHI < 5 events/h n=6 Scorea Range 5.5 ± 1.6 2.7-6.7 4.9 ± 1.7 2.2-6.6 4.7 ± 1.5 3.3-6.4 4.8 ± 1.5 3.0-6.6 3.0 ± 1.1 1.8-4.5

p* AHI ≥ 5 events/h n = 16 Scorea Range 5.6 ±1.4 2.8-7.0 4.9 ±1.4 2.3-6.7 4.5 ±1.4 1.7-6.1 4.7 ±1.4 2.4-6.8 3.9 ±1.2 6.0-1.6

0.84 0.95 0.73 0.87 0.12

AHI: apnea-hypopnea index. aValues expressed as mean ± SD. *Independent sample t-test. J Bras Pneumol. 2017;43(5):331-336

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Portuguese-language expert, and the questionnaire version intended for use during cognitive debriefing was then produced. To ensure that the entire translated instrument was easy to understand, cognitive debriefing involved an item-by-item analysis. The instrument was reviewed by discussing the response findings. No item needed to be reformulated, the minimum score being 0.81 and the maximum score being 0.99 (Figure 1). Therefore, the version tested during cognitive debriefing was accepted without changes, after full agreement by all researchers (Appendix is available online at http:// jornaldepneumologia.com.br/detalhe_anexo.asp?id=55). DISCUSSION In the present study, a specific instrument for measuring quality of life in OSA patients, the QSQ, was cross-culturally adapted for use in Brazil. Cognitive debriefing results showed that the level of understandability of all items of the instrument was appropriate. This finding is of great relevance because it demonstrates the consistency of the translation and cross-cultural adaptation process. However, although all items had a clarity score greater than 0.8, when we consider the performance of item 13–”Você tem se sentido culpado em seu relacionamento com familiares ou amigos íntimos?”–we observe that this item had the lowest mean score of all (0.81). We believe that, rather than reflecting patient difficulty in understanding, this finding may have reflected the essentially subjective content of the question. The process of cross-cultural adaptation of a questionnaire includes not only a translated version that

is conceptually equivalent to the original instrument but also one that is culturally acceptable in the country in which it will be used. Therefore, in order to achieve technical and semantic equivalence between the source and target language versions, the present study was conducted according to recommendations in the literature.(27,30) By ensuring this equivalence, distortions that could compromise the instrument’s psychometric properties that have been documented in previous studies are avoided.(31) We chose the QSQ because it is a validated specific self-administered questionnaire that is easy to complete and is structured in different domains. In addition, the QSQ has the characteristic of being responsive to changes induced by therapeutic interventions.(32) In recent years, various studies have used the QSQ to measure quality of life in OSA patients. For instance, the QSQ was useful in revealing improved quality of life in OSA patients undergoing continuous positive airway pressure treatment.(33) In patients with mild positional OSA who wore an electronic sleep position training device, quality of life was found to improve significantly.(34) In another study, the use of the QSQ and the ESS made it possible to demonstrate that OSA patients may underestimate their sleepiness when this symptom is measured by the ESS.(35) More recently, in a systematic review of various questionnaires for use in OSA patients,(36) the QSQ was one of those recommended for assessing OSA patients in clinical practice, notably because of its content validity. We acknowledge that one limitation of the QSQ is that, since it is a specific standardized instrument, individual choices may be restricted, and, therefore, the instrument accuracy in terms of its responsiveness

1 0.9 0.8

Clarity score

0.7 0.6 0.5 CD

0.4 0.3 0.2 0.1 0

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Item

Figure 1. Clarity of each item of the Portuguese-language version of the Quebec Sleep Questionnaire. The blue bars represent the clarity scores obtained during cognitive debriefing. The red line indicates the cut-off point at which an item is considered clear: 0.80. The figure shows that all questionnaire items were considered clear during cognitive debriefing. CD: cognitive debriefing

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Melo Júnior JT, Maurici R, Tavares MGS, Pizzichini MMM, Pizzichini E

to treatment may be affected. With regard to our study design, one could question the choice to maintain patients with complaints of snoring and nonrestorative sleep, among other complaints, but with an AHI < 5 events/h. As to that, we took care to conduct a parallel cognitive debriefing analysis only in those individuals with an AHI < 5 events/h and concluded that there was no difference between the cognitive debriefing results. It is of interest that, regarding the scores on the Portuguese-language version of the QSQ itself, no significant differences were also found in any of the domains between individuals with an AHI < 5 events/h and those with an AHI ≥ 5 events/h. In addition, we emphasize that our objective was the cross-cultural adaptation of the QSQ, which is a complementary process in the validation of psychometric properties. Since the translation and adaptation process followed a rigorous and recommended methodology, we can infer that the translated instrument retained the properties of the original instrument and is therefore suitable for use in Brazil. Additional studies using the

translated instrument may help expand and confirm our observations. In summary, the QSQ has now been translated into Portuguese and adapted for use in Brazil. We believe that the future use of this version of the QSQ in multicenter epidemiological studies in various regions could make it possible to compare results and to estimate the degree to which sociocultural differences influence the impact that OSA has on the quality of life of populations. It is of note that the QSQ is a single measure of OSA-related quality of life, now available in a Brazilian Portuguese-language version. ACKNOWLEDGMENTS The authors would like to thank the developer of the Quebec Sleep Questionnaire, Dr. Yves Lacasse, for his receptiveness to the present project and his participation when necessary. We would also like to thank Dr. Luciano Nogueira for his valuable participation in the initial translation process.

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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. 26. Caminha GP, Melo Junior JT, Hopkins C, Pizzichini E, Pizzichini MM. SNOT-22: psychometric properties and cross-cultural adaptation into the Portuguese language spoken in Brazil. Braz J Otorhinolaryngol. 2012;78(6):34-9. https://doi.org/10.5935/1808-8694.20120030 27. Wild D, Grove A, Martin M, Eremenco S, McElroy S, VerjeeLorenz A, et al. Principles of Good Practice for the Translation and 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. https://doi.org/10.1111/ j.1524-4733.2005.04054.x 28. American Academy of Sleep Medicine. The international classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 29. Melo SI. Coeficiente de atrito: um sistema de avaliação [thesis]. Santa Maria: Universidade Federal de Santa Maria; 1994. p. 94-9. 30. 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. https://doi. org/10.1016/0895-4356(93)90142-N

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ORIGINAL ARTICLE

Factors associated with malnutrition in adolescent and adult patients with cystic fibrosis Gabriela Cristofoli Barni1, Gabriele Carra Forte1, Luis Felipe Forgiarini1,2, Claudine Lacerda de Oliveira Abrahão3, Paulo de Tarso Roth Dalcin1,4 1. Programa de Pós-Graduação em Ciências Pneumológicas, Universidade Federal do Rio Grande do Sul – UFRGS – Porto Alegre (RS) Brasil. 2. Laboratório de Vias Aéreas e Pulmão, Hospital de Clínicas de Porto Alegre – HCPA – Universidade Federal do Rio Grande do Sul – UFRGS – Porto Alegre (RS) Brasil. 3. Serviço de Nutrição, Hospital de Clínicas de Porto Alegre – HCPA – Universidade Federal do Rio Grande do Sul – UFRGS – Porto Alegre (RS) Brasil. 4. Serviço de Pneumologia, Hospital de Clínicas de Porto Alegre – HCPA – Universidade Federal do Rio Grande do Sul – UFRGS – Porto Alegre (RS) Brasil. Submitted: 27 October 2016. Accepted: 26 February 2017. Study carried out at the Hospital de Clínicas de Porto Alegre – HCPA – Universidade Federal do Rio Grande do Sul – UFRGS – Porto Alegre (RS) Brasil.

ABSTRACT Objective: To determine the prevalence of malnutrition in patients attending an adult cystic fibrosis (CF) program and to investigate the associations of malnutrition with the clinical characteristics of those patients. Methods: This was a cross-sectional study involving patients with clinically stable CF patients (16 years of age or older). The patients underwent clinical assessment, nutritional assessments, pulmonary function tests, and pancreatic function assessment. They also completed a questionnaire regarding diet compliance. On the basis of their nutritional status, the patients were classified divided into three groups: adequate nutrition; at nutritional risk; and malnutrition. Results: The study has included 73 patients (mean age, 25.6 ± 7.3 years), 40 of whom (54.8%) were female. The mean body mass index was 21.0 ± 3.0 kg/m2 and the mean FEV1 was 59.7 ± 30.6% of predicted. In this sample of patients, 32 (43.8%), 23 (31.5%), and 18 (24.7%) of the patients were allocated to the adequate nutrition, nutritional risk, and malnutrition groups, respectively. The logistic regression analysis identified three independent factors associated with the risk of malnutrition: Shwachman-Kulczycki score, percent predicted FEV1; and age. Conclusions: Malnutrition remains a common complication in adolescents and adults with CF, despite dietary advice. Malnutrition is associated with age, clinical severity, and lung function impairment. Keywords: Cystic fibrosis; Malnutrition; Exocrine pancreatic insufficiency; Respiratory function tests.

INTRODUCTION Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in caucasians, and it is caused by the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Mutations in the CFTR gene are known to alter the airway and the intestinal microenvironment.(1,2) This protein is expressed as a chloride channel in the apical membrane of airway cells, as well as in intestine, liver, and reproductive tissues; it affects exocrine pancreatic function and sweat ducts. The CFTR protein regulates and participates in the electrolyte transport across the membranes of those cells. Thus, its absence or partial functioning is related to the pathophysiology of CF.(3,4) The clinical manifestations of the disease result from an increased viscosity of secretions, which leads to the obstruction of ductal epithelial cells. The classic phenotype of the CF, or mucoviscidosis, is characterized by pulmonary infections, pancreatic insufficiency, malabsorption of nutrients, liver disease, male infertility, and loss of sweat electrolytes.(5) In recent years, medical and technological advances have increased the mean survival rates worldwide, primarily through the early diagnosis of CF, input of

experts, better treatments, and organ transplantations. Nearly half of the CF population is ≥ 18 years of age.(5) The clinical course of CF and the quality of life of the patients are directly affected by their nutritional status, and malnutrition is one of the most serious and difficult challenges in CF treatment.(6) Malnutrition results from a discrepancy between energy/nutrient requirements and food intake, which can be caused by malabsorption.(7) Malnutrition and lung disease are inextricably woven together in CF. Studies have shown that lung function decline and malnutrition are related and are dependent factors. The occurrence of malnutrition is associated with reductions in lung function and survival. Chronic pulmonary infections and decreased lung function result in increased calorie needs and reduced appetite, which worsen the nutritional status of CF patients.(8,9) There is a growing body of literature looking at malnutrition and CF; however, those studies are mostly related to pediatric patients.(10,11) The aims of the present study were to determine the prevalence of malnutrition in patients attending an adult CF program and to investigate the associations of malnutrition with the clinical characteristics of those patients.

Correspondence to:

Gabriela Cristofoli Barni. Rua João Berutti, 492, Chácara das Pedras, CEP 91330-370, Porto Alegre, RS, Brasil. Tel.: 55 51 9191-9307. E-mail: gabicbarni@hotmail.com Financial support: This study received financial support from the Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA, Research Incentive Fund of the Porto Alegre Hospital de Clínicas). Gabriela Cristofoli Barni is the recipient of a grant from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Factors associated with malnutrition in adolescent and adult patients with cystic fibrosis

METHODS

Study design This was a single-center, cross-sectional study of prospectively collected data, and it was approved by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre, located in the city of Porto Alegre, Brazil. All of the subjects gave written informed consent.

Population The study included patients with CF who were 16 years of age or older. We included only CF patients who had been diagnosed on the basis of consensus criteria. (12) All patients had to be clinically stable in order to be included in the study, clinical stability being defined as no current changes in medications and no use of i.v. or p.o. antibiotics due to pulmonary exacerbations in the last 30 days. Patients were excluded if they declined to participate in the study, did not meet the inclusion criteria, or were pregnant.

Clinical variables The following data were recorded: age, gender, ethnicity, presence of the F508del mutation (homozygous, heterozygous, or other mutations), presence of diabetes mellitus, and a liver score (normal or abnormal).(13)

Nutritional evaluation Nutritional status was assessed using the body mass index (BMI) and its percentile. BMI was calculated from the ratio weight/height2 (kg/m2). Patients younger than 20 years of age had their BMI percentile calculated. On the basis of their nutritional status, the patients were divided into three groups: adequate nutrition (AN): BMI > 22 kg/m2 for women and BMI > 23 kg/ m2 for men (for patients ≥ 20 years of age) or BMI percentile > 25 (for patients < 20 years of age); at nutritional risk (NR): BMI = 19-22 kg/m2 for women and 19-23 kg/m2 for men (for patients ≥ 20 years of age) or BMI percentile = 10-25 (for patients < 20 years of age); and malnutrition (MN): BMI < 19 kg/ m2 (for patients ≥ 20 years of age) or BMI percentile < 10 (for patients < 20 years of age).(6,14)

Bacteriological status Bacterial isolates from sputum cultures of the participants were assessed in the Microbiology Department of the Hospital de Clínicas de Porto Alegre. The presence of Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia was registered. The presence of any of the aforementioned pathogens was confirmed by their isolation from routine sputum samples in the laboratory on at least two occasions, at least 12 months apart.

Clinical score The clinical score used was the Shwachman-Kulczycki (S-K) score,(15) assessed by the physician of the CF team at an outpatient setting. 338

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Pulmonary function tests Pulmonary function tests were performed with a computerized spirometer (MasterScreen v4.31; Jaeger, Würzburg, Germany). At least three curves were obtained, the best ones being selected, for the determination of FVC and FEV1, both in L and percentage of predicted values for age, stature, and gender.(16)

Assessment of pancreatic function The fecal elastase-1 test was performed using monoclonal ELISA. Stool samples were collected and stored at a temperature of −22°C until being tested. The cut-off point of 200 µg/g was used in order to classify the exocrine pancreatic function of the patients (≥ 200 µg/g: sufficiency; < 200 µg/g: insufficiency). Patients whose results were ≥ 100 µg/g but < 200 µg/g were classified as having moderate exocrine pancreatic insufficiency. Patients with elastase-1 levels < 100 µg/g were classified as having severe exocrine pancreatic insufficiency.(17)

Compliance with dietary treatment Patients were asked to complete a questionnaire (adapted from another study)(18) with three questions about their compliance with pancreatic enzyme replacement therapy, multivitamin supplement (vitamins A, D, E, and K) intake, and a hypercaloric diet (a diet high in energy, protein, and fat, based on a nutritional care plan and tailored to meet the nutritional requirements of each individual). Each question was to be answered on the basis of their weekly frequency of intake, as follows: a) every day or almost every day; b) 3-5 days a week; c) less than 3 days a week or never; and d) not applicable.

Statistical analysis All data were processed and analyzed using the Statistical Package for the Social Sciences, version 18.0 (SPSS Inc., Chicago, IL, USA). Quantitative results were expressed as means and standard deviations or as medians and interquartile ranges, whereas qualitative variables were expressed as numbers of cases and proportions. Quantitative data with normal distribution were subjected to one-way ANOVA with Tukey’s post hoc test. For continuous data with nonnormal distribution, the Kruskal-Wallis test and the post hoc Z test were used. The chi-square test was applied to all qualitative data, as was Yates’ correction or Fisher’s exact test, as required. Multivariate analyses were generated through logistic regression analysis using the enter method. On this basis, the odds ratio was the odds ratio for malnutrition. Selected variables with p < 0.10 were introduced in the binary logistic regression controlled by gender and age. ROC curves were then created for each predictor variable identified in the logistic regression analysis and used to calculate the sensitivity, specificity, and predictive values of the clinical variables related to malnutrition. All statistical tests used were two-tailed. The level of significance was set at p < 0.05.

Barni GC, Forte GC, Forgiarini LF, Abrahão CLO, Dalcin PTR

RESULTS In the period between May of 2013 and May of 2014, 104 patients were invited to participate in the study. Of these, 6 patients died before all the tests were completed, 1 moved to another country, 6 declined to participate, and 18 patients did not perform the fecal elastase-1 test; therefore, the total sample comprised 73 patients who completed the study. The result of the fecal elastase-1 test was inconclusive for 7 patients (of 66 patients), although the test was run twice. The mean age of the subjects was 25.6 ± 7.3 years (19 adolescents and 54 adults), 40 (54.8%) of whom were females and 33 (45.2%) of whom were males. All subjects were White. The mean BMI was 21.0 ± 3.0 kg/m2, and the mean FEV1 was 59.7 ± 30.6% of the predicted value. Groups were formed on the basis of the nutritional status of the patients: AN group (n = 32; 43.8%); NR group (n = 23; 31.5%); and MN group (n = 18; 24.7%; Table 1). Table 2 presents a comparison of the clinical characteristics among the aforementioned groups. There were no significant differences among the Table 1. Clinical characteristics of the patients included in the study (N = 73).a

Variable Gender Male Female Age, years BMI, kg/m2 Nutritional classification Adequate nutrition Nutritional risk Malnutrition CFRD Type of mutation Homozygous for F508del Heterozygous for F508del Other/unidentified mutations Age at diagnosis, yearsb S-K score Lung function FVC, L FVC, % predicted FEV1, L FEV1, % predicted Fecal elastase-1, µg/g Bacterial colonization Pseudomonas aeruginosa Staphylococcus aureus MRSA Burkholderia cepacia

Result 33 (45.2) 40 (54.8) 25.6 ± 7.3 21.0 ± 3.0 32 (43.8) 23 (31.5) 18 (24.7) 10 (13.7) 13 (17.8) 33 (45.2) 27 (37.0) 8 (16) 70.41 ± 16.4 3.0 ± 1.24 71.3 ± 31.5 2.1 ± 1.1 59.7 ± 30.6 92.3 ± 36.8 48 (65.8) 50 (68.5) 8 (11.0) 15 (20.5)

BMI: body mass index; S-K: Shwachman-Kulczycki; CFRD: cystic fibrosis-related diabetes; and MRSA: methicillin-resistant Staphylococcus aureus. aValues expressed as n (%) or mean ± SD, except where otherwise indicated. bValue expressed as median (interquartile range).

groups regarding gender, age, presence of F508del mutation, and liver score. The proportion of patients with diabetes mellitus was significantly higher in the NR group than in the AN and MN groups (p = 0.014). The S-K score was significantly lower in the NR and MN groups than in the AN group (p < 0.001). Percent predicted FVC and FEV1 were significantly lower in the MN group than in the AN and NR groups (p < 0.001 for both). Fecal elastase-1 levels were significantly lower in the NR group than in the AN and MN groups (p < 0.001 for both). Fifty-six patients were on pancreatic enzyme replacement therapy, and the number of enzyme units/kg/meal was significantly higher in the MN group than in the AN group (p < 0.001) and in the NR group (p = 0.001). Table 3 shows the self-reported compliance with the high calorie diet, pancreatic enzyme replacement therapy, and vitamin supplementation intake in the three nutritional groups. No significant differences were found among the groups regarding those variables. The logistic regression analysis identified three independent factors associated with malnutrition: age (OR = 0.78; p = 0.013), S-K score (OR = 0.90; p = 0.015), and FEV1 in % of the predicted value (OR = 0.95; p = 0.046; Table 4). The ROC curve analyses showed that the area under the curve for the S-K score was 0.85. Using a cut-off value of ≤ 65 points as a predictor of malnutrition, we found a sensitivity of 78.8%, a specificity of 67.3%, a positive predictive value of 43.8%, and a negative predictive value of 90.2%. The area under the curve for FEV1 in % of the predicted value was 0.83. Using a cut-off value of ≤ 40% as a predictor of malnutrition, we found a sensitivity of 67.7%, a specificity of 81.8%, a positive predictive value of 54.5%, and a negative predictive value of 88.2%. As for age, the area under the curve was 0.57. Using a cut-off value of ≤ 22 years of age as a predictor of malnutrition, we found a sensitivity of 50.0%, a specificity of 58.2%, a positive predictive value of 28.1%, and a negative predictive value of 78.1%. DISCUSSION The current cross-sectional study provided relevant information about the prevalence of malnutrition and the clinical characteristics associated with malnutrition in CF patients attending an adult program at a large tertiary care center in southern Brazil. First, half of the patients presented adequate nutrition, and one-fourth was malnourished. Second, we identified some independent factors associated with the risk of malnutrition: S-K score, FEV1 in % of the predicted value, and age. Therefore, our findings contribute to raising the awareness of the multifactorial aspects of malnutrition in adolescent and adult patients with CF. In an attempt to improve nutrition in clinical practice, the CF multidisciplinary team should take into account patients at a younger age, with low clinical scores and with impaired pulmonary function. J Bras Pneumol. 2017;43(5):337-343

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Table 2. Comparison of clinical characteristics among the study groups.a

Variable

Group Nutritional risk

Malnutrition

(n = 23)

(n = 18)

11(34.4) 21 (65.6) 25.8 ± 8.8 12.0 (18.0) 79.5 ± 12.1A

12 (52.2) 11 (47.8) 26.7 ± 6.2 4.0 (8.0) 70.6 ± 10B

10 (55.6) 8 (44.4) 23.8 ± 5.5 9.5 (18.0) 53.9 ± 17.0C

5 (15.6) 13 (40.6) 14 (43.8)

3 (13.0) 10 (43.5) 10 (43.5)

5 (27.8) 10 (55.6) 3 (16.7)

0.326

24 (75.0) 8 (25.0) 1 (3.1)

17 (73.9) 6 (26.1) 7 (30.4)

12 (66.7) 6 (33.3) 2 (11.1)

0.806 0.014

3.4 ± 1.2A 83.9±32.3A 2.5 ± 1.0A 74.2 ± 30.8A

3.0 ± 1.1AB 73.1±25.5A 2.1 ± 1.0A 58.9 ± 25.9A

2.2 ± 1.1B 46.7± 23.0B 1.3 ± 0.7B 35.0 ± 18.1B

0.002 < 0.001 < 0.001 < 0.001

17 (56.7) 13 (43.3) 94.0 ± 32.6A

6 (28.6)* 15 (71.4)* 70.8 ± 35.4B

13 (86.7)* 2 (13.3)* 119.2 ± 28.9C

0.002 < 0.001

20 (62.5) 22 (68.8) 1 (3.1) 6 (18.8) 725.0 ± 476.4A

16 (69.6) 14 (60.9) 4 (17.4) 6 (26.1) 830.2 ± 456.9A

12 (66.7) 14 (77.8) 3 (16.7) 3 (16.7) 1423.9 ± 404.3B

0.858 0.512 0.166 0.718 <0.001

Adequate nutrition (n = 32) Gender Male Female Age, years Age at diagnosis, yearsb S-K score Type of mutation Homozygous for F508del Heterozygous for F508del Other/unidentified mutations Liver score Normal Abnormal CFRD Lung function FVC, L FVC, % predicted FEV1, L FEV1, % predicted Fecal elastase-1 test classificationc Moderate pancreatic insufficiency (100-200 µg/g) Severe pancreatic insufficiency (< 100 µg/g ) Fecal elastase-1, µg/g Bacterial colonization Pseudomonas aeruginosa Staphylococcus aureus MRSA Burkholderia cepacia Enzyme units of lipase/kg/meal

0.254 0.454 0.043 < 0.001

S-K: Shwachman-Kulczycki; CFRD: cystic fibrosis-related diabetes; and MRSA: methicillin-resistant Staphylococcus aureus. aValues expressed as n (%) or mean ± SD, except where otherwise indicated. bValues expressed as median (interquartile range). cn = 66. *Adjusted standard residual > 1.96 or < -1.96 implies significantly different percentages. One-way ANOVA with Tukey’s post hoc test and Kruskal-Wallis with post-hoc Z test: the means or medians were significantly different when subscript letters (A, B, and C) are different (chi-square test for categorical variables).

To discuss nutritional status is challenging, since authors use different parameters to assess it. Moreover, the definition of malnutrition varies in the literature. Although guidelines recommend BMI as a simple anthropometric indicator to classify nutritional status with the purpose of improving nutritional care for CF patients, the use of multiple and appropriate nutritional indicators could be of great importance to improve care for individual patients in CF health care practices.(7,14,19,20) The proportion of CF patients with malnutrition in the present study (24.7%) is similar to findings reported in other studies.(21-24) A cross-sectional study conducted in Greece(21) and using the same methodology and the same cut-off points in order to classify nutritional status showed that 23% of 68 patients with CF were malnourished. However, that study involved 37 children and adolescents.(21) In contrast, a study carried out 340

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in an adult tertiary CF center in France with 163 patients showed that 49.7% of the patients suffered from malnutrition.(22) That study also used the same methodology and the same cut-off points for classifying malnutrition.(22) A retrospective cross-sectional study conducted in São Paulo, Brazil, and involving 30 adolescents (in the 10.1- to 19.8-year age bracket), using a different methodology (BMI for age) to evaluate their nutritional status.(23) The cut-off points were the following: ≥ z-score −3 and < z-score −2 (thinness); z-score −2 and ≤ z-score +1 (normal weight); and > z-score +1 (overweight or obesity). The median (minimum; maximum) BMI-for-age z-score was −0.6 (−3.7; +2.6), which corresponds to adequate nutritional status in accordance with the World Health Organization parameters.(23) In 2007, a previous study conducted in our hospital included 41 CF patients (16-47 years of age), used the same methodology and the same cut-off

Barni GC, Forte GC, Forgiarini LF, Abrahão CLO, Dalcin PTR

Table 3. Self-reported adherence to a high-calorie diet, pancreatic enzyme replacement therapy, and vitamin supplementation intake, by group.

Variable High-calorie diet High Moderate Low Pancreatic enzyme replacement therapya High Moderate Low Vitamin supplementationb High Moderate Low

Adequate nutrition

Group Nutritional risk

Malnutrition

25 (78.1) 4 (12.5) 3 (9.4)

15 (65.2) 6 (26.1) 2 (8.7)

10 (55.6) 5 (27.8) 3 (16.7)

0.49

15 (93.8) 0 (0.0) 1 (6,3)

20 (87.0) 3 (13.0) 0 (0.0)

15 (88.2) 2 (11.8) 0 (0.0)

0.33

17 (89.5) 1 (5.3) 1 (5.3)

20 (87.0) 1 (4.3) 2 (8.7)

16 (94.1) 1 (5.9) 0 (0.0)

0.816

n = 56; pancreatic enzyme replacement therapy not indicated in 17 patients. bn = 59: vitamin supplementation not indicated in 14 patients.

Table 4. Logistic regression analysis (enter method) for malnutrition.

Variable Male gender Age S-K score FEV1, % predicted Constant

Beta −0.41 −0.24 −0.11 −0.05 14.65

p 0.961 0.013 0.015 0.046 0.002

OR 0.96 0.78 0.90 0.95 2,312,450.04

95% CI for OR 0.19-4.95 0.65-0.95 0.82-0.98 0.90-0.99 -

S-K: Shwachman-Kulczycki.

point for malnutrition, and identified 9 malnourished patients (22%).(24) These remarkable discrepancies in the prevalence of malnutrition in CF patients can be attributed to the heterogeneity of the disease, the survival effect observed in cohorts of adult subjects, interpopulation variations, and differences in quality of health care or in study design (sample selection, age groups included, indicators of malnutrition, and cut-off values). The association between nutritional status and lung function has been long recognized. Numerous studies have noted the negative effect of malnutrition on respiratory function and prognosis.(25,26) The results of the present study confirm that nutrition and lung function are codependent variables in CF patients, poor lung function being predictive of malnutrition. In a recent study, Hulzebos et al.(27) showed that the use of BMI combined with FEV1 could accurately predict mortality in CF patients. Another recent study with 14,732 patients (≥ 6 years of age) from the European Cystic Fibrosis Society Patient Registry confirmed that poor BMI was significantly associated with poor lung function.(28) The authors emphasized that BMI is a preventable or potentially treatable factor; however, despite the available guidelines for the prevention and correction of nutritional deficiencies in CF, 9.5% of the patients with CF in Europe still suffer from chronic severe malnutrition.(28) Exocrine pancreatic insufficiency has been found to be a prognostic factor for malnutrition. Couper et

al.,(29) in a longitudinal study, showed that patients with pancreatic sufficiency developed pancreatic insufficiency at an older age. In the current study, the fecal elastase-1 test was used in order to quantify the severity of pancreatic insufficiency and to predict malnutrition. All of the patients in our sample had levels of fecal elastase-1 < 200 µg/g. Surprisingly, fecal elastase-1 levels were higher in the MN group than in the AN group, as well as being higher in the AN group than in the NR group. One possible explanation for this finding is that the differences in mean levels of fecal elastase-1 among the groups, although statistically significant, were of low magnitude and did not impact on the nutritional outcome. Another finding in the present study was that the malnourished patients were treated with significantly higher pancreatic enzyme replacement dosing than were those in the other groups. This finding contrasts with a recent retrospective analysis by Haupt et al.,(30) who suggested that pancreatic enzyme replacement dosing is associated with better nutritional status; however, that study included children only. The mean enzyme replacement dosing in our patients was in agreement with recommendations of the guidelines(7): not greater than 2,500 lipase units/kg/meal. The S-K score(15) is a general clinical severity score with four domains: general activity, physical examination, nutrition, and radiological findings. Each domain ranges from 0 to 25 points, and the domain scores are added to give the overall score (up to 100). Higher scores J Bras Pneumol. 2017;43(5):337-343

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reflect better clinical status. In the current study, low clinical scores were predictive of malnutrition. The S-K score was not used in three previous studies of the nutritional status in CF patients.(21-23) In contrast, there was no significant association between malnutrition and the S-K score in the study by Ziegler et al.(24) Longitudinal studies have demonstrated that malnutrition can be expected to increase with aging. (31,32) However, it is interesting that our results showed that young age was a predictor of malnutrition only in the multivariable analysis. Nevertheless, it is likely that age and the preservation of nutritional status are related to milder disease, and that a later onset of the disease has a positive impact on the nutritional status of the patients. One hypothesis for this finding is the survival bias in the present CF population. Patients with poor lung function and malnutrition did not reach the age range under consideration in the present study. In our study, the self-reported compliance with a high calorie diet, pancreatic enzyme replacement therapy, and vitamin supplementation intake was high and was not associated with the nutritional status. In a previous

study,(33) 65.8%, 96.3%, and 79.4% of the patients, respectively, self-reported good compliance with a highcalorie diet, pancreatic enzyme replacement therapy, and vitamin supplementation intake. Arias Llorente et al.(34) suggested that patients would be more compliant with their treatment if they believed it to be beneficial and to improve their quality of life. Moreover, previous studies demonstrated that patients who understand the importance of following medical instructions and trust their physicians are probably more compliant. The fact that treatment adherence tends to diminish with age has also been mentioned.(18,35) The present study has potential limitations. Because it was a cross-sectional study, it was impossible to establish the temporal sequence of the factors studied and malnutrition. In addition, our sample of patients was also small. In conclusion, the present study has demonstrated that malnutrition remains a common complication in adolescents and adults with CF, despite dietary advice. Malnutrition is associated with age, clinical severity, and lung function impairment.

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13. Williams SG, Evanson JE, Barrett N, Hodson ME, Boultbee JE, Westaby D. An ultrasound scoring system for the diagnosis of liver disease in cystic fibrosis. J Hepatol. 1995;22(5):513-21. https://doi. org/10.1016/0168-8278(95)80444-7 14. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002;35(3):246-59. https://doi.org/10.1097/00005176-20020900000004 15. Shwachman H, Kulczychi L. Long-term study of one hundred five patients with cystic fibrosis; studies made over a five- to fourteen-year period. AMA J Dis Child. 1958;96(1):6-15. https://doi. org/10.1001/archpedi.1958.02060060008002 16. 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. 17. Löser C, Möllgaard A, Fölsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996;39(4):580-6. https://doi.org/10.1136/gut.39.4.580 18. Conway SP, Pond MN, Hamnett T, Watson A. Compliance with treatment in adult patients with cystic fibrosis. Thorax. 1996;51(1):2933. https://doi.org/10.1136/thx.51.1.29 19. Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman HG, et al. Nutrition in patients with cystic fibrosis: a European Consensus. J Cyst Fibros. 2002;1(2):51-75. https://doi. org/10.1016/S1569-1993(02)00032-2 20. Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: consensus conference report. Chest. 2004;125(1 Suppl):1S-39S. https://doi.org/10.1378/chest.125.1_suppl.1S 21. Panagopoulou P, Fotoulaki M, Nikolaou A, Nousia-Arvanitakis S. Prevalence of malnutrition and obesity among cystic fibrosis patients. Pediatr Int. 2014;56(1):89-94. https://doi.org/10.1111/ped.12214 22. Dray X, Kanaan R, Bienvenu T, Desmazes-Dufeu N, Dusser D, Marteau P, et al. Malnutrition in adults with cystic fibrosis. Eur J Clin Nutr. 2005;59(1):152-4. https://doi.org/10.1038/sj.ejcn.1602039 23. Del Ciampo IR, Del Ciampo LA, Sawamura R, de Oliveira LR, Fernandes MI. Nutritional status of adolescents with cystic fibrosis treated at a reference center in the southeast region of Brazil. Ital J Pediatr. 2015;41:51. https://doi.org/10.1186/s13052-015-0159-x 24. Ziegler B, Rovedder PM, Lukrafka JL, Abrahão CL, Dalcin PT. Estado nutricional em pacientes atendidos por um programa de adultos para fibrose cística. Rev HCPA. 2007;27(3):13-9. 25. Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol. 1988;41(6):583-91.

Barni GC, Forte GC, Forgiarini LF, Abrahão CLO, Dalcin PTR

https://doi.org/10.1016/0895-4356(88)90063-7 26. Zemel BS, Jawad AF, FitzSimmons S, Stallings VA. Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry. J Pediatr. 2000;137(3):37480. https://doi.org/10.1067/mpd.2000.107891 27. Hulzebos EH, Bomhof-Roordink H, van de Weert-van Leeuwen PB, Twisk JW, Arets HG, van der Ent CK, et al. Prediction of mortality in adolescents with cystic fibrosis. Med Sci Sports Exerc. 2014;46(11):2047-52. https://doi.org/10.1249/ MSS.0000000000000344 28. Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, et al. Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur Respir J. 2014;43(1):125-33. https:// doi.org/10.1183/09031936.00166412 29. Couper RT, Corey M, Moore DJ, Fisher LJ, Forstner GG, Durie PR. Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency. Pediatr Res. 1992;32(2):179-82. https://doi. org/10.1203/00006450-199208000-00011 30. Haupt ME, Kwasny MJ, Schechter MS, McColley SA. Pancreatic

enzyme replacement therapy dosing and nutritional outcomes in children with cystic fibrosis. J Pediatr. 2014;164(5):1110-1115.e1. https://doi.org/10.1016/j.jpeds.2014.01.022 31. Steinkamp G, Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax. 2002;57(7):596-601. https://doi.org/10.1136/thorax.57.7.596 32. Nir M, Lanng S, Johansen HK, Koch C. Long-term survival and nutritional data in patients with cystic fibrosis treated in a Danish centre. Thorax. 1996;51(10):1023-7. https://doi.org/10.1136/ thx.51.10.1023 33. Dalcin Pde T, Rampon G, Pasin LR, Ramon GM, Abrahão CL, Oliveira VZ. Adherence to treatment in patients with cystic fibrosis [Article in Portuguese]. J Bras Pneumol. 2007;33(6):663-70. 34. Arias Llorente RP, Bousoño García C, Díaz Martín JJ. Treatment compliance in children and adults with cystic fibrosis. J Cyst Fibros. 2008;7(5):359-67. https://doi.org/10.1016/j.jcf.2008.01.003 35. Abbott J, Dodd M, Gee L, Webb K. Ways of coping with cystic fibrosis: implications for treatment adherence. Disabil Rehabil. 2001;23(8):315-24. https://doi.org/10.1080/09638280010004171

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J Bras Pneumol. 2017;43(5):344-350 http://dx.doi.org/10.1590/S1806-37562016000000261

ORIGINAL ARTICLE

Parapneumonic pleural effusion: early versus late thoracoscopy Rodrigo Romualdo Pereira1, Cristina Gonçalves Alvim2, Cláudia Ribeiro de Andrade2, Cássio da Cunha Ibiapina2 1. Hospital da Previdência, Instituto de Previdência dos Servidores do Estado de Minas Gerais – IPSEMG – Belo Horizonte (MG) Brasil. 2. Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte (MG) Brasil. Submitted: 28 August 2016. Accepted: 26 February 2017. Study carried out in the Departamento de Pediatria da Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte (MG) Brasil.

ABSTRACT Objective: To evaluate the best time to perform thoracoscopy for the treatment of complicated parapneumonic pleural effusion in the fibrinopurulent phase in patients ≤ 14 years of age, regarding the postoperative evolution and occurrence of complications. Methods: This was a retrospective comparative study involving patients with parapneumonic pleural effusion presenting with septations or loculations on chest ultrasound who underwent thoracoscopy between January of 2000 and January of 2013. The patients were divided into two groups: early thoracoscopy (ET), performed by day 5 of hospitalization; and late thoracoscopy (LT), performed after day 5 of hospitalization. Results: We included 60 patients, 30 in each group. The mean age was 3.4 years; 28 patients (46.7%) were male; and 47 (78.3%) underwent primary thoracoscopy (no previous simple drainage). The two groups were similar regarding gender, age, weight, and type of thoracoscopy (p > 0.05 for all). There was a significant difference between the ET and the LT groups regarding the length of the hospital stay (14.5 days vs. 21.7 days; p < 0.001). There were also significant differences between the groups regarding the duration of fever in days; the total number of days from admission to the initiation of drainage; and the total number of days with the drain in place. Eight patients (13.6%) had at least one post-thoracoscopy complication, there being no difference between the groups. There were no deaths. Conclusions: Performing ET by day 5 of hospitalization was associated with shorter hospital stays, shorter duration of drainage, and shorter duration of fever, although not with a higher frequency of complications, requiring ICU admission, or requiring blood transfusion. Keywords: Empyema, pleural; Thoracoscopy; Pneumonia.

INTRODUCTION It is estimated that between 28% and 53% of children hospitalized with bacterial pneumonia have complications such as pleural effusion or empyema.(1) Although there has been a reduction in the frequency of hospitalizations for pneumonia, especially in countries where there is universal vaccination for Streptococcus pneumonia, the incidence of parapneumonic pleural effusion (PPE) has increased and appears to be related to the emergence of antibiotic-resistant strains.(1,2) The critical factor in the prognosis of PPE is the time from the onset of the condition to the initiation of adequate treatment.(1,2) Until the early 1990s, surgical debridement via thoracoscopy was indicated after a period of simple drainage, if there was no clinical improvement.(3) Currently, there is evidence from retrospective studies,(4-17) prospective studies,(18-20) systematic reviews,(21-25) and a meta-analysis(26) in favor of the superiority of thoracoscopy over simple drainage in the treatment of pleural empyema, indicating that thoracoscopy should be performed, especially when ultrasound shows septations or loculations.(27) However, PPE being approached late is still common, there being delay and difficulty in referring such children to referral centers.

Early referral for thoracoscopy has the advantage of the procedure being easy to perform, allowing better drainage, less perioperative bleeding, shorter surgical time, shorter duration of chest drain in place, and a greater likelihood of obtaining full expansion of the affected lung, avoiding thoracotomy for pulmonary decortication.(5,8,18) In addition, early thoracoscopy (ET) allows a shorter length of hospital stay (LOS), shorter duration of fever, and reduced risk of complications of prolonged drainage (pain, bronchopleural fistula, lung entrapment, and nosocomial infection).(1,26) This study is motivated by the need to evaluate the optimal timing of thoracoscopy, as well as the postprocedure course and complications. The objective was to compare ET vs. late thoracoscopy (LT) as an approach for complicated PPE in the fibrinopurulent phase. METHODS This was a retrospective comparative study involving analysis of the medical charts of children diagnosed with complicated PPE in the fibrinopurulent phase who were admitted to a pediatric referral hospital. The study project was approved by the Research Ethics Committee of the Federal University of Minas Gerais (Ruling no. 353.069).

Correspondence to:

Cássio da Cunha Ibiapina. Avenida Professor Alfredo Balena, 110, CEP 30160-042, Belo Horizonte, MG, Brasil. Tel.: 55 31 3409-9772. E-mail: cassioibiapina@terra.com.br Financial support: None.

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Being retrospective, this study was granted a waiver of written informed consent.

day 5 of hospitalization; and LT, performed after day 5 of hospitalization.

The course of complicated PPE involves three phases: exudative; fibrinopurulent; and organizing. In the exudative phase, which occurs within 72h after the development of the initial effusion, simple chest drainage is usually sufficient. However, in the fibrinopurulent phase, which occurs within 3 to 14 days after the development of the initial effusion, we have to resort to the use of fibrinolytic agents or to mechanical debridement via thoracoscopy for correct cleaning of the various loculations in the pleural cavity.

Secondary thoracoscopy was defined as surgical debridement after simple drainage. Primary thoracoscopy (no previous simple drainage) was performed when there were ultrasound indications for it (septations, debris, or loculations).

We included all children admitted to the inpatient unit with a diagnosis of complicated PPE who presented with septations, debris, or loculations on chest ultrasound and who underwent thoracoscopy between January of 2000 and January of 2013. Indications for thoracoscopy were persistent fever or respiratory symptoms (clinical criteria) and loculations (ultrasound criteria). In all cases, the fibrinopurulent phase was confirmed during surgery. We excluded patients with complicated PPE who, at the time of the first evaluation by pediatric surgery, were found to be in the organizing phase, underwent pulmonary decortication via thoracotomy, or presented with necrotizing pneumonia on chest CT. We also excluded patients who were transferred to another hospital after the procedure. Between 2000 and 2004, thoracoscopy was performed using a mediastinoscope (Carlensâ&#x20AC;&#x2122; technique) under general anesthesia without selective intubation, with patients in a lateral decubitus position, lying on the nonaffected side. The mediastinoscope was inserted into the thoracic cavity through a small incision in the 4th intercostal space at the midaxillary line, and the other instruments (vacuum pump and clamp forceps) were inserted through the mediastinoscope. A 22-gauge chest drain was inserted into the pleural cavity after the mediastinoscope was removed. Between 2004 and 2013, thoracoscopy was performed as a video-assisted procedure under general anesthesia without selective intubation, with patients in a lateral decubitus position, lying on the nonaffected side. A small incision was made in the 4th intercostal space at the midaxillary line, through which a 5- or 10-mm trocar was inserted and a 30Â° endoscope was passed. Subsequently, carbon dioxide insufflation at a pressure of 6 mmHg created an artificial pneumothorax and partially collapsed the lung, and a 5-mm trocar was inserted in the same intercostal space at the posterior axillary line, through which instruments (vacuum pump, forceps, and the endoscope itself) could be handled. Septations and fibrin clots were removed, and the thoracic cavity was flushed with saline. At the end of the procedure, a 22-gauge chest drain was put in place through the first trocar incision. The mean procedure time was 40 min, and all patients underwent chest drainage at the end of the procedure. Whenever possible, pleural fluid was collected and sent for bacteriological examination. For the purpose of comparison, the patients were divided into two treatment groups: ET, performed by

The intervening variables analyzed were age, weight, gender, duration of fever before admission, undergoing thoracentesis before thoracoscopy, undergoing simple drainage before thoracoscopy, requiring ICU admission, requiring blood transfusion, undergoing chest CT, and occurrence of complications. In order to assess patient course in the ET and the LT groups, the response variables were LOS; LOS after thoracoscopy; duration of fever in days; duration of fever in days, after admission; total number of days from admission to the initiation of drainage; total number of days with the drain in place; and total number of days with the drain in place after thoracoscopy. Data were analyzed with the Statistical Package for the Social Sciences, version 14.0 (SPSS Inc., Chicago, IL, USA). Associations between treatment group (ET and LT) and each of the variables of interest were assessed with the chi-square test and Studentâ&#x20AC;&#x2122;s t-test, assuming non-equality of variances. The level of significance was set at 5% (p < 0.05). RESULTS We analyzed the medical charts of 65 children, of whom 2 were excluded because they were transferred to another hospital after the surgical procedure and 3 were excluded because they underwent thoracotomy for decortication or presented with necrotizing pneumonia in the first evaluation by surgery. The final sample therefore consisted of 60 patients. The mean age was 3.4 years, and 28 (46.7%) were male. Most (83%) resided in the city of Belo Horizonte, Brazil. Chest ultrasound revealed septations, debris, or loculations in all patients, 42 (70.2%) of whom presented with these changes on the first ultrasound. Chest CT was performed in only 3 patients (5.0%), of whom 1 was in the ET group and 2 were in the LT group (p = 0.576). The mean time from hospital admission to thoracoscopy was 6.4 days (2.9 and 9.8 days, respectively, in the ET and the LT groups). The mean time from hospital admission to the first chest drainage was 5 days (range: 0-17 days). In the ET group, the time from fever onset to thoracoscopy was less than 15 days in all patients. In the LT group, the time from fever onset to thoracoscopy was greater than 21 days in only 1 patient. Therefore, 59 patients (98.3%) underwent thoracoscopy within the first three weeks of the fever course. Of the sample as a whole, 47 patients (78.3%) underwent thoracoscopy as the primary intervention (no previous simple drainage). Pleuroscopy was J Bras Pneumol. 2017;43(5):344-350

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performed in 19 patients (31.7%), and video-assisted thoracoscopic surgery was performed in 41 (68.3%). The ET and the LT groups each had 30 patients. Table 1 shows the patient descriptive characteristics and the procedures performed before thoracoscopy, by treatment group and total. The ET and the LT groups were similar (p > 0.05) regarding male/female proportion, mean age, mean weight, and type of thoracoscopy. The proportion of patients undergoing thoracentesis and the proportion of patients undergoing simple drainage were higher in the LT group, with a trend toward a statistically significant difference in the latter proportion (p = 0.057). The patients in the ET group showed longer duration of fever before hospital admission (p < 0.001). Table 2 presents data regarding patient course by treatment group and total. There were statistically significant differences between the ET and the LT groups (p < 0.05) regarding the mean LOS, the duration of fever in days, the total number of days from admission to resolution of fever, the total number of days from admission to the initiation of drainage, and the total number of days with the drain in place. With regard to the LOS after thoracoscopy and the total number of days with the drain in place after thoracoscopy, the two groups were similar, with no statistically significant differences being found. Of the sample as a whole, 47 patients (78.3%) were admitted to the ICU after surgical debridement. The proportion of patients who required ICU care was similar in the ET and the LT

groups (76.7% and 80.0%, respectively; p = 0.754). When taking into account only the patients admitted to the ICU, there was no difference in the length of ICU stay between the ET and the LT groups (4.6 vs. 7.7 days; p = 0.310). Eight patients (13.6%) had at least one complication after thoracoscopy: bronchopleural fistula, in 4 (6.8%); lung entrapment, in 2 (3.4%); fistula and entrapment, in 1 (1.7%); and pneumothorax, in 1 (1.7%); there being no significant difference between the groups (p = 0.959). There were no deaths among the patients included in the study. One patient in the LT group required thoracotomy for decortication. Overall, 21 patients (35%) required blood transfusion at some point during hospitalization. This proportion was higher in the LT group (n = 13; 43.3%) than in the ET group (n = 8; 26.7%), but there was no statistically significant difference (p = 0.176). DISCUSSION Various studies have shown that, when approaching pleural empyema, surgical debridement via thoracoscopy is a safe, effective procedure that allows a shorter LOS compared with simple drainage.(1,23,25,26) However, few studies have compared timing of thoracoscopy (ET vs. LT) in children, as has been done in the present study.(4-9) ET, performed by day 5 of hospitalization, was associated with a better course, characterized by a

Table 1. Patient descriptive and comparative statistics regarding gender, age, weight, type of thoracoscopy, and procedures before thoracoscopy, by treatment group and total.

Variable

Gender, n (%) Male Female Age, years Median (min-max) Mean ± SD Weight, kga Median (min-max) Mean ± SD Fever before admission, daysb Median (min-max) Mean ± SD Type of thoracoscopy, n (%) Pleuroscopy Video-assisted thoracoscopic surgery Thoracentesis, n (%) Yes No Simple drainage before thoracoscopy, n (%) Yes No

Early (n = 30)

Treatment Late (n = 30)

Total (N = 60)

11 (36.7) 19 (63.3)

17 (56.7) 13 (43.3)

28 (46.7) 32 (53.3)

0.121

3.0 (0.0-8.0) 3.4 ± 2.2

3.0 (0.0-14.0) 3.4 ± 2.7

3.0 (0.0-14.0) 3.4 ± 2.5

0.983

14.75 (10.50-34.00) 17.06 ± 5.79

15.00 (7.50-52.00) 17.13 ± 8.46

15.00 (7.50-52.00) 17.10 ± 7.11

0.972

5.5 (0.0-9.0) 5.6 ± 2.6

3.0 (0.0-7.0) 3.2 ± 2.1

4.0 (0.0-9.0) 4.4 ± 2.6

<0.001

8 (26.7) 22 (73.3)

11 (36.7) 19 (63.3)

19 (31.7) 41 (68.3)

0.405

15 (50) 15 (50)

21 (70) 9 (30)

36 (60) 24 (30)

0.114

3 (10) 27 (90)

10 (33) 20 (67)

13 (22) 47 (78)

0.057

min: minimum; and max: maximum. aData regarding 27 patients in the late treatment group. bData regarding 28 patients in the early treatment group and 26 patients in the late treatment group.

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Table 2. Patient descriptive and comparative statistics regarding patient course, by treatment group and total.

Variable Early (n = 30) Length of hospital stay, daysa Median (min-max) 13.0 (7.0-42.0) Mean ± SD 14.5 ± 6.5 Length of hospital stay after thoracoscopy, days Median (min-max) 10.0 (7.0-39.0) Mean ± SD 11.7 ± 6.3 21 Fever, daysb Median (min-max) 11.0 (3.0-27.0) Mean ± SD 12.8 ± 5.9 Time from admission to resolution of fever, daysc Median (min-max) 7.0 (0.0-23.0) Mean ± SD 7.8 ± 5.9 Time from admission to the initiation of drainage, daysa Median (min-max) 3.0 (−5.0 a 7.0) Mean ± SD 2.6 ± 2.3 Duration of drain in place, daysd Median (min-max) 3.0 (2.0-10.0) Mean ± SD 3.6 ± 2.4 Duration of drain in place after thoracoscopy, daysd Median (min-max) 3.0 (0.0-8.0) Mean ± SD 3.3 ± 2.0

Treatment Late (n = 30)

Total (N = 60)

19.5 (11.0-49.0) 21.7 ± 8.2

16.0 (7.0-49.0) 18.1 ± 8.2

< 0.001

10.0 (4.0-30.0) 11.9 ± 6.2 22 17.0 (10.0-40.0) 17.6 ± 6.2

11.8 (4.0-39.0) 10.0 ± 6.2 43 14.0 (3.0-40.0) 15.1 ± 6.4

0.885

13.0 (7.0-41.0) 15.6 ± 7.8

10.5 (0.0-41.0) 11.7 ± 7.9

0.001

7.0 (0.0-17.0) 7.4 ± 3.9

5.0 (−5.0 a 17.0) 5.0 ± 4.0

< 0.001

3.5 (2.0-27.0) 7.4 ± 6.6

3.0 (2.0-7.0) 5.5 ± 5.3

0.027

3.0 (0.0-18.0) 4.3 ± 4.2

3.0 (0.0-18.0) 3.8 ± 3.3

0.330

0.014

min: minimum; and max: maximum. aData regarding 29 patients in the early treatment group. bData regarding 21 patients in the early treatment group and 22 patients in the late treatment group. cData regarding 21 patients in each of the two treatment groups. dData regarding 19 patients in the early treatment group and 20 patients in the late treatment group.

shorter LOS, shorter duration of drainage, and shorter duration of fever, and was not associated with a higher frequency of complications, requiring ICU admission, or requiring blood transfusion. The fact that the ET and the LT groups were similar regarding age, gender, and weight and were in the same stage of the effusion (fibrinopurulent phase, as determined on the basis of chest ultrasound findings and duration of fever) improves the reliability of our results. It should be noted that the LOS after thoracoscopy and the duration of drainage after thoracoscopy were similar in the two groups, suggesting that the timing of thoracoscopy was a determinant of patient course. Chest ultrasound performed with quality equipment by professionals experienced in evaluating children in 100% of the patients provided the basis for a thoracoscopy approach, since there is evidence of the ineffectiveness of a conservative approach in cases of pleural effusion with septations and loculations.(27) CT was rarely required, which is in line with other studies and with the concern over the use of procedures involving radiation, especially in children.(27) The longer duration of fever before admission in the patients in the ET group could be the explanation for the decision to pursue earlier surgical intervention. It is of interest to observe that, despite the longer duration of fever before admission, the patients in this group had a better course, underscoring the importance of

ET. However, since the present study was retrospective, other factors that were not analyzed, such as clinical severity, time from admission to surgical evaluation, and the surgeon’s decision regarding the initial approach, may have influenced the decision regarding the timing of the surgical intervention. At the hospital where the study was conducted, there is a protocol recommending that chest ultrasound should be performed in all cases of PPE and that thoracoscopy should be performed in cases with septations and loculations. However, the team is composed of seven surgeons, and this may have introduced a bias. The decision regarding the timing of thoracoscopy was made at the discretion of the surgeon, there being variations in the decision regarding optimal timing within the team. Nevertheless, patient course after thoracoscopy was the same in the two groups, suggesting that treatment responses and, probably, the quality of the surgical technique were similar. Simple drainage was performed in the two groups (in 10% and 33% of the patients in the ET and the LT groups, respectively). The proportion of patients undergoing simple drainage was higher in the LT group, with a trend toward a statistically significant difference (p = 0.057). Some authors have shown that primary thoracoscopy is superior to secondary thoracoscopy (performed after simple drainage).(7-9) However, it is known that some cases may respond well to conservative treatment (with or without J Bras Pneumol. 2017;43(5):344-350

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Parapneumonic pleural effusion: early versus late thoracoscopy

simple drainage) and that it is not easy, a priori, to distinguish between such cases and those that will require thoracoscopy.(27,28) What this study intended to show is that thoracoscopy should not be delayed, even if other procedures are performed. The LOS is the main variable analyzed in order to assess the courses of patients undergoing thoracoscopy for complicated PPE because it is a reliable datum, even for retrospective analysis, and reflects several other aspects of the patients’ courses. The mean LOS has been reported to range from 5.8 to 21 days.(4-11,13-20,29,30) There are studies that report the LOS, the duration of chest drainage, the success rate, and the frequency of complications, but with no comparison group regarding the timing of thoracoscopy.(13-17,29,30) Other authors have compared primary thoracoscopy or ET with other approaches for the treatment of PPE.(10,11,18-20) The superiority of thoracoscopy over conservative treatment, with or without simple drainage, is well established. Avansino et al.(26) showed in a meta-analysis that the surgical intervention rate is ten times higher in patients undergoing simple drainage than in those undergoing primary thoracoscopy. Shah et al.(11) found that, in addition to a longer LOS, the simple drainage group had a higher cost of hospitalization attributable to medication use and tests performed. Recent prospective studies have shown that there is a similarity between fibrinolytic drainage and the thoracoscopic approach, the cost being lower and the frequency of therapeutic failure being higher for the former.(19,20) Three studies have compared primary with secondary thoracoscopy, and four, including the present study,

have compared timing of thoracoscopy (ET vs. LT; Chart 1). In all of them, the results showed a shorter LOS for ET and/or primary thoracoscopy (range: 10.1-14.5 days).(4-9) Regardless of being comparative or not, some studies have shown surprising results, reporting mean LOS rates of less than 10 days. Analysis of these studies shows that it is possible that not all patients were in the fibrinopurulent phase, there being some very early referrals for thoracoscopy, which was performed within the first 24-48 h of hospital admission.(12-14,18) Some of those patients could have benefited simply from a simple drainage (exudative phase). One difficulty in comparing results is the criteria for patient selection. Shah et al.(11) excluded children younger than 1 year, and, in most studies, not all patients underwent an ultrasound evaluation. The mean age in our study was lower than that reported in some other studies,(8-10) which may have affected the LOS. The inclusion of patients with PPE who did not undergo an ultrasound evaluation, along with very early referral for thoracoscopy, may mean excessive referral for thoracoscopy and explain the shorter LOS observed in some studies. In addition, there are differences in access to health care and in the organization of health care systems, all of which can affect the response variable “LOS”. For example, in the study by Bishay et al.,(14) addressing primary thoracoscopy and primary thoracotomy, the mean duration of preoperative symptoms was 10 days, and other interventions (thoracentesis, simple drainage, and fibrinolytic drainage) were performed at the secondary referral center, before admission to

Chart 1. Thoracoscopy as an approach for pleural effusion in pediatric patients, 2004-2013. Studies comparing timing of thoracoscopy (early vs. late or primary vs. secondary).

Authors

Design

Age, yearsa

Kalfa et al.(5)

4.00 (0.42-16.00)

Kalfa et al.(4)

4.00 (0.83-15.00)

Schultz et al.(6)

4 (0-17)

Meier et al.(7)

< 18

Schneider et al.(8)

< 17

Aziz et al.(9)

5.8c < 18.0

Present study

3.4 (0.6-14.0)

Participants, Type of n thoracoscopy 26 24

Early (≤ 4 d) Late

Early (≤ 4 d)

Late

49 76 107 44 31 18 13 15 30 30

Early (≤ 48 h) Late Primary Secondary Primary Secondary Primary Secondary Early (≤ 5 d) Late

LOS, daysb 10.9 ± 4.3 17.0 ± 8.4 11.8 (5-23) 19.9 (6-40) 11.5 ± 6.6 15.2 ± 8.6 10.1 14.3 10.5 15.0 11 18 14.5 ± 6.5 21.7 ± 8.2

Postsurgery LOS, days

Drain, Complications, days % 4.5 8.0

3.8 29.0

5.3

9.4

13.8

7.4 10.3

4.2 7.7

11.7 11.9

3.6 7.4

13.3 13.8

LOS: length of hospital stay; P: prospective; d: days; R: retrospective; Primary: thoracoscopy as the first therapeutic intervention; Secondary: thoracoscopy after simple drainage; NR: not reported; and NS: not significant. aValues expressed as median (interquartile range) or as age bracket. bValues expressed as mean (± SD) or as median (interquartile range). cValue expressed as mean.

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Pereira RR, Algim CG, Andrade CR, Ibiapina CC

the tertiary center where the study was conducted. The LOS at the referral hospital was not included in the calculation of LOS. It is also possible that the presence of comorbidities, the clinical severity of pneumonia, the virulence of the etiologic agents, and the criteria for hospital admission and discharge (either more or less conservative) are different among the various studies and that these variables, which were not analyzed, also affect the LOS. The frequencies of therapeutic failure and complications were low (3.3% and 13.3%, respectively) and similar to those reported in the literature when thoracoscopy is performed in the fibrinopurulent phase, before the organizing phase. The occurrence of complications can explain the longer LOS in some cases.(17,30) The frequency of therapeutic failure was lower than that reported in a study that did not exclude patients with empyema in the organizing phase or with necrotizing pneumonia, two factors that are known to be related to a higher occurrence of complications and a longer LOS.(16) ICU admission occurred after thoracoscopy in most cases, it being indicated because of perioperative respiratory instability and because of the need for careful postoperative monitoring, in addition to the ICU bed availability at the hospital where the study was conducted. Such care may have been a contributing factor to the favorable courses experienced by the patients. The present studyâ&#x20AC;&#x2122;s limitations are mainly due to the fact that it was retrospective, which is

common to most studies on this topic because of the small number of annual cases at each facility. In order to minimize the bias of retrospective data collection, we analyzed different course-related variables, and the results were consistent. Another limitation to extrapolating the results obtained in the present study is due to the need for training of pediatric surgeons in thoracoscopy and the need for a structure of care, given that the procedures have significant morbidity (13.3%). The Department of Pediatric Surgery of the hospital where the study was conducted is a referral center in the city of Belo Horizonte, Brazil, and its surgeons are trained in thoracoscopy, as are the anesthesiologists and the pediatric intensive care team. This unfortunately is not the reality in many hospitals providing pediatric care in Brazil, and multiple drainage attempts are still common in cases of loculated and septated effusion, which prolongs hospitalization. We conclude that there should be early referral for thoracoscopy, within the first 5 days of hospital admission, for surgical debridement of PPE in the fibrinopurulent phase (with septations or loculations). Reducing the LOS in children benefits not only the children themselves, minimizing their physical and emotional suffering, but also their families and the population as a whole, because it allows a reduction in costs and the release of hospital beds. Prospective studies, comparison with the initial fibrinolytic approach, and evaluation of the costs of the different approaches in Brazil should be the object of future study.

REFERENCES 1. Islam S, Calkins CM, Goldin AB, Chen C, Downard CD, Huang EY, et al. The diagnosis and management of empyema in children: a comprehensive review from the APSA Outcomes and Clinical Trials Committee. J. Pediatr. Surg. 2012;47(11):2101-10. https://doi. org/10.1016/j.jpedsurg.2012.07.047 2. Janahi IA, Fakhoury K. Management and prognosis of parapneumonic effusion and empyema in children. In: Rose BD, editor. UpToDate. Waltham, MA: UpToDate; 2013. 3. Fraga JC, Lima A, Schopf L, Antunes C. Thoracoscopy with mediastinoscope in pediatric complicated parapneumonic effusion [Article in Portuguese]. J Pediatr (Rio J). 1999;75(6):470-6. https://doi. org/10.2223/JPED.364 4. Kalfa N, Allal H, Montes-Tapia F, Lopez M, Forgues D, Guibal MP, et al. Ideal timing of thoracoscopic decortication and drainage for empyema in children. Surg Endosc. 2004;18(3):472-7. https://doi. org/10.1007/s00464-002-9206-6 5. Kalfa N, Allal H, Lopez M, Saguintaah M, Guibal MP, Sabatier-Laval E, et al. Thoracoscopy in pediatric pleural empyema: a prospective study of prognostic factors. J Pediatr Surg. 2006;41(10):1732-7. https://doi.org/10.1016/j.jpedsurg.2006.05.066 6. Schultz KD, Fan LL, Pinsky J, Ochoa L, Smith EO, Kaplan SL, et al. The changing face of pleural empyemas in children: epidemiology and management. Pediatrics. 2004;113(6):1735-40. https://doi. org/10.1542/peds.113.6.1735 7. Meier AH, Hess CB, Cilley RE. Complications and treatment failures of video-assisted thoracoscopic debridement for pediatric empyema. Pediatr Surg Int. 2010;26(4):367-71. https://doi.org/10.1007/s00383010-2562-0 8. Schneider CR, Gauderer MW, Blackhurst D, Chandler JC, Abrams RS. Video-assisted thoracoscopic surgery as a primary intervention in pediatric parapneumonic effusion and empyema. Am Surg. 2010;76(9):957-61. 9. Aziz A, Healey JM, Qureshi F, Kane TD, Kurland G, Green M, et al.

Comparative analysis of chest tube thoracostomy and video-assisted thoracoscopic surgery in empyema and parapneumonic effusion associated with pneumonia in children. Surg Infect (Larchmt). 2008;9(3):317-23. https://doi.org/10.1089/sur.2007.025 10. Li ST, Gates RL. Primary operative management for pediatric empyema: decreases in hospital length of stay and charges in a national sample. Arch Pediatr Adolesc Med. 2008;162(1):44-8. https://doi.org/10.1001/archpediatrics.2007.10 11. Shah SS, Ten Have TR, Metlay JP. Costs of treating children with complicated pneumonia: a comparison of primary video-assisted thoracoscopic surgery and chest tube placement. Pediatr Pulmonol. 2010;45(1):71-7. https://doi.org/10.1002/ppul.21143 12. Shah SS, DiCristina CM, Bell LM, Ten Have T, Metlay JP. Primary early thoracoscopy and reduction in length of hospital stay and additional procedures among children with complicated pneumonia: results of a multicenter retrospective cohort study. Arch Pediatr Adolesc Med. 2008;162(7):675-81. https://doi.org/10.1001/archpedi.162.7.675 13. Velaiutham S, Pathmanathan S, Whitehead B, Kumar R. Videoassisted thoracoscopic surgery of childhood empyema: early referral improves outcome. Pediatr Surg Int. 2010;26(10):1031-5. https://doi. org/10.1007/s00383-010-2663-9 14. Bishay M, Short M, Shah K, Nagraj S, Arul S, Parikh D, et al. Efficacy of video-assisted thoracoscopic surgery in managing childhood empyema: a large single-centre study. J Pediatr Surg. 2009;44(2):33742. https://doi.org/10.1016/j.jpedsurg.2008.10.083 15. Pappalardo E, Laungani A, Demarche M, Erpicum P. Early thoracoscopy for the management of empyema in children. Acta Chir Belg. 2009;109(5):602-5. https://doi.org/10.1080/00015458.200 9.11680495 16. Chen JS, Huang KC, Chen YC, Hsu HH, Kuo SW, Huang PM, et al. Pediatric empyema: Outcome analysis of thoracoscopic management. J Thorac Cardiovasc Surg. 2009;137(5):1195-9. https:// doi.org/10.1016/j.jtcvs.2008.10.031 J Bras Pneumol. 2017;43(5):344-350

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17. Freitas S, Fraga JC, Canani F. Thoracoscopy in children with complicated parapneumonic pleural effusion at the fibrinopurulent stage: a multi-institutional study. J Bras Pneumol. 2009;35(7):660-8. https://doi.org/10.1590/S1806-37132009000700007 18. Kurt BA, Winterhalter KM, Connors RH, Betz BW, Winters JW. Therapy of parapneumonic effusions in children: video-assisted thoracoscopic surgery versus conventional thoracostomy drainage. Pediatrics. 2006;118(3):e547-53. https://doi.org/10.1542/peds.20052719 19. St Peter SD, Tsao K, Spilde TL, Keckler SJ, Harrison C, Jackson MA, et al. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial. J. Pediatr. Surg. 2009;44(1):106-11; discussion 111. https://doi. org/10.1016/j.jpedsurg.2008.10.018 20. Sonnappa S, Cohen G, Owens CM, Van Doorn C, Cairns J, Stanojevic S, et al. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am J Respir Crit Care Med. 2006;174(2):221-7. https://doi.org/10.1164/rccm.200601027OC 21. Gates RL, Caniano DA, Hayes JR, Arca MJ. Does VATS provide optimal treatment of empyema in children? A systematic review. J Pediatr Surg. 2004;39(3):381-6. https://doi.org/10.1016/j. jpedsurg.2003.11.045 22. Balfour-Lynn IM, Abrahamson E, Cohen G, Hartley J, King S, Parikh D, et al. BTS guidelines for the management of pleural infection in children. Thorax. 2005;60 Suppl 1:i1-21. https://doi.org/10.1136/ thx.2004.030676 23. Coote N, Kay ES. WITHDRAWN: Surgical versus non-surgical

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management of pleural empyema. Cochrane Database Syst Rev. 2009;(4):CD001956. 24. Kokoska ER, Chen MK; New Technology Committee. Position paper on video-assisted thoracoscopic surgery as treatment of pediatric empyema. J Pediatr Surg. 2009;44(1):289-93. https://doi. org/10.1016/j.jpedsurg.2008.08.037 25. Scarci M, Zahid I, BillĂŠ A, Routledge T. Is video-assisted thoracoscopic surgery the best treatment for paediatric pleural empyema? Interact Cardiovasc Thorac Surg. 2011;13(1):70-6. https://doi.org/10.1510/ icvts.2010.254698 26. Avansino JR, Goldman B, Sawin RS, Flum DR. Primary operative versus nonoperative therapy for pediatric empyema: a meta-analysis. Pediatrics. 2005;115(6):1652-9. https://doi.org/10.1542/peds.20041405 27. Calder A, Owens CM. Imaging of parapneumonic pleural effusions and empyema in children. Pediatr Radiol. 2009;39(6):527-37. https:// doi.org/10.1007/s00247-008-1133-1 28. Carter E, Waldhausen J, Zhang W, Hoffman L, Redding G. Management of children with empyema: Pleural drainage is not always necessary. Pediatr Pulmonol. 2010;45(5):475-80. https://doi. org/10.1002/ppul.21200 29. Knudtson J, Grewal H. Pediatric empyema--an algorithm for early thoracoscopic intervention. JSLS. 2004;8:31-4. 30. Kang DW, Campos JR, Andrade Filho Lde O, Engel FC, Xavier AM, Macedo M, et al. Thoracoscopy in the treatment of pleural empyema in pediatric patients. J Bras Pneumol. 2008;34(4):205-11. https://doi. org/10.1590/S1806-37132008000400004

J Bras Pneumol. 2017;43(5):351-356 http://dx.doi.org/10.1590/S1806-37562017000000028

ORIGINAL ARTICLE

Frequency of COPD in health care workers who smoke Ivan Kopitovic1,2, Aleksandar Bokan1,2, Ilija Andrijevic1,2, Miroslav Ilic1,2, Sanja Marinkovic3, Dragana Milicic1,2, Marija Vukoja1,2 1. Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Republic of Serbia. 2. Medical Faculty Novi Sad, University of Novi Sad, Novi Sad, Republic of Serbia. 3. General Hospital Sremska Mitrovica, Sremska Mitrovica, Republic of Serbia. Submitted: 26 January 2017. Accepted: 14 April 2017. Study carried out at the Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Republic of Serbia.

ABSTRACT Objective: COPD is one of the major causes of morbidity and mortality worldwide. Health care providers should counsel their smoking patients with COPD to quit smoking as the first treatment step. However, in countries with high prevalences of smoking, health care workers may also be smokers. The aim of this study was to determine the frequency and severity of COPD in health care workers who smoke. Methods: This was a cross-sectional study. All health care workers who smoke, from nine health care centers in Serbia, were invited to participate in the study and perform spirometry. The diagnosis of COPD was based on a post-bronchodilator FEV1/FVC ratio of < 0.70. All patients completed the COPD Assessment Test and the Fagerström Test for Nicotine Dependence. Results: The study involved 305 subjects, and 47 (15.4%) were male. The mean age of the participants was 49.0 ± 6.5 years. Spirometry revealed obstructive ventilatory defect in 33 subjects (10.8%); restrictive ventilatory defect, in 5 (1.6%); and small airway disease, in 96 (31.5%). A diagnosis of COPD was made in 29 patients (9.5%), 25 (86.2%) of whom were newly diagnosed. On the basis of the Global Initiative for COPD guidelines, most COPD patients belonged to groups A or B (n = 14; 48.2%, for both); 1 belonged to group D (3.6%); and none, to group C . Very high nicotine dependence was more common in those with COPD than in those without it (20.7% vs. 5.4%, p = 0.01). Conclusions: In this sample of health care workers, the frequency of COPD was comparable with that in the general population. The presence of COPD in health care workers who smoke was associated with higher nicotine dependence. Keywords: Pulmonary disease, chronic obstructive/prevention & control; Smoking; Health personnel.

INTRODUCTION COPD is one of the most common chronic diseases in adults and a major cause of chronic morbidity and mortality throughout the world. According to the World Health Organization, more than 210 million people suffer from COPD at a global level, and 80 million present its moderate-to-severe form.(1) In the period between 1990 and 2010, there was an increase in the prevalence of COPD, from 10.7% to 11.7%.(2) Population studies have estimated that the absolute number of patients with COPD will increase by 150% in the period between 2010 and 2030, the largest increase being in people over 75 years of age.(3) In 2005, more than 3 million people died of COPD, which corresponds to 5% of all adult deaths globally. (4) A study regarding the global burden of COPD, which was the fourth leading cause of death in 1990 and the third leading cause of death in 2010,(5) projected that the disease will remain the third leading cause of death worldwide by 2020. Despite the significant burden of COPD on health and quality of life, the disease is often unrecognized and undertreated because the most common symptoms, such as fatigue and dyspnea on exertion, are

commonly perceived as normal for the aging population. Recent data show that smokers who do not have COPD often have COPD symptoms and express common COPD features, such as exacerbations and activity limitation, and almost half of those use bronchodilators.(6) Symptomatic smokers and those who are at early COPD stages are most likely to benefit from early treatment strategies, such as smoking cessation. Even though tobacco smoking is the major preventable risk factor associated with the development of COPD,(7) according to two national studies in the USA,(8) only 20.9% of current tobacco users have received physician counseling on tobacco cessation. Moreover, studies suggest that the number of health care workers who smoke is high, especially in countries with high prevalences of smokers.(9) The primary aim of the present study was to determine the frequency and severity of COPD in health care workers who smoke. The secondary aim was to determine the occurrence of respiratory symptoms, abnormal patterns in their lung function, and the influence of the level of nicotine dependence on the development of COPD in health care workers.

Correspondence to:

Ivan Kopitovic. Institute for Pulmonary Diseases of Vojvodina, Put doktora Goldmana 4, 21204, Sremska Kamenica, Republic of Serbia. Tel./Fax: 38 121 4805175. E-mail: ikopitovic@gmail.com or ivan.kopitovic@mf.uns.ac.rs Financial support: This study received financial support from the Provincial Secretariat for Science and Technological Development, Autonomous Province of Vojvodina, Republic of Serbia (Project no. 114-451-718/2015-02). © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Frequency of COPD in health care workers who smoke

METHODS

Study design and population The study was designed as a cross-sectional study including adult health care workers who smoke to form a convenience sample. It was conducted in the period between August 1, 2015 and August 1, 2016, and the participants were selected from nine medical institutions in Vojvodina, Serbia. Vojvodina is a northern province of Serbia, with an estimated 1.9 million population, which comprise 21.56% of the total population in Serbia. The nine medical centers had a total of 5,635 medical workers, 4,318 (76.63%) being female. The study included subjects ≥ 40 years of age who were current cigarette smokers. The volunteers were invited to perform spirometry. The study was approved by the Research Ethics Committee of the Institute for Pulmonary Diseases in Sremska Kamenica, Serbia.

Study variables We collected basic demographic data and the medical history of the subjects, including information regarding a diagnosis of COPD, asthma, and other lung diseases. Demographic data included gender, age, occupation, and smoking history (in pack-years). All participants completed a closed questionnaire on COPD symptoms and the number of respiratory infections requiring treatment with antibiotics or corticosteroids in the previous year. The COPD Assessment Test (CAT) was used to determine the presence and severity of respiratory symptoms. If a patient had a CAT score > 0 on a specific item, the patient was classified as having that symptom. The intensity of symptoms was measured by the total and item-specific CAT score. The Fagerström Test for Nicotine Dependence (FTND) was used for assessing nicotine dependence. Spirometry was performed according to the standards of the American Thoracic Society and European Respiratory Society.(10) Obstructive ventilatory defect was defined as a FEV1/ FVC ratio < 0.70 on initial spirometry. We performed the bronchodilator reversibility test in those patients with detected airway obstruction. The diagnosis of COPD was based on post-bronchodilator FEV1/FVC ratio < 0.70. Small airway disease was defined as FEF25-75%, FEF50%, or FEF75% < 50%.(11) Restrictive ventilatory defect was defined as FVC < 80% in patients with a FEV1/FVC ratio > 70%. The assessment of disease severity was based on the CAT questionnaire and the number of exacerbations that the patient had in the previous year. All patients were classified according to the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD severity.(12)

Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutions involved and the national research committee, as well as with the Helsinki declaration and its later amendments or 352

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comparable ethical standards. The study was approved by the Research Ethics Committee of the Institute for Pulmonary Diseases in Sremska Kamenica, Serbia.

Statistical analysis Continuous variables are presented as means and standard-deviations, whereas categorical variables are presented as frequencies and proportions. We used the Student’s t-test for the comparison of continuous variables, the chi-square test for the comparison of categorical variables, and ANOVA for the comparison of continuous variables across three or more categories. The level of significance was set at 5% (p < 0.05) for all tests. RESULTS The study involved 305 health care workers (47 men and 258 women). The mean age was 49.0 ± 6.5 years, and the mean history of smoking was 23.0 ± 14.2 pack-years. The mean FTND score was 4.48 ± 4.47. Most of the subjects showed low nicotine dependence (28.9%), followed by high nicotine dependence (27.8%), very low nicotine dependence (18.5%), moderate nicotine dependence (17.9%) and very high nicotine dependence (6.9%). Most of the respondents were nurses (n = 169; 55.4%). Basic demographic data are presented in Table 1. Respiratory symptoms were present in 186 subjects (61.0%). The most common symptoms were “breathlessness while walking up a hill or a flight of stairs” (n = 104; 34.0%); “cough” (n = 96; 31.5%); “expectoration” (n = 68; 22.3%); “wheezing” (n = 46; 15.0%); “shortness of breath” (n = 40; 13.1%); “chest tightness” (n = 7; 2.3%); and “impaired sleep due to breathing problems” (n = 6; 2.0%). Breathing problems disrupted daily physical activity in 14 subjects (4.6%). The mean CAT score was 7.69 ± 7.10. Respiratory infection requiring the use of antibiotics in previous year was present in 57 subjects (18.7%). Regarding COPD, 16 subjects (5.2%) had been previously diagnosed with the disease. Chronic extrapulmonary diseases were present in 54 subjects (17.7%), hypertension being the most common disease (11.0%). Spirometry confirmed obstructive ventilatory defect in 33 subjects (10.8%), restrictive ventilatory defect, in 5 (1.6%), and small airway disease, in 96 (31.5%). There was no statistically significant difference between the subjects with and without airway obstruction regarding gender. Patients with airway obstruction were older and heavier smokers. Very high nicotine dependence was more common in patients with airflow obstruction (18.2% vs. 5.6%; p = 0.016). A diagnosis of COPD was made in 29 subjects (9.5%), 4 of whom had been previously diagnosed with COPD, whereas 25 (86.2%) were newly diagnosed patients. On the basis of the GOLD spirometric classification, most of the subjects with COPD were in stage I (n = 20; 68.9%), followed by those in stage II (n = 8; 27.6%). Only 1 subject was in stage III, having previously

Kopitovic I, Bokan A, Andrijevic I, Ilic M, Marinkovic S, Milicic D, Vukoja M

been diagnosed with COPD. On the basis of the GOLD classification based on symptoms and risk, the majority of respondents were in group A (n = 14; 48.2%) or B (n = 14; 48.2%). One subject (3.6%) had a severe form of COPD and belonged to group D. None of the subjects belonged to group C. There were no significant differences between patients with and without COPD in relation to occupation, gender, and body mass index; however, there was a significant difference between those subjects in relation to age, smoking history, and level of nicotine dependence (Table 2). There was no association between occupation (physicians, nurses, and allied health professionals) and level of nicotine dependence (mean FTND score, 4.26 ± 2.36 vs. 4.51 Table 1. Characteristics of the study population (N = 305).a

Characteristic Male Female Age, years Smoking history, years Smoking history, pack-years Nicotine dependence, FTND score Very low, 0-2 Low, 3-4 Moderate, 5 High, 6-7 Very high, 8-10 Occupation, n (%) Doctors and pharmacists Nurses Allied health care professionals

Result 47 (15.4) 258 (84.6) 49.0 ± 6.5 25.0 ± 8.4 23.0 ± 14.2 56 (18.5) 88 (28.8) 55 (17.9) 85 (27.8) 21 (6.9) 54 (17.7) 169 (55.4) 82 (26.9)

FTND: Fagerström Test for Nicotine Dependence. a Values expressed as n (%) or mean ± SD.

± 2.17 vs. 4.54 ± 2.15, respectively; p = 0.72). The subjects with higher levels of nicotine dependence had a higher burden of respiratory symptoms (a mean CAT score of 6.10 ± 5.95 and an FTND score of 0-4 vs. a mean CAT score of 7.83 ± 7.24 and an FTND score of 5-7 vs. a mean CAT score of 9.78 ± 8.10 and an FTND score of 8-10; p < 0.001). In subjects with no diagnosis of COPD, the presence of other spirometric defects was not associated with higher CAT scores (mean CAT score, 7.80 ± 6.42 in subjects with a restrictive pattern vs. 5.70 ± 7.37 in subjects with an obstructive pattern vs. 8.41 ± 7.94 in subjects with small airway obstruction vs. 7.14 ± 6.81 in subjects with normal spirometry; p = 0.66). Impaired sleep due to breathing problems and chest tightness were significantly more common in subjects with COPD than in those without the disease. Although cough, expectoration, and shortness of breath were found to be more common in subjects with COPD than in those without it, the differences were not statistically significant (Figure 1). The intensity of cough and shortness of breath, as measured by the CAT score, was significantly higher in subjects with COPD than in those without the disease (1.9 ± 1.3 vs. 1.2 ± 1.2; p = 0.004; and 2.2 ± 1.7 vs. 1.5 ± 1.5; p = 0.03). There was no difference in the frequency of respiratory infections requiring antibiotic treatment in the previous year between subjects with and without COPD (20.69% vs. 18.48%; p = 0.77). DISCUSSION The present study has provides an insight into the health of health care workers when it comes to COPD,

Table 2. Characteristics of the subjects with and without COPD (N = 305).a

Characteristic Male, % Female, % Age, years Smoking history, years Smoking history, pack-years Very high nicotine dependence, % BMI, kg/m2 Occupation Doctors and pharmacists Nurses Allied health care professionals Spirometry FEV1, % of predicted FVC, % of predicted FEV1/FVC ratio, % PEF, % of predicted FEF50%, % of predicted FEF75%, % of predicted FEF25-75%, % of predicted

COPD

Yes

17.0 8.1 53.7 ± 5.1 29.5 ± 8.3 32.5 ± 17.7 20.7 26.6 ± 4.9

83.0 91.9 48.7 ± 6.0 24.5 ± 8.2 22.8 ± 13.5 5.4 25.9 ± 6.3

48 (88.9) 152 (90.0) 76 (92.7)

6 (11.1) 17 (10.0) 6 (7.3)

84.4 ± 22.6 105.9 ± 15.8 64.0 ± 4.0 81.9 ± 21.6 40.5 ± 12.2 44.2 ± 21.3 39.2 ± 13.0

101.7 ± 15.7 109.4 ± 15.3 79.0 ± 0.1 98.2 ± 20.3 82.3 ± 24.6 75.2 ± 29.4 80.4 ± 26.3

0.09 < 0.001 0.004 0.001 0.013 0.57 0.71

< 0.001 0.24 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

BMI: body mass index. aValues expressed as n (%) or mean ± SD, except where otherwise indicated. J Bras Pneumol. 2017;43(5):351-356

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the most common lung disease in the world. We found an incidence of COPD of 9.5% in our sample of health care workers who smoke. The vast majority of the COPD cases in our sample of health care workers were newly diagnosed (86.2%).

results are in line with the those found in a study by Regan et al., who showed that respiratory symptoms, limitation of daily activities, and abnormalities on CT scans of the chest are often present in smokers who do not manifest airway obstruction on spirometry.(19) This suggests that clinical COPD, which includes chronic cough, dyspnea, and chronic sputum production, together with a history of exposure to risk factors, is often present in smokers and that it is likely that this group of patients would largely benefit from early prevention strategies, such as smoking cessation. Despite the high burden of symptoms in health care workers, they were unaware of the possibility of having COPD, as evidenced by the fact that most of the COPD cases had not been previously diagnosed. In addition, most of the COPD cases were heavy smokers. This is of utmost importance because health care workers play a major role in counseling their patients on the importance of smoking cessation and have the responsibility to deliver nonpharmacological interventions in the treatment of their COPD patients. In addition, the benefit of smoking cessation spreads far beyond the treatment of COPD. Importantly, none of the centers involved in the present study had an established smoking prevention program.

The prevalence of COPD in the general population ranges from 0.2% to 18.3%. In Europe, it is estimated to range from 4% to 10%,(13) whereas the incidence of newly diagnosed cases of COPD in high-risk populations varies from 10.9% to 29.5%,(14-17) depending on the geographic location, the structure of the study population, and the scope of previous screening for COPD. The major reason for a late diagnosis of COPD is that the majority of patients with decreased FEV1 do not complain of any respiratory symptoms. The slow, progressive nature of COPD appears to lead to a reduced awareness of the signs of the disease. For example, a smoker coughing every morning is often perceived as a normal phenomenon.(18) Results of the present study demonstrate that 61% of the health care workers who smoke have respiratory symptoms, the most common being breathless while walking up a hill or one flight of stairs (34.0%), cough (31.5%), sputum expectoration (22.3%), and wheezing (15.0%). Similar results were found in a recent five-year study involving 1,812 smokers and former smokers, in which 50% of the participants had respiratory symptoms, despite having preserved pulmonary function, which was significantly more common than in nonsmokers (16%).(6) Although there were no significant differences regarding the frequency of cough and of shortness of breath between the subjects with and without COPD, the intensity of these symptoms was more pronounced in those with COPD. Subjects with COPD had sleep disruption and chest tightness more commonly than did smokers without COPD, suggesting that these complaints might be more specific in the smoking population with COPD. These

On spirometry, obstructive ventilatory defect was confirmed in 33 participants (10.8%); restrictive ventilatory defect, in 5 (1.6%); and small airway disease, in 96 (31.5%). On the basis of the GOLD classification, the majority of the respondents with COPD were in groups A or B (n = 14; 48.2%, for both), and only 1 patient (3.6%) was in group D. Since we performed screening in a high-risk population in our study, most of the COPD patients were newly diagnosed and in the early stages of the disease. This is very important because most patients with COPD are diagnosed in the third or fourth stage of the disease, when the respiratory reserve is reduced by more than 50%, and the largest

Impaired sleep due to breathing problems Chest tightness

42.86%

8,72%

Shortness of breath

8.30%

17.50%

15.22% 8.49%

Wheezing

12.50% 8.13%

Cough

11.54%

Breathlessness while walking up a hill or one flight of stairs

8% 10.30% 9.00%

Expectoration

0% COPD

50%

10%

20%

Without COPD

Figure 1. Frequency of respiratory symptoms in patients with and without COPD.

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30%

40%

50%

60%

Kopitovic I, Bokan A, Andrijevic I, Ilic M, Marinkovic S, Milicic D, Vukoja M

decline in lung function occurs in the first and second stages of the disease.(20) Timely diagnosis and treatment reduce health and socioeconomic consequences for the individual and society. In the USA, the results of a follow-up study based on the First National Health and Nutrition Examination Survey showed that the risk of mortality was 1.3, 1.7, and 3.1, respectively, in patients in GOLD COPD stage I, stage II, and stages III-IV.(21) In addition, the five-year mortality rate depends on the stage of the disease, ranging from 17% in stage I patients to 73% in stage IV patients.(22) The frequency of COPD is primarily the result of cumulative exposure to different risk factors for many decades. The prevalence of COPD is often directly related to the frequency of tobacco use and level of air pollution. A meta-analysis of studies conducted in 28 countries between 1990 and 2004 and a study in Japan provide evidence that the prevalence of COPD is significantly higher in smokers and former smokers than in nonsmokers, in those older than 40 years of age than in those younger than 40 years of age, and in men than in women.(23,24) From 1965 to 2012, the prevalence of cigarette smoking in the USA decreased from 42.4% to 18.1%.(25) According to data from 2013, it is estimated that 34.7% of the population of Serbia are smokers, with the highest proportion of smokers in the 18-64 year age group, i.e., the working population. Despite recent law regulations that restrict smoking in Serbia, there have been no changes in the number of smokers since 2006.(26) In our study, the participants with COPD were older and had a longer smoking history (in pack-years) when compared with the participants without COPD. These results are expected, since age and smoking history are two dominant risk factors for the development of COPD.(27) In general, COPD is more prevalent in males. (28,29) However, in our study, most of the subjects were female, and the results of our study could be related to the occupation of the subjects. The majority of the respondents were nurses, and there is a possibility that they were more interested in having their health status investigated than were doctors. In addition, most health care workers in the participating centers were female (77%). The results of our study also showed a statistically significant association between smoking history (pack-years) and a diagnosis of COPD. Respondents with very high nicotine dependence were significantly more commonly diagnosed with COPD. This is in line with previous studies that showed that, for each point increase in the FTND score, the probability of a smoker developing COPD increases by 11%.(30) Our study has several limitations. First, the study included a selected group of health care workers who volunteered to participate in the study, and they are not necessarily representative of all health care workers who smoke. Second, since we included only current smokers,

the prevalence of COPD in health care workers might be higher. However, we were specifically interested in health care workers who continue to smoke, who present with the obvious health-related risks. Third, we acknowledge the well-known limitation of using a fixed spirometric value for determining obstruction, which can cause the overdiagnosis of the disease in the elderly and its underdiagnosis in younger patients. However, current COPD guidelines favor the use of this threshold due to its consistency, simplicity, and limited risk of misdiagnosis.(12) Fourth, although we reported the spirometric indices of small airway disease, these are highly variable and nonspecific, and therefore are not generally recommended.(31) Finally, the present study is prone to recall bias with regard to the number of exacerbations in the previous year, which is often inaccurately reported in COPD patients.(32) Despite these limitations, to our knowledge, this is the first contemporary study that explores the occurrence of respiratory symptoms and COPD in health care workers who smoke. The study is strengthened by the use of spirometry to make a diagnosis of COPD and by the standardized approach of measuring symptoms and grading COPD severity. We believe that our study is important because it provides an insight on the smoking impact in a country with a high prevalence of smokers. In such countries, the detrimental effects of smoking-related diseases are likely to be seen in upcoming years in contrast to those where there has been a significant reduction in the prevalence of smoking. Needless to say, the role of health care workers in such settings is of paramount importance, and the present study highlights the need for education and prevention programs in this population. In conclusion, we showed that the frequency of COPD in health care workers is comparable to that in the general population and that it is associated with higher nicotine dependence. Despite being symptomatic, health care workers were unaware of the possibility that they might have COPD, as evidenced by the fact that most of the COPD cases were newly diagnosed. The present study demonstrates the necessity of educational programs for COPD prevention and of early treatment among health care workers. ACKNOWLEDGMENTS We would like to thank the following institutions: Clinical Centre of Vojvodina in Novi Sad; Institute of Occupational Health “Zeleznice Srbije” in Novi Sad; Dispensary for Pulmonary Diseases and Tuberculosis in Subotica; General Hospital in Sremska Mitrovica; General Hospital “Dr Radivoj Simonovic” in Sombor; General Hospital “Djordje Joanovic” in Zrenjanin; Special Hospital for Pulmonary Disease “Dr Vasa Savic” in Zrenjanin; and Community Health Center in Zabalj.

REFERENCES 1. Cruz AA, Bousquet J, Khaltaev NG, editors. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach

[monograph on the Internet]. Geneva: World Health Organization; 2007 [cited 2016 Sep 23]. Available from: https://goo.gl/dBZK4R J Bras Pneumol. 2017;43(5):351-356

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2. Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Global and regional estimates of COPD prevalence: Systematic review and meta–analysis. J Glob Health. 2015;5(2)020415. https:// doi.org/10.7189/jogh.05.020415 3. Khakban A, Sin DD, FitzGerald JM, McManus BM, Ng R, Hollander Z, et al. The Projected Epidemic of Chronic Obstructive Pulmonary Disease Hospitalizations over the Next 15 Years. A Population-based Perspective. Am J Respir Crit Care Med. 2016;195(3):287-291. 4. Laniado-Laborín R. Smoking and chronic obstructive pulmonary disease (COPD). Parallel epidemics of the 21st century. Int J Environ Res Public Health. 2009;6(1):209-24. https://doi.org/10.3390/ ijerph6010209 5. European Lung White Book [homepage on the Internet]. Lausanne: European Respiratory Society; c2016 [cited 2016 Oct 1]. The burden of lung disease; [about 32 screens]. Available from: http://www. erswhitebook.org/chapters/the-burden-of-lung-disease/ 6. Woodruff PG, Barr RG, Bleecker E, Christenson SA, Couper D, Curtis JL, et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med. 2016;374(19):181121. https://doi.org/10.1056/NEJMoa1505971 7. Miravitlles M, de la Roza C, Naberan K, Lamban M, Gobartt E, Martin A. Use of spirometry and patterns of prescribing in COPD in primary care. Respir Med. 2007;101(8):1753-60. https://doi.org/10.1016/j. rmed.2007.02.019 8. Jamal A, Dube SR, Malarcher AM, Shaw L, Engstrom MC; Centers for Disease Control and Prevention (CDC). Tobacco use screening and counseling during physician office visits among adults--National Ambulatory Medical Care Survey and National Health Interview Survey, United States, 2005-2009. MMWR Suppl. 2012;61(2):38-45. 9. Korzybski D, Bilska A, Skrzypczyńska E, Górecka D. Smoking habits among Polish pulmonary physicians [Article in Polish]. Pneumonol Alergol Pol. 2008;76(3):142-7. 10. 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. https://doi.org/10.1183/09031936.05.00034805 11. Hyatt RE, Scanlon PD, Nakamura M. Interpretation of pulmonary function tests: a practical guide. 4th ed. Philadelphia: Wolters Kluwer Health; 2014. 12. Global Initiative for Chronic Obstructive Lung Disease-GOLD [homepage on the Internet]. Bethesda: GOLD; c2016 [cited 2017 Mar 25]. GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD; [about 2 screens]. Available from: http:// goldcopd.org/gold-2017-global-strategy-diagnosis-managementprevention-copd/ 13. European COPD Coalition-ECC [homepage on the Internet]. Brussels: ECC; c2016 [cited 2016 Sep 15] Prevalence in EU; [about 3 screens]. Available from: http://www.copdcoalition.eu/about-copd/prevalence 14. Vandevoorde J, Verbanck S, Gijssels L, Schuermans D, Devroey D, De Backer J, et al. Early detection of COPD: a case finding study in general practice. Respir Med. 2007;101(3):525-30. https://doi. org/10.1016/j.rmed.2006.06.027 15. Konstantikaki V, Kostikas K, Minas M, Batavanis G, Daniil Z, Gourgoulianis KI, et al. Comparison of a network of primary care physicians and an open spirometry programme for COPD diagnosis. Respir Med. 2011;105(2):274-81. https://doi.org/10.1016/j. rmed.2010.06.020 16. Fukahori S, Matsuse H, Takamura N, Hirose H, Tsuchida T, Kawano T, et al. Prevalence of chronic obstructive pulmonary diseases in general clinics in terms of FEV1/FVC. Int J Clin Pract. 2009;63(2):26974. https://doi.org/10.1111/j.1742-1241.2008.01873.x 17. Vukoja M, Rebić P, Lazić Z, Mitić Milikić M, Milenković B, Zvezdin B, et al. Early detection of asthma and chronic obstructive pulmonary

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disease in primary care patients. Med Pregl. 2013;66(1-2):46-52. https://doi.org/10.2298/MPNS1302046V 18. van Schayck CP, Chavannes NH. Detection of asthma and chronic obstructive pulmonary disease in primary care. Eur Respir J Suppl. 2003;39:16s-22s. https://doi.org/10.1183/09031936.03.00040403 19. Regan EA, Lynch DA, Curran-Everett D, Curtis JL, Austin JH, Grenier PA, et al. Clinical and Radiologic Disease in Smokers With Normal Spirometry. JAMA Intern Med. 2015;175(9):1539-49. https://doi. org/10.1001/jamainternmed.2015.2735 20. Tantucci C, Modina D. Lung function decline in COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:95-9. https://doi.org/10.2147/COPD. S27480 21. Mannino D, Buist A, Petty T, Enright P, Redd S. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study. Thorax. 2003;58(5): 388-93. https://doi.org/10.1136/thorax.58.5.388 22. Raherison C, Girodet PO. Epidemiology of COPD. Eur Respir Rev. 2009;18(114):213-21. https://doi.org/10.1183/09059180.00003609 23. National Institute for Health and Care Excellence-NICE [homepage on the Internet]. London: NICE; c2016 [cited 2016 Feb 26]. Chronic obstructive pulmonary disease in over 16s: diagnosis and management; [about 4 screens]. Available from: https://www.nice. org.uk/guidance/cg101 24. Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-91. https:// doi.org/10.7326/0003-4819-155-3-201108020-00008 25. Lavinghouze SR, Malarcher A, Jama A, Neff L, Debrot K, Whalen L. Trends in Quit Attempts Among Adult Cigarette Smokers - United States, 2001-2013 MMWR Morb Mortal Wkly Rep. 2015;64(40):112935. https://doi.org/10.15585/mmwr.mm6440a1 26. Ilić D. Rezultati istraživanja zdravlja stanovništva Srbije, 2013. Godina. Beograd: Službeni glasnik (SR); 2014. Report No.:978-86-7358-060-9. 27. Lindberg A, Bjerg A, Rönmark E, Larsson LG, Lundbäck B. Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med. 2006;100(2):264-72. https:// doi.org/10.1016/j.rmed.2005.04.029 28. Čovinović Šternić N. Nacionalni vodič dobre kliničke prakse za dijagnostikovanje i lečenje hronične opstruktivne bolesti pluća. Beograd: Republička stručna komisija za izradu i implementaciju vodiča dobre kliničke prakse, Ministarstvo zdravlja Republike Srbije (SR); 2013. Report No.:978-86-83607-85-3. 29. Roberts NJ, Patel IS, Partridge MR. The diagnosis of COPD in primary care; gender differences and the role of spirometry. Respir Med. 2016;111:60-3. https://doi.org/10.1016/j.rmed.2015.12.008 30. Jiménez-Ruiz C, Miravitlles M, Sobradillo V, Gabriel R, Viejo JL, Masa JF, et al. Can cumulative tobacco consumption, FTND score, and carbon monoxide concentration in expired air be predictors of chronic obstructive pulmonary disease? Nicotine Tob Res. 2004;6(4):649-53. https://doi.org/10.1080/14622200410001727948 31. Agnew M. Ask the Expert: Lung function measurement. Breathe. 2009;5(3):224-6. https://doi.org/10.1183/18106838.0503.224 32. Frei A, Siebeling L, Wolters C, Held L, Muggensturm P, Strassmann A, et al. The Inaccuracy of Patient Recall for COPD Exacerbation Rate Estimation and Its Implications: Results from Central Adjudication. Chest. 2016;150(4):860-868. https://doi.org/10.1016/j. chest.2016.06.031

J Bras Pneumol. 2017;43(5):357-362 http://dx.doi.org/10.1590/S1806-37562016000000199

ORIGINAL ARTICLE

Quality of Communication Questionnaire for COPD patients receiving palliative care: translation and cross-cultural adaptation for use in Brazil Flávia Del Castanhel1, Suely Grosseman2 1. Programa de Pós-Graduação em Ciências Médicas – PPGCM – Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil. 2. Departamento de Pediatria, Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil. Submitted: 4 July 2016. Accepted: 4 May 2017. Study carried out under the auspices of the Programa de Pós-Graduação em Ciências Médicas – PPGCM – Universidade Federal de Santa Catarina – UFSC – Florianópolis (SC) Brasil.

ABSTRACT Objective: To translate the Quality of Communication Questionnaire (QOC) to Portuguese and adapt it for use in Brazil in COPD patients receiving palliative care. Methods: After approval from the first author of the original QOC and the local research ethics committee, the original, 13-item version of the questionnaire was independently translated to Brazilian Portuguese by two Brazilian translators fluent in English. The two translations were analyzed by a bilingual physician and the two Brazilian translators, who reached a consensus and produced another Portuguese version of the QOC. That version was back-translated to English by two translators originally from Englishspeaking countries and fluent in Portuguese. In order to resolve any discrepancies, an expert panel compared the original version of the QOC with all five versions produced up to that point, the “prefinal” version of the QOC for use in Brazil being thus arrived at. A total of 32 patients admitted to any of three public hospital ICUs in the greater metropolitan area of Florianopolis, in southern Brazil, participated in the pretesting phase of the study, which was aimed at assessing the clarity and cultural acceptability of the prefinal version of the QOC for use in Brazil. Results: Mean patient age was 48.5 ± 18.8 years. Most of the items were well understood and accepted, being rated 8 or higher. One item, regarding death, was considered difficult to understand by the participants in the pretesting phase. After analyzing the back-translated version of the QOC, the first author of the original questionnaire requested that the items “Caring about you as a human being” and “Talking about what death might be like” be changed to “Caring about you as a person” and “Talking about how dying might be”, respectively. The final version of the QOC for use in Brazil was thus arrived at. Conclusions: The QOC was successfully translated to Portuguese and adapted for use in Brazil. Keywords: Pulmonary disease, chronic obstructive; Surveys and questionnaires; Communication; Intensive care units.

INTRODUCTION The importance of physician-patient communication is well established(1,2) and has been confirmed in several studies demonstrating its association with positive patient health outcomes,(3-5) including better treatment response, easier decision-making,(6) better patient emotional well-being, and, consequently, greater patient satisfaction with care.(7,8) Studies have shown that the quality of physician-patient communication is currently low,(9) and that physicians are often unaware of the preferences of their patients.(9,10) In a study conducted in Germany(11) and involving patients with multiple sclerosis, as well as in a study conducted in Australia(12) and involving patients with ductal carcinoma in situ, it was found that many of the participating patients were dissatisfied with the communication process and felt that they needed more information on the progression of their disease.

In a study conducted in eight European countries(13) and investigating the views of ICU patients and their relatives of what makes a good intensivist, it was found that desirable characteristics included medical knowledge and skills, as well as communication skills. In Brazil, most of the studies addressing the issue of communication between health professionals and patients have focused on nurse-patient communication. (14-17) We found only one study addressing the issue of communication with physicians.(18) The study in question was a descriptive study aimed at determining the views that relatives of terminal ICU patients held on patient choice in end-of-life decisions, patient preferences and satisfaction with communication with the medical team being examined. The study showed that 53.3% of the patients had discussed their end-of-life care wishes with their relatives, but not with their physicians. In a qualitative study involving focus groups of AIDS patients and physicians specializing in AIDS care, Curtis

Correspondence to:

Flávia Del Castanhel. Hospital Universitário Polydoro Ernani de São Thiago, UFSC, Campus Universitário, Trindade, CEP 88040-970, Florianópolis, SC, Brasil. Tel./Fax: 55 48 37219100. E-mail: flaviadelcastanhel@gmail.com Financial support: Flávia Del Castanhel is the recipient of a master’s scholarship grant from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Office for the Advancement of Higher Education). © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Quality of Communication Questionnaire for COPD patients receiving palliative care: translation and cross-cultural adaptation for use in Brazil

et al.(19) developed the Quality of Communication Questionnaire (QOC), which is aimed at evaluating the quality of patient-physician communication in palliative care settings. In 1999, the QOC was validated in a cohort of AIDS patients and their physicians,(20) and, in 2002,(21) it was used in a qualitative study involving focus groups of patients with AIDS, cancer, or COPD. In a study conducted in 2006,(22) principal component analysis was performed, having revealed two subscales, namely general communication skills and communication about end-of-life care, both of which showed good internal consistency (α = 0.91 and α = 0.79, respectively); the content validity of the QOC showed significant associations (p < 0.01). In the USA, the QOC has been used in COPD patients receiving palliative care(21,22) and in studies involving a variety of patients with different clinical conditions. In Germany, the QOC has been used in order to assess the quality of communication between physicians and patients with multiple sclerosis.(11) In the USA(23-25) and in Canada,(26) the QOC has been used in order to assess the quality of communication between physicians and severely ill patients with a ≥ 50% chance of mortality. In the Netherlands, the QOC has been used in endstage renal disease patients on dialysis,(27) as well as in patients with advanced COPD, chronic heart failure, or chronic kidney disease.(28) Given the lack of studies evaluating physician-patient communication in Brazil with the use of a valid and reliable instrument in patients receiving palliative care, in terminally ill patients, and in ICU patients, we contacted the first author of the original QOC to ask whether it would be possible to translate it to Portuguese and adapt it for use in ICU patients in Brazil. After having received permission from the original author, we conducted the present study, the objective of which was to translate the QOC to Portuguese and adapt it for use in Brazil. METHODS The present study was aimed at translating the QOC to Portuguese and adapting it for use in Brazil. The QOC is an instrument that can be used in order to evaluate the quality of communication between physicians and COPD patients receiving palliative care. The QOC consists of 13 items divided into two domains: general communication skills (items 1 through 6) and communication skills about end-of-life care (items 7 through 13), with scores ranging from 0 (the very worst I could imagine) to 10 (the very best I could imagine). Patients are offered two additional response options: “my doctor did not do this” (allowing patients to leave the item unrated when it does not occur); and “don’t know” (indicating that they are unsure of how to rate their doctor on a particular skill). Permission to translate the QOC to Portuguese and adapt it and validate it for use in Brazil was granted by the first author of the original instrument via 358

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email. The study project was approved by the Human Research Ethics Committee of the Federal University of Santa Catarina (Protocol no. 938.326), and the study was performed in accordance with established ethical standards. The QOC was translated to Portuguese and adapted for use in Brazil in accordance with the method proposed by Beaton et al.(29) Initially, the original version of the QOC was independently translated to Portuguese by two Brazilian translators fluent in English. One of the translators was familiar with the QOC, whereas the other was not, having had no training in health care. The translated versions of the QOC were designated T1 and T2. Subsequently, the two translators and a bilingual physician compared T1 and T2 with the original version of the QOC, resolved all discrepancies, and, after reaching a consensus, produced a synthesis of T1 and T2, which was designated T12. Two translators originally from English-speaking countries, fluent in Portuguese, with no training in health care, and unfamiliar with the original QOC, independently back-translated T12 to English. The back-translated versions of the QOC were designated BT1 and BT2. In order to achieve semantic, idiomatic, conceptual, and cultural equivalence among all five versions produced up to that point (i.e., T1, T2, T12, BT1, and BT2), an expert panel comprising two bilingual intensivists, two translators (the one who produced T1 and the one who produced BT1), a teacher of Portuguese, and a professor of methodology reviewed each item on the translated QOC, the “prefinal” version of the QOC for use in Brazil being thus arrived at. That was the version that was used in the pretesting phase of the study. According to Beaton et al.,(29) the pretesting phase should include 30-40 participants. A convenience sample of ICU patients was used in the present study. The inclusion criteria were as follows: having been in the ICU for more than 24 h; being over 18 years of age; and being awake and lucid. The exclusion criteria were as follows: being in a coma; having a neurological or psychiatric disorder; presenting with hearing loss or any other condition affecting communication; and using medications that can alter the level of consciousness. Data were collected between October and December of 2015 at times scheduled by the heads of the ICUs. The decision to study patients who were not terminally ill was based on the fact that this would open an avenue for further studies involving severely ill patients receiving intensive care. The first author of the original QOC gave us permission to study such patients. After having received information regarding the objectives of the study and its ethical principles, participants were asked to evaluate the clarity and cultural appropriateness of the QOC. All participants gave written informed consent. A total of 32 patients admitted to any of three public hospital ICUs in the greater metropolitan area of Florianópolis, in southern Brazil, participated in the study.

Del Castanhel F, Grosseman S

The clarity and cultural appropriateness of all of the QOC components (i.e., instructions, items, and response options) were rated in accordance with the criteria proposed by Melo(30) on a scale ranging from 1 (not clear/appropriate at all) to 10 (completely clear/ appropriate), items rated 8 or higher being considered satisfactory. Participants were asked for suggestions on how to improve the clarity and cultural appropriateness of items that were rated as being unclear or culturally inappropriate. After analysis of all patient responses and suggestions, a review committee comprising three ICU physicians, two ICU nurses, and one ICU physical therapist made adjustments and prepared the final version of the QOC for use in Brazil, which was back-translated to English and sent to the first author of the original QOC. A flowchart of the process of translation and cross-cultural adaptation of the QOC is provided in Figure 1. For statistical analysis, descriptive measures of frequency and central tendency were calculated. For between-group comparisons, the Student’s t-test and the chi-square test were used for continuous and categorical variables, respectively. All statistical analyses were performed with the IBM SPSS Statistics

software package, version 19.0 (IBM Corporation, Armonk, NY, USA). RESULTS Of the 32 participants, 21 were male (65.6%) and 11 were female (34.4%). Patient age ranged from 18 years to 82 years, the mean age being 48.5 ± 18.8 years. With regard to patient level of education, 10 (31.3%) had had fewer than nine years of schooling, 5 (15.6%) had had nine years of schooling, 4 (12.5%) had not completed high school, and 11 (40.6%) had completed high school. The mean length of hospital stay was 4.8 ± 4.1 days. Of the 32 patients, 16 (50%) had been admitted to the ICU for clinical reasons and 16 (50%) had been admitted to the ICU for surgical reasons (Table 1). As can be seen in Table 2, item 10 was the only item that was rated as being unclear and culturally inappropriate (mean score, 5.59 ± 3.2) and was therefore revised. Of the 32 patients who participated in the pretesting phase of the study, 62.5% rated that item 5 or lower, with no significant difference between males and females (p = 0.27). The review committee considered the suggestions

Quality of Communication Questionnaire - original version

Initial translation to Portuguese

Translation I (T1)

Translation II (T2)

Synthesis of T1 and T2 (T12)

Back-translation I (BT1)

Back-translation II (BT2)

Expert panel and preparation of the "prefinal" version

Pretesting (n = 32)

Review committee and preparation of the final version of the QOC for use in Brazil

Approval from the first author of the original QOC

QOC—final version Figure 1. Flowchart of the process of translation and cross-cultural adaptation of the Quality of Communication Questionnaire (QOC) for use in Brazil. J Bras Pneumol. 2017;43(5):357-362

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Table 1. Reasons for ICU admission in the individuals who participated in the process of translation and cross-cultural adaptation of the Quality of Communication Questionnaire for use in Brazil (N = 32), by gender.

Reasons for ICU admission

Gender

Clinical reasons (n = 16) Stroke Unstable angina Acute myocardial infarction COPD Pulmonary embolism Severe pneumonia Liver cirrhosis Pancreatitis Sepsis Severe allergic reaction Surgical reasons (n = 16) Multiple trauma Aortic valve replacement Coronary artery bypass grafting Lobectomy Pneumonectomy Partial colectomy Hemicolectomy Fournier’s syndrome (necrotizing fasciitis) Intestinal obstruction Liver transplantation Appendectomy Placental abruption Postpartum complications and hysterectomy

Total

Male n (%)

Female n (%)

n (%)

2 (25.0) 1 (12.5) 1 (12.5) 1 (12.5) 3 (37.5) -

1 (12.5) 1 (12.5) 1 (12.5) 1 (12.5) 1 (12.5) 2 (25.0) 1 (12.5)

2 (12.5) 1 (6.3) 1 (6.3) 2 (12.5) 1 (6.3) 1 (6.3) 1 (6.3) 1 (6.3) 5 (31.3) 1 (6.3)

1 (7.7) 2 (15.4) 2 (15.4) 1 (7.7) 2 (15.4) 1 (7.7) 1 (7.7) 1 (7.7) 1 (7.7) 1 (7.7) -

1 (33.3) 1 (33.3) 1 (33.3)

1 (6.3) 2 (12.5) 2 (12.5) 1 (6.3) 1 (6.3) 2 (12.5) 1 (6.3) 1 (6.3) 1 (6.3) 1 (6.3) 1 (6.3) 1 (6.3) 1 (6.3)

Table 2. Clarity and cultural appropriateness of each item on the Portuguese version of the Quality of Communication Questionnaire for use in Brazil, according to the 32 individuals who participated in the study.a

Number

1 2 3 4 5 6 7 8 9 10 11 12 13

Item

Clarity

Usar palavras que você consiga compreender

9.94 ± 0.25

Cultural appropriateness 9.94 ± 0.25

Olhar em seus olhos

9.88 ± 0.42

Responder a todas as suas dúvidas sobre sua doença

9.81 ± 0.64

Ouvir o que você tem a dizer

9.94 ± 0.25

Preocupar-se com você como ser humano

9.91 ± 0.30

Dar atenção plena a você

9.88 ± 0.42

Falar sobre os seus sentimentos se acaso você piorar

9.72 ± 0.58

Falar sobre detalhes se acaso você piorar

9.56 ± 1.01

Falar sobre quanto tempo você tem de vida

9.78 ± 0.49

Falar sobre como pode ser o processo do morrer

5.59 ± 3.16

Envolver você nas discussões do tratamento para seu cuidado

9.34 ± 1.56

Perguntar sobre coisas importantes na sua vida

9.75 ± 0.67

Perguntar sobre suas crenças espirituais ou religiosas

9.69 ± 1.03

Values expressed as mean ± SD.

made by the participants and changed item 10 to read “Falar sobre como a morte pode ser.” The Portuguese version of the QOC produced by the review committee was back-translated to English and sent to the first author of the original questionnaire, who suggested that items “Caring about you as a 360

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human being” and “Talking about what death might be like” be changed to “Caring about you as a person” and “Talking about how dying might be”, respectively. The two items were then changed to “Preocupar-se com você como pessoa” and “Falar sobre como morrer poderia ser” in the Portuguese version of the QOC.

Del Castanhel F, Grosseman S

With the consent of the original author, the wording of the instructions was changed to increase the applicability of the QOC to a wider range of clinical conditions, the term “lung/respiratory problems” (problemas respiratórios in the translated version) being replaced by the term “health problems” (problemas de saúde in the translated version). The Portuguese version of the QOC for use in Brazil, entitled Questionário sobre a Qualidade da Comunicação (Chart 1), was thus arrived at. DISCUSSION The objective of the present study was to translate the QOC to Portuguese and adapt it for use in Brazil. All steps of the process of translation and cross-cultural adaptation were successfully completed, and the Portuguese version of the QOC will be ready for use after its validation. In the present study, the QOC was found to be easy to understand, the exception being one item regarding

how dying might be. One of the possible reasons why that particular item was not well understood is that the prefinal version of the QOC for use in Brazil was administered to ICU patients. Another possible reason is that physicians in Brazil do not habitually talk with patients about the possibility of dying. These issues can only be clarified when studies aimed at validating the QOC in patients receiving intensive care and in terminally ill patients receiving palliative care are conducted. The QOC was developed to evaluate the quality of communication between physicians and terminally ill patients receiving palliative care. Some studies have employed only one of its two domains or subscales (general communication skills and communication about end-of-life care). The general communication skills subscale has been used in a study conducted in the USA,(23) whereas the communication about end-of-life care subscale has been used in studies conducted in Germany(11) and the Netherlands.(28)

Chart 1. Portuguese version of the Quality of Communication Questionnaire for use in Brazil.

Questionário sobre a Qualidade da Comunicação Versão administrada pelo entrevistador Gostaríamos de saber, o mais detalhadamente possível, o quanto o médico que cuida dos seus problemas de saúde é bom em falar com você sobre a sua doença e os tipos de cuidados que você gostaria de receber se ficasse pior ou doente demais para responder por si mesmo. Sabemos que muitas pessoas têm grande admiração por seus médicos. Para nos ajudar a melhorar a comunicação entre médicos e pacientes, por favor, seja crítico(a). Usando a seguinte escala, em que “0” é o pior que você poderia imaginar e “10” o melhor que você poderia imaginar, por favor, circule o melhor número para cada questão. Entrevistador: usar a resposta 888 quando o médico não fez Vire o cartão de escala de respostas e leia as opções de resposta Ao falar com o(a) médico(a) _____ sobre questões importantes como você ficar muito doente, o quanto ele(a) é bom / boa em: O pior que eu poderia O melhor que eu Não Não imaginar poderia imaginar fez sabe 1. Usar palavras que você consiga 0 1 2 3 4 5 6 7 8 9 10 888 999 compreender. 2. Olhar em seus olhos. 0 1 2 3 4 5 6 7 8 9 10 888 999 3. Responder todas as dúvidas 0 1 2 3 4 5 6 7 8 9 10 888 999 sobre sua doença. 4. Ouvir o que você tem a dizer. 0 1 2 3 4 5 6 7 8 9 10 888 999 5. Preocupar-se com você como 0 1 2 3 4 5 6 7 8 9 10 888 999 pessoa. 6. Dar atenção plena a você. 0 1 2 3 4 5 6 7 8 9 10 888 999 7. Falar sobre seus sentimentos se 0 1 2 3 4 5 6 7 8 9 10 888 999 acaso você piorar. 8. Dar detalhes da sua condição se 0 1 2 3 4 5 6 7 8 9 10 888 999 acaso você piorar. 9. Falar sobre quanto tempo você 0 1 2 3 4 5 6 7 8 9 10 888 999 tem de vida. 10. Falar sobre como o morrer 0 1 2 3 4 5 6 7 8 9 10 888 999 poderia ser. 11. Envolver você nas discussões 0 1 2 3 4 5 6 7 8 9 10 888 999 do tratamento para o seu cuidado. 12. Perguntar sobre coisas 0 1 2 3 4 5 6 7 8 9 10 888 999 importantes em sua vida. 13. Perguntar sobre suas crenças 0 1 2 3 4 5 6 7 8 9 10 888 999 espirituais ou religiosas. J Bras Pneumol. 2017;43(5):357-362

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Quality of Communication Questionnaire for COPD patients receiving palliative care: translation and cross-cultural adaptation for use in Brazil

We decided to translate the QOC to Portuguese and adapt it for use in Brazil because the questionnaire has consistent psychometric properties, which allow comparisons across studies conducted in different countries. We expect that, after its psychometric properties have been tested, the Portuguese version of the QOC for use in Brazil will be used in studies examining the quality of communication between physicians and patients receiving palliative care or severely ill patients in Brazil, thus allowing comparisons across studies conducted in different countries. The QOC was used in COPD patients in a study conducted

in 2002,(21) and the validation of the Portuguese version of the questionnaire will allow its use in COPD patients receiving palliative care in Brazil. ACKNOWLEDGMENTS We would like to thank Dr. Jared Randall Curtis and his team for giving us permission to translate the QOC to Portuguese and adapt it for use in Brazil. We would also like to thank all of the patients who agreed to participate in the present study.

REFERENCES 1. Grosseman S, Stoll C. O Ensino-aprendizagem da relação médicopaciente: estudo de caso com estudantes do último semestre do curso de medicina. Rev Bras Educ Med. 2008;32(3):301-8. https:// doi.org/10.1590/S0100-55022008000300004 2. Zill JM, Christalle E, Müller E, Härter M, Dirmaier J, Sholl I. Measurement of physician-patient communication--a systematic review. PLoS One. 2014;9(12): e112637. https://doi.org/10.1371/ journal.pone.0112637 3. Claramita M, Utarini A, Soebono H, Van Dalen J, Van der Vleuten C. Doctor-patient communication in a Southeast Asian setting: the conflict between ideal and reality. Adv Health Sci Educ Theory Pract. 2011;16(1):69-80. https://doi.org/10.1007/s10459-010-9242-7 4. Ting X, Yong B, Yin L, Mi T. Patient perception and the barriers to practicing patient-centered communication: A survey and in-depth interview of Chinese patients and physicians. Patient Educ Couns. 2016;99(3):384-69. https://doi.org/10.1016/j.pec.2015.07.019 5. Simpson M, Buckman R, Stewart M, Maguire P, Lipkin M, Novack D, et al. Doctor-patient communication: the Toronto consensus statement. BMJ. 1991;303(6814):1385-7. https://doi.org/10.1136/ bmj.303.6814.1385 6. Moritz RD, Lago PM, Souza RP, Silva NB, Meneses FA, Othero JC, et al. End of life and palliative care in intensive care unit. Rev Bras Ter Intensiva. 2008;20(4):422-8. https://doi.org/10.1590/S0103507X2008000400016 7. Moritz RD. How to improve the communication and to prevent the conflicts at terminality situations in Intensive Care Unit [Article in Portuguese]. Rev Bras Ter Intensiva. 2007;19(4):485-9. 8. Zandbelt LC, Smets EM, Oort FJ, Godfried MH, de Haes HC. Medical specialist’s patient-centered communication and patient-reported outcomes. Med Care. 2007;45(4):330-9. https://doi.org/10.1097/01. mlr.0000250482.07970.5f 9. Curtis JR, Ciechanowski PS, Downey L, Gold J, Nielsen EL, Shannon SE, et al. Development and evaluation of an interprofessional communication intervention to improve family outcomes in the ICU. Contemp Clin Trials. 2012;33(6):1245-54. https://doi.org/10.1016/j. cct.2012.06.010 10. Visser M, Deliens L, Houttekier D. Physician-related barriers to communication and patient- and family-centred decision-making towards the end of life in intensive care: a systematic review. Crit Care. 2014;18(6):604. https://doi.org/10.1186/s13054-014-0604-z 11. Buecken R, Galushko M, Golla H, Strupp J, Hahn M, Ernstmann N, et al. Patients feeling severely affected by multiple sclerosis: how do patients want to communicate about end-of-life issues? Patient Educ Couns. 2012;88(2):318-24. https://doi.org/10.1016/j.pec.2012.03.010 12. De Morgan S, Redman S, D’Este C, Rogers K. Knowledge, satisfaction with information, decisional conflict and psychological morbidity amongst women diagnosed with ductal carcinoma in situ (DCIS). Patient Educ Couns. 2011;84(1):62-8. https://doi. org/10.1016/j.pec.2010.07.002 13. CoBaTrICE Collaboration. The views of patients and relatives of what makes a good intensivist: a European survey. Intensive Care Med. 2007;33(11):1913-20. https://doi.org/10.1007/s00134-007-0799-4 14. Rennó CS, Campos CJ. Comunicação interpessoal: valorização pelo paciente oncológico em uma unidade de alta complexidade em oncologia. Rev Mineira Enferm. 2014;18(1):106-15. http://www. dx.doi.org/10.5935/1415-2762.20140009 15. Rodrigues MV, Ferreira ED, Menezes TM. Comunicação da enfermeira com pacientes portadores de câncer fora de possibilidade

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de cura. Rev Enferm UERJ. 2010;18(1):86-91. 16. de Araújo MM, da Silva MJ. Communication with patients in palliative care: favoring cheerfulness and optimism [Article in Portuguese]. Rev Esc Enferm USP. 2007;41(4):668-74. 17. Razera AP, Braga EM. The importance of communication during the postoperative recovery period. Rev Esc Enferm USP. 2011;45(3):6305. 18. Santos MF, Bassit DP. End of life in intensive care: family members’ acceptance of orthotanasia. Rev Bras Ter Intensiva. 2011;23(4):44854. https://doi.org/10.1590/S0103-507X2011000400009 19. Curtis JR, Patrick DL. Barriers to communication about end-of-life care in AIDS patients. J Gen Intern Med. 1997;12(12):736-41. https:// doi.org/10.1046/j.1525-1497.1997.07158.x 20. Curtis JR, Patrick DL, Caldwell E, Greenlee H, Collier AC. The quality of patient-doctor communication about end-of-life care: a study of patients with advanced AIDS and their primary care clinicians. AIDS. 1999;13(9):1123-31. https://doi.org/10.1097/00002030-19990618000017 21. Curtis JR, Wenrich MD, Carline JD, Shannon SE, Ambrozy DM, Ramsey PG. Patients’ perspectives on physician skill in end-of-life care: differences between patients with COPD, cancer, and AIDS. Chest. 2002;122(1):356-62. https://doi.org/10.1378/chest.122.1.356 22. Engelberg R, Downey L, Curtis JR. Psychometric characteristics of a quality of communication questionnaire assessing communication about end-of-life care. J Palliative Med. 2006;9(5):1086-98. https:// doi.org/10.1089/jpm.2006.9.1086 23. Slatore CG, Cecere LM, Reinke LF, Ganzini L, Udris EM, Moss BR, et al. Patient-clinician communication: associations with important health outcomes among veterans with COPD. Chest. 2010;138(3):628-34. https://doi.org/10.1378/chest.09-2328 24. Dickson RP, Engelberg RA, Back AL, Ford DW, Curtis JR. Internal medicine trainee self-assessments of end-of-life communication skills do not predict assessments of patients, families, or clinicianevaluators. J Palliat Med. 2012;15(4):418-26. https://doi.org/10.1089/ jpm.2011.0386 25. Smith-Howell ER, Hickman SE, Meghani SH, Perkins SM, Rawl SM. End-of-Life Decision Making and Communication of Bereaved Family Members of African Americans with Serious Illness. J Palliat Med. 2016;19(2):174-82. https://doi.org/10.1089/jpm.2015.0314 26. Abdul-Razzak A, Sherifali D, You J, Simon J, Brazil K. ‘Talk to me’: a mixed methods study on preferred physician behaviours during endof-life communication from the patient perspective. Health Expect. 2016:19(4):883-96. https://doi.org/10.1111/hex.12384 27. Janssen DJ, Spruit MA, Schols JM, van der Sande FM, Frenken LA, Wouters EF. Insight into advance care planning for patients on dialysis. J Pain Symptom Manage. 2013;45(1):104-13. https://doi. org/10.1016/j.jpainsymman.2012.01.010 28. Houben CH, Spruit MA, Schols JM, Wouters EF, Janssen DJ. Patient-Clinician Communication About End-of-Life Care in Patients With Advanced Chronic Organ Failure During One Year. J Pain Symptom Manage. 2015;49(6):1109-15. https://doi.org/10.1016/j. jpainsymman.2014.12.008 29. 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. https://doi. org/10.1097/00007632-200012150-00014 30. Melo SIL. Coeficiente de atrito: um sistema de avaliação. [thesis]. Santa Maria: Universidade Federal de Santa Maria; 1994.

J Bras Pneumol. 2017;43(5):363-367 http://dx.doi.org/10.1590/S1806-37562016000000339

ORIGINAL ARTICLE

Lung cancer: changes in histology, gender, and age over the last 30 years in Brazil Maria Teresa Ruiz Tsukazan1,2, Álvaro Vigo2, Vinícius Duval da Silva3, Carlos Henrique Barrios4, Jayme de Oliveira Rios1, José Antônio de Figueiredo Pinto1 1. Serviço de Cirurgia Torácica, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. 2. Departamento de Estatística e Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul – UFRGS – Porto Alegre (RS) Brasil. 3. Departamento de Patologia, Hospital Mãe de Deus, Porto Alegre (RS) Brasil. 4. Hospital do Câncer, Hospital Mãe de Deus, Porto Alegre (RS) Brasil. Submitted: 11 November 2016. Accepted: 18 June 2017. Study carried out at the Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil.

ABSTRACT Objective: To describe the trends in tumor histology, gender and age among patients with non-small cell lung cancer (NSCLC) treated with lung resection. The histology of lung cancer has changed in developed countries, and there is still little information available on the topic for developing countries. Methods: This was a retrospective study of 1,030 patients with NSCLC treated with lung resection between 1986 and 2015 at a university hospital in southern Brazil. Differences in histology, stage, and type of surgery were analyzed by gender and for three periods (1986-1995, 1996-2005, and 2006-2015). Results: Most (64.5%) of the patients were males, and the main histological types were squamous cell carcinoma (in 40.6%) and adenocarcinoma (in 44.5%). The mean age at surgery during the first period was 56.4 years for women and 58.9 years for men, compared with 62.2 for women and 64.6 for men in the third period (p < 0.001). The proportion of females increased from 26.6% in the first period to 44.1% in the third. From the first to the third period, the proportion of patients with squamous cell carcinoma decreased from 49.6% to 34.8% overall (p < 0.001), decreasing to an even greater degree (from 38.9% to 23.2%) among men. Among the NSCLC patients in our sample, females with adenocarcinoma accounted for 11.9% in the first period and 24.0% in the third period (p < 0.001). Conclusions: As has been seen in developed countries, the rates of lung cancer in females in southern Brazil have been rising over the last three decades, although they have yet to surpass those observed for males in the region. The incidence of squamous cell carcinoma has decreased in males, approaching adenocarcinoma rates, whereas adenocarcinoma has significantly increased among women. Keywords: Lung neoplasms; Epidemiology; Histology; Adenocarcinoma; Carcinoma, nonsmall-cell lung; Carcinoma, squamous cell.

INTRODUCTION Non-communicable diseases (NCDs) are responsible for more than 67% of deaths worldwide.(1) In Brazil, cancer represents the second leading cause of NCD-related deaths and lung cancer is the leading cause of cancer-related deaths,(2) despite strong anti-smoking policies that reduced the smoking rate by half from 1989 to 2008.(3) According to the World Health Organization, 1.6 million deaths per year are attributable to lung cancer.(4) It is one of the few cancers with a well-known cause—smoking.(1,3-6) The great efforts to reduce smoking and to introduce the use of cigarette filters have changed the epidemiology of lung cancer in developed countries, with an increase in the incidence of adenocarcinoma and a decrease in that of squamous cell carcinoma, as seen in the United States, Europe, and Asia.(7-18) The rising number of women with lung cancer is also notable, as are the changes in their histological profile.(7) Changes in the histological profile of lung cancer in Latin American countries have been poorly described in the literature.(19) Little information regarding lung cancer histology, gender difference, and trends is available for the population of Brazil. This paper aims to describe

and improve understanding of the epidemiology of lung cancer, including histology, gender distribution, patient age, and stage of the disease, in southern Brazil over the last 30 years. METHODS From records on file in the prospective surgery database of the Thoracic Surgery Division of the Hospital São Lucas, in the city of Porto Alegre, Brazil, we selected all patients with primary non-small cell lung cancer who were treated with anatomical resection between 1986 and 2015. We reviewed the pathology reports and charts of 1,062 patients. Thirty-two records were excluded because of missing data related to patient gender, patient age at surgery, type of resection, histology, and staging classification. Therefore, the final sample comprised 1,030 patients. Information about smoking was available in less than 37% of the charts, and that variable was therefore disregarded. All histological diagnoses were made by the same pathology group, and all staging was updated according to the 7th edition of the International Association for the Study of Lung Cancer classification system.(20-22)

Correspondence to:

Maria Teresa Ruiz Tsukazan. Centro Clínico da PUCRS, Avenida Ipiranga, 6690, Conj. 615, CEP 90610-000, Porto Alegre, RS, Brasil. Tel.: 55 51 3336-8190. Fax: 55 51 3339-9040. E-mail: maria.tsukazan@pucrs.br Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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Patients with different clinical characteristics (in terms of histology, stage, and type of surgery) were analyzed by gender and for three different periods (1986-1995, 1996-2005, and 2006-2015). Proportions were compared by Pearson’s chi-square test or Fisher’s exact test. Two-way ANOVA was used in order to compare the mean age of the patients by gender and period. Means were compared by using adjusted least squares means and the Tukey-Kramer test. All analyses were performed using the Statistical Analysis System software, version 9.4 (SAS Institute, Cary, NC, USA), and the level of significance was set at 5%. The study was approved by the Research Ethics Committee of the Hospital São Lucas of the Pontifícia Universidade Católica do Rio Grande do Sul. Because of the retrospective nature of the study, the requirement for consent was waived. RESULTS A total of 1,062 patients underwent lung resection for primary lung cancer at the Hospital São Lucas in the last 30 years, and 1,030 met the criteria for inclusion in this analysis. Of those 1,030 patients, 665 (64.5%)

were male. The overall mean age at surgery was 62.8 years for the men and 60.8 years for the women. Table 1 shows the clinical characteristics of the patients, overall and by gender. Overall, the predominant histological type was adenocarcinoma (44.5%), followed by squamous cell carcinoma (40.6%). The histological types differed by gender (p < 0.001), squamous cell carcinoma being more common in men than in women (with a prevalence of 46.9% and 29.0%, respectively), whereas the opposite was found for adenocarcinoma (which had a prevalence of 40.4% and 51.8% among men and women, respectively). Differences between genders were also observed for the degree of tumor invasion (p < 0.001), lymph node classification (p < 0.023), and staging (p < 0.001), suggesting that the disease was more advanced in the men than in the women (Table 1). According to two-way ANOVA, there was no evidence of an interaction between gender and period, suggesting that the mean age did not differ between men and women in any of the three periods studied (Figure 1). However, regardless of the period, the adjusted least squares mean ages at surgery were 62.4 and 59.7 years for men and women, respectively, approximately

Table 1. Clinical characteristics of the patients, in the sample as a whole and by gender.a

Characteristic Histological type Squamous cell carcinoma Adenocarcinoma Carcinoid tumor Large-cell carcinoma Mucoepidermoid carcinoma Adenosquamous carcinoma Undifferentiated NSCLC Other Degree of tumor invasion T1a T1b T2a T2b T3 T4 Lymph node involvement N0 N1 N2 N3 Stage IA IB IIA IIB IIIA IIIB IV

Total (N = 1,030)

Male (n = 665)

Female (n = 365)

418 (40.6) 458 (44.5) 36 (3.5) 32 (3.1) 7 (0.7) 49 (4.8) 11 (1.0) 19 (1.8)

312 (46.9) 269 (40.4) 15 (2.3) 19 (2.9) 3 (0.4) 31 (4.7) 7 (1.0) 9 (1.4)

106 (29) 189 (51.8) 21 (5.8) 13 (3.6) 4 (1.1) 18 (4.9) 4 (1.1) 10 (2.7)

144 (14) 109 (10.6) 340 (33) 152 (14.8) 237 (23.0) 48 (4.6)

73 (11) 71 (10.7) 191 (28.7) 107 (16.1) 183 (27.5) 40 (6.0)

71 (19.5) 38 (10.4) 149 (40.8) 45 (12.3) 54 (14.8) 8 (2.2)

654 (63.5) 197 (19.1) 174 (16.9) 5 (0.5)

410 (61.6) 145 (21.8) 107 (16.1) 3 (0.5)

244 (66.9) 52 (14.2) 67 (18.4) 2 (0.5)

188 (18.3) 225 (21.8) 147 (14.3) 175 (17.0) 237 (23.0) 21 (2.0) 37 (3.6)

106 (15.9) 124 (18.7) 102 (15.3) 131 (19.7) 157 (23.6) 16 (2.4) 29 (4.4)

82 (22.5) 101 (27.7) 45 (12.3) 44 (12.0) 80 (21.9) 5 (1.4) 8 (2.2)

< 0.001

< 0.023

< 0.001

NSCLC: non-small cell lung cancer. aValues expressed as n (%).

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Tsukazan MTR, Vigo A, Silva VD, Barrios CH, Rios JO, Pinto JAF

2.7 years higher for men (p < 0.001). Similarly, regardless of gender, the adjusted least squares mean ages were 57.7 years for the 1986-1995 period, 62.1 years for the 1996-2005 period, and 63.4 years for the 2006-2015 period, translating to an increase of approximately 5.7 years from the first period to the last (p < 0.001). As can be seen in Table 2, there were significant differences among the three periods in terms of the histological type (p < 0.001), especially for squamous cell carcinoma, the prevalence of which declined from 49.6% in the 1986-1995 period to 43.0% in the 19962005 period and to 34.8% in the 2006-2015 period. However, in those same periods, the prevalence of adenocarcinoma increased from 38.1% to 41.2% and 49.5%, respectively. The most common type of surgery was lobectomy, which was performed in 72.5% of cases in the first period, compared with 83.6% in the third

Adjusted mean age at surgery (year)

68 66 64 62 60 58 56 54 52 1986-1995

1996-2005

The distribution of histological types was determined by gender and period (Figure 2). In the 2006-2015 period, squamous cell carcinoma and adenocarcinoma were the main histological types among men, whereas adenocarcinoma was the predominant histological type among women. Overall, the prevalence of adenocarcinoma increased from 38.1% to 41.2% and 49.5% in the 1986-1995 period, 1996-2005 period, and 2006-2015 period, whereas that of squamous cell carcinoma decreased from 49.6% to 43.0% and 34.8%, respectively. Overall, squamous cell carcinoma was the most common histological type among men, although its prevalence declined from 38.9% in the 1986-1995 period to 23.2% in the 2006-2015 period, being equal to that of adenocarcinoma in the latter. Although the proportion of women with lung cancer was lower than was that of men with lung cancer in all three periods, the prevalence of adenocarcinoma among women seems to be increasing over time. Other histological types were less common in both genders and did not show an apparent trend over the study period.

2006-2015

DISCUSSION

Period Woman

period (p < 0.001). The proportion of cases in which pneumonectomy was performed trended down, from 19.7% in the first period to 9.7% in the third period, as did that in which bilobectomy was performed, from 7.8% in the first period to 4.1% in the third period. There was also a significant difference among the periods in terms of the staging (p < 0.001), with an increase in the proportion of cases classified as stage I.

Men

Figure 1. Adjusted mean age at surgery, by gender.

In southern Brazil, the characteristics of lung cancer have changed over the past 30 years. The increase

Table 2. Clinical characteristics of the patients, by period.a

Characteristic

Histological type Squamous cell carcinoma Adenocarcinoma Carcinoid tumor Large-cell carcinoma Other NSCLC Type of surgery Lobectomy Segmentectomy Bilobectomy Pneumonectomy Stage IA IB IIA IIB IIIA IIIB IV

1986-1995 (n = 244)

Period 1996-2005 (n = 291)

2006-2015 (n = 495)

121 (49.6) 93 (38.1) 9 (3.7) 6 (2.5) 15 (6.1)

125 (43.0) 120 (41.2) 2 (0.7) 12 (4.1) 32 (11.0)

172 (34.8) 245 (49.5) 25 (5.0) 14 (2.8) 39 (7.9)

177 (72.5) 0 19 (7.8) 48 (19.7)

229 (78.7) 0 16 (5.5) 46 (15.8)

414 (83.6) 13 (2.6) 20 (4.1) 48 (9.7)

33 (13.5) 57 (23.4) 38 (15.6) 51 (20.9) 55 (22.5) 8 (3.3) 2 (0.8)

44 (15.1) 46 (15.8) 39 (13.4) 56 (19.2) 84 (28.9) 8 (2.8) 14 (5.0)

111 (22.4) 122 (24.7) 70 (14.1) 68 (13.8) 98 (19.8) 5 (1.0) 21 (4.2)

< 0.001

NSCLC: non-small cell lung cancer. aValues expressed as n (%). J Bras Pneumol. 2017;43(5):363-367

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The significant decrease in pneumonectomy rates observed in the present study reflects changes in surgical management techniques and treatment indications. The decrease in the incidence of squamous cell carcinoma is directly related to a lower prevalence of central lesions requiring pneumonectomy.(23) In addition, the use of sleeve resection allows part of the lung to be spared.

% of histological type

60 50 40 30 20 10 0 1986-1995

1996-2005

2006-2015

Period Squamous cell (W)

Squamous cell (M)

Adenocarcinoma (W)

Adenocarcinoma (M)

Figure 2. Histological type, by period and gender. W: women; M: men.

in the mean age at surgery could be indicative of the aging of the lung cancer patient population, not only at diagnosis but also eligible patients for surgical treatment. Other chronic diseases are now better controlled, leading to an increase in life expectancy and allowing enough time for lung cancer to develop. When compared with that reported for developed nations, the mean patient age at surgery was rather low in the present study, even if we consider only the most recent period, when the mean age was 62.8 years, compared with the 71 years reported for the United States in the Surveillance, Epidemiology and End Results data for the 2004-2008 period.(23) As has been seen in developed countries, our data indicate that the rates of lung cancer in females have risen over the last three decades but have yet to surpass those observed for males. That could be related to the fact that, in historical terms, women took up the practice of smoking later than did men, as well as being related to the latency period. Women started smoking in the 1950s and 1960s, which was also when filters began to be added to cigarettes because of the link found between lung cancer and smoking. During that same period, the tar content was also a concern and the tobacco industry was forced to reduce the levels of tar in cigarettes. Those factors could explain the higher incidence of adenocarcinoma in women. (9,13,24)

The observed increase in the incidence of adenocarcinoma and decrease in that of the squamous cell subtype are in accordance with findings reported for developed countries, such as the United States, Japan, and western European countries.(9,13,24) In contrast, a study performed in northern India showed no changes in the histology of lung cancer over the past three decades.(25) The diagnosis of adenocarcinoma is currently extremely important, because it is more frequently associated with particular molecular abnormalities (epidermal growth factor receptor mutations and anaplastic lymphoma kinase fusions), and international guidelines recommend routine testing of adenocarcinoma patients. Current practice requires having the necessary information available in order to make the most appropriate therapeutic recommendation. 366

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The observed decrease in the incidence of squamous cell lung cancer in Brazil is believed to be attributable to the decline in the number of smokers since 1960, as well as to the increased availability of low-tar and filter-tipped cigarettes, as also occurred in developed countries.(8) That is probably due to the inability of filters to eliminate small particles and to the fact that the smoker tends to increase the time inhaling in order to compensate for the smaller amount of smoke passing through the filter. The immediate consequence is greater deposition of the smaller carcinogens in the periphery, the most common site for adenocarcinoma.(8,9) The reported increase in the incidence of adenocarcinoma only among smokers supports that theory. In addition, one multicenter study demonstrated that smokers of filter-tipped cigarettes are at a lower risk of developing squamous cell carcinoma than are smokers of unfiltered cigarettes, although the risk for adenocarcinoma did not differ between the two groups.(13) It is well known that observational analyses based on clinical data have methodological limitations,(26) such as the lack of information regarding smoking status or other important clinical variables. Nevertheless, we believe that our findings are relevant. They provide a description of the histological profile of lung cancer in one state in southern Brazil, which has had a higher incidence of lung cancer over the last 30 years than has any other state in the country. Whether or not our results can be generalized to other states in Brazil is a subject for further research. One strength of our study is that all of the slides were analyzed by the same pathology group, according to the most recent staging classification system, and that the surgical team remained uniform throughout the study period. In summary, there were significant changes in the epidemiology of lung cancer in southern Brazil over the past three decades. The incidence of lung cancer among women in the region has increased. Adenocarcinoma has become the most common histological type, especially among women, and the mean age of patients eligible for lung cancer resection has increased for both genders. ACKNOWLEDGMENTS The authors want to thank the Hospital SĂŁo Lucas of the PontifĂcia Universidade CatĂłlica do Rio Grande do Sul, especially the Pathology Department, and the Universidade Federal do Rio Grande do Sul, for providing access to information and for supporting this project.

Tsukazan MTR, Vigo A, Silva VD, Barrios CH, Rios JO, Pinto JAF

REFERENCES 1. World Health Organization [homepage on the Internet]. Geneva: WHO; c2016 [cited 2017 Apr 9]. Global status report on noncommunicable diseases 2014 [about 2 screens]. Available from: http://www.who.int/nmh/publications/ncd-status-report-2014/en/ 2. Schmidt MI, Duncan BB, Azevedo e Silva GA, Menezes AM, Monteiro CA, Barreto SM, et al. Chronic non-communicable diseases in Brazil: burden and current challenges. Lancet. 2011;377(9781):1949-61. https://doi.org/10.1016/S0140-6736(11)60135-9 3. Levy D, de Almeida LM, Szklo A. The Brazil SimSmoke policy simulation model: the effect of strong tobacco control policies on smoking prevalence and smoking-attributable deaths in a middle income nation. PLoS Med. 2012;9(11):e1001336. https://doi. org/10.1371/journal.pmed.1001336 4. World Health Organization; International Agency for Research on Cancer (IARC) [homepage on the Internet]. Lyon: IARC; c2016 [cited 2017 Apr 9]. World Cancer Report 2014 [about 2 screens]. Available from: http://publications.iarc.fr/Non-Series-Publications/WorldCancer-Reports/World-Cancer-Report-2014 5. Shopland DR, Eyre HJ, Pechacek TF. Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States? J Natl Cancer Inst. 1991;83(16):1142-8. https://doi.org/10.1093/jnci/83.16.1142 6. Osann KE. Epidemiology of lung cancer. Curr Opin Pulm Med. 1998;4(4):198-204. https://doi.org/10.1097/00063198-19980700000002 7. Chen K, Wang PP, Sun B, Li Q, Perruccio A, Power D, et al. Twentyyear secular changes in sex specific lung cancer incidence rates in an urban Chinese population. Lung Cancer. 2006;51(1):13-9. https://doi. org/10.1016/j.lungcan.2005.08.013 8. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol. 2005;23(14):3175-85. https://doi. org/10.1200/JCO.2005.10.462 9. Janssen-Heijnen ML, Coebergh JW. Trends in incidence and prognosis of the histological subtypes of lung cancer in North America, Australia, New Zealand and Europe. Lung Cancer. 2001;31(2-3):12337. https://doi.org/10.1016/S0169-5002(00)00197-5 10. Charloux A, Quoix E, Wolkove N, Small D, Pauli G, Kreisman H. The increasing incidence of lung adenocarcinoma: reality or artefact? A review of the epidemiology of lung adenocarcinoma. Int J Epidemiol. 1997;26(1):14-23. https://doi.org/10.1093/ije/26.1.14 11. Janssen-Heijnen ML, Coebergh JW. The changing epidemiology of lung cancer in Europe. Lung Cancer. 2003;41(3):245-58. https://doi. org/10.1016/S0169-5002(03)00230-7 12. Chang JW, Asamura H, Kawachi R, Watanabe S. Gender difference in survival of resected non-small cell lung cancer: histology-related

phenomenon? J Thorac Cardiovasc Surg. 2009;137(4):807-12. https://doi.org/10.1016/j.jtcvs.2008.09.026 13. Patel JD. Lung cancer in women. J Clin Oncol. 2005;23(14):3212-8. https://doi.org/10.1200/JCO.2005.11.486 14. Tan YK, Wee TC, Koh WP, Wang YT, Eng P, Tan WC, et al. Survival among Chinese women with lung cancer in Singapore: a comparison by stage, histology and smoking status. Lung Cancer. 2003;40(3):23746. https://doi.org/10.1016/S0169-5002(03)00038-2 15. Rivera MP, Stover DE. Gender and lung cancer. Clin Chest Med. 2004;25(2):391-400. https://doi.org/10.1016/j.ccm.2004.01.006 16. Xie L, Ugnat AM, Morriss J, Semenciw R, Mao Y. Histology-related variation in the treatment and survival of patients with lung carcinoma in Canada. Lung Cancer. 2003;42(2):127-39. https://doi.org/10.1016/ S0169-5002(03)00283-6 17. Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of nonsmall cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer. 2007;57(3):253-60. https://doi. org/10.1016/j.lungcan.2007.03.012 18. Caldarella A, Crocetti E, Comin CE, Janni A, Pegna AL, Paci E. Gender differences in non-small cell lung cancer: a population-based study. Eur J Surg Oncol. 2007;33(6):763-8. https://doi.org/10.1016/j. ejso.2007.01.001 19. Novaes FT, Cataneo DC, Ruiz Junior RL, Defaveri J, Michelin OC, Cataneo AJ. Lung cancer: histology, staging, treatment and survival. J Bras Pneumol. 2008;34(8):595-600. https://doi.org/10.1590/S180637132008000800009 20. Goldstraw P. New TNM classification: achievements and hurdles. Transl Lung Cancer Res. 2013;2(4):264-72. 21. Goldstraw P. Updated staging system for lung cancer. Surg Oncol Clin N Am. 2011;20(4):655-66. https://doi.org/10.1016/j.soc.2011.07.005 22. Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32(4):66992. https://doi.org/10.1016/j.ccm.2011.08.005 23. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32(4):605-44. https:// doi.org/10.1016/j.ccm.2011.09.001 24. Hammond EC, Selikoff IJ, Lawther PL, Seidman H. Inhalation of benzpyrene and cancer in man. Ann N Y Acad Sci. 1976;271:116-24. https://doi.org/10.1111/j.1749-6632.1976.tb23100.x 25. Schottenfeld D. The etiology and epidemiology of lung cancer. In: Pass HI, Carbone DP, Johnson DH, Minna JD, Scagliotti GV, Turrisi AT, editors. Principles and Practice of Lung Cancer. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. p.3-22. 26. Overhage JM, Overhage LM. Sensible use of observational clinical data. Stat Methods Med Res. 2013;22(1):7-13. https://doi. org/10.1177/0962280211403598

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ORIGINAL ARTICLE

Epidemiological trends of allergic diseases in adolescents Silvia de Souza Campos Fernandes1, Cláudia Ribeiro de Andrade1, Cristina Gonçalves Alvim1, Paulo Augusto Moreira Camargos1, Cássio da Cunha Ibiapina1 1. Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte (MG) Brasil. Submitted: 21 August 2016. Accepted: 4 May 2017. Study carried out in the Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte (MG) Brasil.

ABSTRACT Objective: To assess the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in adolescents in the city of Belo Horizonte, Brazil, in 2012 by administering the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, as well as to compare the observed prevalences with those found in studies performed 10 years earlier and employing the same methodology used here. Methods: This was a cross-sectional study conducted between May and December of 2012 and involving adolescents in the 13- to 14-year age bracket. Participants were randomly selected from among adolescents studying at public schools in Belo Horizonte and completed the ISAAC questionnaire. Proportions were calculated in order to assess the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in the sample as a whole, and the chi-square goodness-of-fit test was used in order to compare the prevalences observed in 2012 with those found in 2002. Results: The prevalences of symptoms of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in 2012 were 19.8%, 35.3%, and 16.3%, respectively, being significantly higher than those found in 2002 (asthma, p = 0.006; allergic rhinitis, p < 0.01; and allergic rhinoconjunctivitis, p = 0.002). Conclusions: The prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis among adolescents in 2012 were found to be high, having increased in comparison with those found 10 years earlier, despite efforts in prevention, diagnosis, and treatment. Keywords: Asthma; Rhinitis, allergic; Prevalence; Adolescent.

INTRODUCTION Allergic diseases are common in children and adolescents and result in high costs to the health care system, school absenteeism (in the case of the children and adolescents), and work absenteeism (in the case of their parents), as well as having a negative impact on the quality of life of those affected.(1,2) Despite advances in the understanding of the pathophysiology of allergic diseases and the increasing number of treatment options, a relationship has been established between an increased prevalence of allergic diseases and an interaction between genetic and environmental factors, the latter being the major determinants of this increase.(3,4) Epidemiological studies investigating the aforementioned factors have estimated the global and regional prevalences of and risk factors for allergic diseases. One such study is the International Study of Asthma and Allergies in Childhood (ISAAC), aimed at assessing the prevalence and severity of asthma and allergic diseases in children and adolescents in different parts of the world by means of a standardized method(5) and monitoring them over time. The prevalence of allergic diseases is higher in Brazil than in other countries in Latin America and the world. The mean prevalence of asthma-related symptoms in Brazil is 20%, varying across regions. The results of phase III of the ISAAC in Brazil revealed asthma prevalence

rates of 11.8-30.5%; in the city of Belo Horizonte, the prevalence of asthma was 17.8%, which is similar to that found in other Brazilian capitals.(6,7) In a recent study evaluating the prevalence trends of allergic respiratory diseases over a 9-year interval between distinct phases of the ISAAC in seven Brazilian cities, the prevalences of asthma, allergic rhinitis, and atopic dermatitis were found to be variable. Although the prevalences of allergic rhinitis, eczema, and severe asthma increased, the prevalence of active asthma decreased.(8) The objective of the present study was to assess the prevalences of allergic diseases (asthma, allergic rhinitis, and allergic rhinoconjunctivitis) in adolescents in Belo Horizonte in 2012 by administering the ISAAC questionnaire, as well as to compare our findings with the results of studies conducted 10 years earlier(6,7) and employing the same methodology used here. METHODS This was a cross-sectional study involving adolescent public school students in Belo Horizonte and conducted between May and December of 2012 with the use of the ISAAC questionnaire, which assesses the prevalence and severity of symptoms of asthma and allergic rhinitis.(5) According to the ISAAC protocol, the study population should comprise at least 3,000 students in the 13- to

Correspondence to: Cássio da Cunha Ibiapina. Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Avenida Professor Alfredo Balena, 190, Sala 267, CEP 30130-100, Belo Horizonte, MG, Brasil. Tel.: 55 31 3409-9772. E-mail: cassioibiapina@terra.com.br Financial support: None.

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14-year age bracket, randomly selected from at least 14 schools. The Belo Horizonte Municipal Department of Education provided a list of public schools, including the number of students per school and the school year; in accordance with the ISAAC protocol, only schools in which there were at least 200 students in the aforementioned age bracket were considered for participant recruitment. The schools were randomly selected from a list that was randomly generated in the program Epi Info, version 6.04. Students in the 13- to 14-year age bracket and enrolled in the selected schools were included in the study. The aforementioned age bracket was selected because most such adolescents attend school. This increases the number of respondents and therefore facilitates data collection. In order to assess the prevalence of symptoms of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in the study population, we used a questionnaire that has been translated to Portuguese and validated for use in Brazil by Solé et al.(9) Chart 1 shows the questions aimed at determining the prevalence of symptoms of asthma, allergic rhinitis, and allergic rhinoconjunctivitis. The questions regarding “the last 12 months” were aimed at limiting the time between the presence or absence of symptoms and the administration of the questionnaire, thus reducing recall bias and increasing the sensitivity and specificity of the questions.(5) In addition, the seasonal distribution of symptoms of asthma, allergic rhinitis, and allergic rhinoconjunctivitis can be controlled for by limiting the data collection period to 12 months. The question “have you ever had asthma?” was included in order to determine whether or not participants had ever been diagnosed with asthma. At the selected schools, the questionnaire was administered to all eighth and ninth graders in the 13- to 14-year age bracket. Each school was visited at least twice in order to avoid losses resulting from school absenteeism. The questionnaire was completed by the adolescents themselves in the classroom, under the supervision of one of the researchers, who had been trained and instructed not to interfere with the process. Data analysis was performed with the Statistical Package for the Social Sciences, version 14.0 (SPSS Inc., Chicago, IL, USA). Proportions were calculated in order to assess the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in the sample as a whole. The chi-square goodness-of-fit test, which is used in order to test whether the observed frequency distribution fits a specific distribution, was used in order to compare the prevalences of the

aforementioned allergic diseases in 2012 with those found in 2002 (in studies conducted in the same city by practically the same group of researchers using the same methodology used here).(6,7) The study project was approved by the Research Ethics Committee of the Federal University of Minas Gerais (on August 31, 2011; Protocol no. 237) and by the Belo Horizonte Municipal Department of Education. After permission was granted by all 14 school boards, written informed consent was obtained from all participating adolescents and their parents or legal guardians. RESULTS The study sample consisted of 3,325 adolescents, 1,825 (54.9%) of whom were 13 years old. Most of the participants were female (n = 1,858; 56.1%). The prevalence of asthma symptoms in the sample as a whole was 19.8% (651/3,282). There was a statistically significant difference between genders regarding the prevalence of asthma (p = 0.014), which was 21.4% (391/1,827) and 18.0% (259/1,442) in females and males, respectively. The prevalence of allergic rhinitis symptoms was 35.3% (1,140/3,225). The prevalence of allergic rhinitis symptoms was higher among females (40.8%; 738/1,810) than among males (28.4%; 398/1,403), the difference being significant (p < 0.001). The prevalence of symptoms of allergic rhinoconjunctivitis was 16.3%. The prevalence of symptoms of allergic rhinoconjunctivitis was higher among females (19.3%) than among males (12.5%), the difference being significant (p < 0.001). In order to compare the prevalences observed in 2012 with those found in 2002, we used the results of previously published studies showing data for 2002(6,7): among 3,088 adolescents in the 13- to 14-year age bracket, the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis were 17.8%, 26.1%, and 14.5%, respectively (Table 1). After statistical sample adjustment, the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis were found to have been significantly higher in 2012 than in 2002. DISCUSSION The present study showed high prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis among adolescents in Belo Horizonte in 2012. These results are consistent with those obtained in several other cities in

Chart 1. Questions regarding the prevalence of symptoms of asthma, allergic rhinitis, and allergic rhinoconjunctivitis.a

Question “Have you had wheezing or whistling in the chest in the past 12 months?” “In the past 12 months, have you had a problem with sneezing, or a runny, or blocked nose when you DID NOT have a cold or the flu?” “In the past 12 months, has this nose problem been accompanied by itchy-watery eyes?”

Disease Asthma Allergic rhinitis Allergic rhinoconjunctivitis

Based on Solé et al.(9)

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Table 1. Prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis in the general populations in the city of Belo Horizonte, Brazil, by year in which the questionnaire was administered.a

Prevalence Asthma Allergic rhinitis Allergic rhinoconjunctivitis Asthma diagnosis (“Have you ever had asthma?”)

Year 2002 550 (17.8) [16.5-19.1] 806 (26.1) [24.6-27.6] 448 (14.5) [13.3-15.7] 303 (9.8) [8.8-10.9]

2012 641 (19.8) [18.4-21.2] 1.103 (35.3) [33.7-36.9] 505 (16.3) [5.0-17.6] 572 (17.6) [16.3-18.9]

p 0.006 < 0.001 0.002 < 0.001

Values expressed as n (%) [95% CI].

Brazil and the world.(6,10) The prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis were found to have significantly increased over the course of 10 years—from 17.8% in 2002 to 19.8% in 2012; from 26.1% in 2002 to 35.3% in 2012; and from 14.5% in 2002 to 16.3% in 2012, respectively—suggesting that allergic diseases are on the rise in Belo Horizonte and other large Brazilian cities.(11) Despite evidence of increased prevalences of asthma and allergic diseases in developed countries, little is known about the trends in the prevalences of these diseases in developing countries.(12-15) In a study conducted in Brazil and comparing phases I and III of the ISAAC in terms of the prevalences of asthma and allergic diseases in adolescents in Brazil, the mean prevalence of wheezing in the last 12 months was found to have decreased, from 27.7% in phase I to 19.9% in phase III (p < 0.01). However, an analysis of the prevalence of asthma-related symptoms in each of the five centers participating in phases I and III of the ISAAC revealed differences in the magnitude and direction of the changes in prevalence, with no uniform trend for an increase. The results for symptoms of rhinitis and atopic dermatitis were similar to those for asthma symptoms.(16) Recent studies conducted in other cities in Brazil and employing the same methodology used here have shown the same trend as that observed in Belo Horizonte; that is, the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis are still high. In the city of Fortaleza, the prevalences of asthma, allergic rhinitis, and allergic rhinoconjunctivitis were 22.6%, 43.2%, and 18.7%, respectively; in the city of Londrina, they were 22.0%, 27.3%, and 13.6%, respectively; and in the city of Taubaté, they were 15.3%, 36.6%, and 17.7%, respectively.(17-19) It is of note that the aforementioned cities are located in very different geographic regions of Brazil. In a recently published study of allergic respiratory diseases in Brazil,(8) the objective of which was to assess the trends in the prevalence of allergic respiratory diseases in the 9-year interval between distinct phases of the ISAAC, the overall prevalences of asthma, allergic rhinitis, and atopic dermatitis were found to be variable, being high (particularly those of asthma and atopic dermatitis) in areas near the equator. In Belo Horizonte, annual percent changes in the prevalences of wheezing in the last 12 months, asthma diagnosis, and nasal symptoms in the last 12 months were 21%, 370

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83%, and 89%, respectively. According to the authors of that study, this might be due to environmental pollution.(8) In a recently published study conducted in the United Kingdom(20) and employing the ISAAC questionnaire to compare the prevalences of allergic rhinitis and asthma between two cohorts approximately 12 years apart, the prevalence of rhinitis was found to have increased, from 22.6% to 28.1% (p = 0.004), whereas the prevalence of asthma was found to have decreased, from 18.9% to 15.0% (p = 0.02). The authors hypothesized that the aforementioned findings were due to changes in the prevalence of aeroallergen sensitization and to cigarette smoke exposure.(20) For comparative epidemiological studies, questionnaires previously adapted and validated for use in the country where they are to be administered constitute the ideal tools because they are simple, easily applicable, and inexpensive, as well as having good acceptability, having good reproducibility, and allowing comparisons within and between populations. (21) Therefore, the ISAAC questionnaire is a valid method for understanding variations in the prevalence of asthma and allergic diseases; however, it is subject to criticism. The main concern when conducting questionnairebased studies is whether the study population is able to understand the questions and provide appropriate responses.(5) Therefore, because the perception that adolescents have of their own symptoms is better than the perception that parents have of the symptoms of their younger children (preschoolers, for example), adolescents constitute an age group in which the use of questionnaires is an appropriate method for assessing disease trends. According to the literature, the fact that the prevalence of allergic diseases is higher in adolescents than in younger children might be due to an actual increase in the prevalence of symptoms during adolescence.(22) With regard to the use of the phrase “presence of wheezing in the last 12 months” in order to assess the prevalence of asthma symptoms, it should be noted that some studies have included the term “bronchitis”, which resulted in an increase in the reported prevalence of asthma symptoms. In Brazil, the fact that asthma is commonly referred to as “bronchitis” and that the two terms are mistakenly used as synonyms by physicians themselves makes it difficult to establish an accurate diagnosis of asthma.(21,23) In a study conducted in the city of São Luís, different prevalences were found for ISAAC questionnaire items “wheezing in the last 12 months” (12.7%) and “asthma/bronchitis ever”(19.1%). (24) In

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the present study, similar prevalences were found for ISAAC questionnaire items “wheezing in the last 12 months” (19.8%) and “have you ever had asthma?” (17.6%), allowing us to infer that, on the basis of data from a study conducted 10 years earlier, the prevalence of asthma diagnosis is on the rise. It is possible that the results of the present study were influenced by the fact that health professionals and the population have gained a deeper understanding of asthma over this period. The prevalences of asthma and allergic diseases have varied widely across phases of the ISAAC, and environmental and lifestyle factors, including socioeconomic status, exposure to allergens, active and passive smoking, eating habits, and early exposure to infections, have been reported to play a major role in the observed differences,(25-27) providing an excellent opportunity for prevention. In Belo Horizonte, the reported prevalence of smoking in individuals in the 15- to 24-year age bracket in 2002 and 2003 was 11.7% (95% CI: 9.1-14.4%).(28) The 2012 Brazilian National School Health Survey(29) evaluated adolescents in 26 Brazilian capitals and the Federal District of Brasília and showed that the prevalence of smoking was 6.1% (95% CI: 5.6-6.6%). However, no data were found on Belo Horizonte alone in order to make a temporal comparison. Nevertheless, the prevalence of smoking in Belo Horizonte has probably decreased, given the national trend toward reduced smoking as a result of antismoking public policies. Therefore, although the design of the present study precludes an analysis of the relationship between smoking and an increased prevalence of allergic diseases, such a relationship seems unlikely in the study population. The observed changes in the prevalences of asthma and allergic rhinitis in Belo Horizonte might be due to an increased prevalence of obesity and overweight and reduced air quality in the city in recent years. In Belo Horizonte, the prevalences of obesity and overweight in 2006 were 3.1% and 8.4%, respectively.(30) On the basis of the findings of a study conducted 5 years earlier by the same research group using the same methodology, the authors found that there was a 13% increase in the prevalences of obesity and overweight in Belo Horizonte.(30) In Belo Horizonte, as in other large cities, air pollutant emissions have increased as a result of a significant and uncontrolled increase in the number of motor vehicles in recent years. However, there are currently no data

correlating increased air pollutant emissions with the prevalences of the diseases investigated in the present study. Environmental monitoring of air pollutants in the greater metropolitan area of Belo Horizonte has shown that, during the winter and spring months, air pollutant levels exceed the limits established by law.(31) The impact of fossil fuel pollution has been shown in a recently published study in which the ISAAC questionnaire was administered to 1,039 adolescents in the 13- to 14-year age bracket enrolled in public or private schools in the city of Taubaté; the study showed that approximately 20% of those living near Presidente Dutra Highway (a heavily traveled highway) had symptoms of asthma and allergic rhinitis, which were absent in 85% of those living far from Presidente Dutra Highway.(32) The impact of genetic factors was not investigated in the present study, because the interval between the two evaluation time points was short. In a recent study conducted in Thailand and employing the ISAAC questionnaire, the prevalence of asthma and allergic rhinitis in combination was 52.7%, directly and significantly affecting the quality of life of Thai adolescents.(33) In contrast, in the city of Aracaju, Brazil, the prevalence of asthma was found to be lower in 2012 than in 2003 (12.8% vs. 18.7%; p < 0.001).(34) This was due to improved quality of life and increased investment in public health policies (as evidenced by increased proportions of schools and Family Health Program teams), as well as to better education resulting in improved health indicators, such as reduced smoking.(34) We believe that the present study contributes to improving the prevention and treatment of allergic respiratory diseases. Government efforts to provide effective public policies and access to asthma treatment can contribute to reducing asthma morbidity and mortality, given that there is currently no nationwide asthma management program aimed at controlling the disease in Brazil.(35) In conclusion, the present study showed high rates of asthma, allergic rhinitis, and allergic rhinoconjunctivitis among adolescents living in Belo Horizonte, as well as showing that, despite public sector efforts to prevent and treat the aforementioned diseases, their prevalences increased significantly over a 10-year period. For effective prevention, further studies are needed in order to determine the causes of increased prevalences of allergic diseases in Belo Horizonte.

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4. Casagrande RR, Pastorino AC, Souza RG, Leone C, Solé D, Jacob CM. Asthma prevalence and risk factors in schoolchildren of the city of São Paulo, Brazil [Article in Portuguese]. Rev Saude Publica. 2008;42(3):517-23. https://doi.org/10.1590/S003489102008000300018 5. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995;8(3):483-91. https://doi.or g/10.1183/09031936.95.08030483 6. Solé D, Wandalsen GF, Camelo-Nunes IC, Naspitz CK; ISAAC J Bras Pneumol. 2017;43(5):368-372

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Brazilian Group. Prevalence of symptoms of asthma, rhinitis, and atopic eczema among Brazilian children and adolescents identified by the International Study of Asthma and Allergies in Childhood (ISAAC) - Phase 3. J Pediatr (Rio J). 2006;82(5):341-6. https://doi.org/10.1590/ S0021-75572006000600006 7. Alvim CG, Fonseca MM, Freire MM, Andrade LC, Fontes MJ, Camargos PA, et al. Prevalence and severity of asthma in adolescents of Belo Horizonte [Article in Portuguese]. Rev Med Minas Gerais. 2009;19(4):304-7. 8. Solé D, Rosário Filho NA, Sarinho ES, Camelo-Nunes IC, Barreto BA, Medeiros ML, et al. Prevalence of asthma and allergic diseases in adolescents: nine-year follow-up study (2003-2012).J Pediatr (Rio J). 2015;91(1):30-5. https://doi.org/10.1016/j.jped.2014.05.002 9. Solé D, Vanna AT, Yamada E, Rizzo MC, Naspitz CK. International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire: validation of the asthma component among Brazilian children. J Investig Allergol Clin Immunol. 1998;8(6):376-82. 10. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351(9111):1225-32. https://doi. org/10.1016/S0140-6736(97)07302-9 11. Barreto ML, Ribeiro-Silva Rde C, Malta DC, Oliveira-Campos M, Andreazzi MA, Cruz AA. Prevalence of asthma symptoms among adolescents in Brazil: National Adolescent School-based Health Survey (PeNSE 2012). Rev Bras Epidemiol. 2014;17 Suppl 1:106-15. https://doi.org/10.1590/1809-4503201400050009 12. Barraza Villarreal A, Sanín Aguirre LH, Téllez Rojo MM, Lacasaña Navarro M, Romieu I. Risk factors for asthma in school children from Ciudad Juarez, Chihuahua. J Asthma. 2003;40(4):413-23. https://doi. org/10.1081/JAS-120018711 13. Chatkin MN, Menezes AM, Victora CG, Barros FC. High prevalence of asthma in preschool children in Southern Brazil: a populationbased study. Pediatr Pulmonol. 2003;35(4):296-301. https://doi. org/10.1002/ppul.10229 14. Wang XS, Tan TN, Shek LP, Chng SY, Hia CP, Ong NB, et al. The prevalence of asthma and allergies in Singapore; data from two ISAAC surveys seven years apart. Arch Dis Child. 2004;89(5):423-6. https://doi.org/10.1136/adc.2003.031112 15. Lee SL, Wong W, Lan YL. Increasing prevalence of allergic rhinitis but not asthma among children in Hong Kong from 1995 to 2001 (Phase 3 International Study of Asthma and Allergies in Childhood). Pediatr Allergy Immunol. 2004;15(1):72-8. https://doi.org/10.1046/ j.0905-6157.2003.00109.x 16. Solé D, Melo KC, Camelo-Nunes IC, Freitas LS, Britto M, Rosário NA, et al. Changes in the prevalence of asthma and allergic diseases among Brazilian schoolchildren (13-14 years old): comparison between ISAAC Phases One and Three. J Trop Pediatr. 2007;53(1):13-21. https://doi.org/10.1093/tropej/fml044 17. Luna Mde F, Almeida PC, Silva MG. Asthma and rhinitis prevalence and co-morbidity in 13-14-year-old schoolchildren in the city of Fortaleza, Ceará State, Brazil [Article in Portuguese]. Cad Saude Publica. 2011;27(1):103-12. 18. Castro LK, Cerci Neto A, Ferreira Filho OF. Prevalence of symptoms of asthma, rhinitis and atopic eczema among students between 6 and 7 years of age in the city of Londrina, Brazil. J Bras Pneumol. 2010;36(3):286-92. https://doi.org/10.1590/S180637132010000300004 19. Toledo MF, Rozov T, Leone C. Prevalence of asthma and allergies in 13- to 14-year-old adolescents and the frequency of risk factors in carriers of current asthma in Taubaté, São Paulo, Brazil. Allergol Immunopathol (Madr). 2011;39(5):284-90. https://doi.org/10.1016/j. aller.2010.09.004 20. Patil VK, Kurukulaaratchy RJ, Venter C, Grundy J, Roberts G, Dean T, et al. Changing prevalence of wheeze, rhinitis and allergic sensitisation in late childhood: findings from 2 Isle of Wight birth

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cohorts 12 years apart. Clin Exp Allergy. 2015;45(9):1430-8. https:// doi.org/10.1111/cea.12534 21. Wandalsen NF, Gonzalez C, Waldensen GF, Solé D. Evaluation of criteria for the diagnosis of asthma using an epidemiological questionnaire. J Bras Pneumol. 2009;35(3):199-205. https://doi. org/10.1590/S1806-37132009000300002 22. Penaranda A, Aristizabal G, Garcia E, Vasquez C, RodriguezMartinez CE, Satizabal CL. Allergic rhinitis and associated factors in schoolchildren from Bogota, Colombia. Rhinology. 2012;50(2):122-8. 23. Boechat JL, Rios JL, Sant’Anna CC, França AT. Prevalence and severity of asthma symptoms in school-age children in the city of Duque de Caxias, Rio de Janeiro, Brazil. J Bras Pneumol. 2005; 31(2):111-7. https://doi.org/10.1590/S1806-37132005000200005 24. Lima WL, Lima EV, Costa Mdo R, Santos AM, Silva AA, Costa ES. Asthma and associated factors in students 13 and 14 years of age in São Luís, Maranhão State, Brazil [Article in Portuguese]. Cad Saude Publica. 2012;28(6):1046-56. https://doi.org/10.1590/S0102311X2012000600004 25. Strachan DP. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax. 2000; 55 Suppl 1:S2-10. https://doi. org/10.1136/thorax.55.suppl_1.S2 26. von Mutius E. The environmental predictors of allergic disease. J Allergy Clin Immunol. 2000;105(1 Pt 1):9-19. https://doi.org/10.1016/ S0091-6749(00)90171-4 27. Macedo SE, Menezes AM, Knorst M, Dias-da-Costa JS, Gigante DP, Olinto MT, et al. Risk factors for asthma in adults in Pelotas, Rio Grande do Sul State, Brazil [Article in Portuguese]. Cad Saude Publica. 2007;23(4):863-74. https://doi.org/10.1590/S0102311X2007000400014 28. Abreu MN, Souza CF, Caiaffa WT. Smoking among adolescents and young adults in Belo Horizonte, Minas Gerais State, Brazil: the influence of family setting and social group [Article in Portuguese]. Cad Saude Publica. 2011;27(5):935-43. https://doi.org/10.1590/ S0102-311X2011000500011 29. Barreto SM, Giatti L, Oliveira-Campos M, Andreazzi MA, Malta DC. Experimentation and use of cigarette and other tobacco products among adolescents in the Brazilian state capitals (PeNSE 2012). Rev Bras Epidemiol. 2014;17 Suppl 1:62-76. https://doi.org/10.1590/18094503201400050006 30. Ribeiro QC, Lotufo PA, Lamounier JA, Oliveira RG, Soares JF, Botter DA. Additional cardiovascular risk factors associated with excess weight in children and adolescents: the Belo Horizonte heart study [Article in Portuguese]. Arq Bras Cardiol. 2006;86(6):408-18. https:// doi.org/10.1590/S0066-782X2006000600002 31. Radicchi AL. A poluição na bacia aérea da região metropolitana de Belo Horizonte e sua repercussão na saúde da população. Rev Bras Estud Popul. 2012;9(1):195-8. https://doi.org/10.1590/S010230982012000100013 32. Toledo MF, Saraiva-Romanholo BM, Oliveira RC, Saldiva PH, Silva LF, Nascimento LF, et al. Changes over time in the prevalence of asthma, rhinitis and atopic eczema in adolescents from Taubaté, São Paulo, Brazil (2005-2012): Relationship with living near a heavily travelled highway. Allergol Immunopathol (Madr). 2016;44(5):439-44. https://doi.org/10.1016/j.aller.2016.02.006 33. Sritipsukho P, Satdhabudha A, Nanthapisal S. Effect of allergic rhinitis and asthma on the quality of life in young Thai adolescents. Asian Pac J Allergy Immunol. 2015;33(3):222-6. https://doi.org/10.12932/ AP0548.33.3.2015 34. Oliveira-Santos S, Motta-Franco J, Barreto I, Solé D, Gurgel R. Asthma in adolescents--Prevalence trends and associated factors in northeast Brazil. Allergol Immunopathol (Madr). 2015;43(5):429-35. https://doi.org/10.1016/j.aller.2014.05.006 35. Fernandes AG, Souza-Machado C, Coelho RC, Franco PA, Esquivel RM, Souza-Machado A, et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014;40(4):364-72. https://doi. org/10.1590/S1806-37132014000400003

J Bras Pneumol. 2017;43(5):373-379 http://dx.doi.org/10.1590/S1806-37562016000000190

META-ANALYSIS

Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a systematic review and metaanalysis of six randomized controlled trials Qiang Lei1, Yunhui Lv2, Kai Li1, Lei Ma1, Guodong Du1, Yan Xiang1, Xuqing Li1 1. Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming, China. 2. Department of Respiratory Medicine, First People’s Hospital of Yunnan Province, Kunming, China. Submitted: 15 July 2016. Accepted: 26 February 2017. Study carried out in the Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Kunming, China.

ABSTRACT Objective: To evaluate systematically the effects of continuous positive airway pressure (CPAP) on blood pressure in patients with resistant hypertension and obstructive sleep apnea (OSA). Methods: The Cochrane Library, PubMed, ScienceDirect, and the Web of Science were searched for studies investigating the effects of CPAP on blood pressure in patients with resistant hypertension and OSA. The selected studies underwent quality assessment and meta-analysis, as well as being tested for heterogeneity. Results: Six randomized controlled trials were included in the meta-analysis. The pooled estimates of the changes in mean systolic blood pressure and mean diastolic blood pressure (as assessed by 24-h ambulatory blood pressure monitoring) were −5.40 mmHg (95% CI: −9.17 to −1.64; p = 0.001; I2 = 74%) and −3.86 mmHg (95% CI: −6.41 to −1.30; p = 0.00001; I2 = 79%), respectively. Conclusions: CPAP therapy can significantly reduce blood pressure in patients with resistant hypertension and OSA. Keywords: C ontinuous positive airway pressure; Sleep apnea, obstructive; Hypertension; Meta-analysis.

INTRODUCTION Obstructive sleep apnea (OSA) is a chronic disease characterized by recurrent upper airway collapse during sleep leading to intermittent hypoxemia and sleep disruption.(1) It has been estimated that 24% of all males in the 30- to 60-year age bracket and 9% of all females in the same age bracket have OSA.(2) Several studies have shown that OSA is a risk factor for cardiovascular diseases, including hypertension, heart failure, atrial fibrillation, and coronary artery disease.(3-6) In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure identified OSA as an important identifiable cause of hypertension.(7) Resistant hypertension has been defined as blood pressure that remains above goal despite concomitant use of at least three classes of antihypertensive medications. Individuals with controlled blood pressure using at least four classes of antihypertensive medications are also considered to have resistant hypertension. International guidelines now recognize OSA as one of the most common risk factors for resistant hypertension.(8) Gonçalves et al. found that the risk of resistant hypertension is nearly five times higher in patients with OSA.(9) Similarly, Calhoun et al. found that 63% of all patients presenting to a clinic for resistant hypertension were at high risk for OSA on the basis of their responses to the Berlin Questionnaire.(10) In a prospective observational study, Lavie et al. found that

the prevalence and severity of hypertension increased as the apnea-hypopnea index (AHI) increased.(11) Continuous positive airway pressure (CPAP) is the most widely accepted form of therapy for OSA and remains the gold standard for treatment. Although there is a significant amount of data on the effect of CPAP on hypertension, data on resistant hypertension are limited.(12) Therefore, we performed a meta-analysis to evaluate the efficacy of CPAP in patients with OSA and resistant hypertension. METHODS

Inclusion criteria We sought to evaluate systematically randomized clinical trials of the effects that CPAP therapy has on the blood pressure of patients with OSA and resistant hypertension. We included studies including patients over 18 years of age diagnosed with OSA and resistant hypertension, the latter having been diagnosed by ambulatory blood pressure monitoring (ABPM). Interventions included a control group receiving conventional antihypertensive therapy or placebo and a treatment group receiving CPAP therapy, treatment group patients having completed the treatment. Endpoints included mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) as assessed by 24-h ABPM.

Correspondence to:

Ma Lei. Faculty of Information Engineering and Automation, Kunming University of Science and Technology, Xinzi Building, room 109, Kunming, Yunnan, China. Tel.: 86 13208809503. E-mail: roy_murray@qq.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

373

Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a systematic review and meta-analysis of six randomized controlled trials

Exclusion criteria The exclusion criteria were as follows: studies in which the sample size was < 10; nonrandomized controlled studies; early studies (i.e., studies published before 2010); repeated trials; studies with no control group; studies in which patients were used as their own controls; studies not providing the full original data; studies whose full-text articles were unavailable; and studies whose authors we were unable to contact.

Literature retrieval We searched the following databases: the Cochrane Library; ScienceDirect; PubMed; and the Web of Science. We used the following search terms: “continuous positive airway pressure”; “CPAP”; “obstructive sleep apnea”; “OSA”; “apnea-hypopnea index”; “AHI”; “resistant hypertension”; “RH”; “refractory hypertension”; “resistant high blood pressure”; “randomized controlled trial”; and “RCT”. The search was limited to original research articles published between January of 2010 and January of 2016. In addition, the ResearchGate social networking website was used in order to contact researchers for additional relevant studies.

Literature screening In order to select the articles for inclusion, two researchers independently applied the inclusion and exclusion criteria to all of the studies selected by the aforementioned method. In cases of disagreement, a third member of the research team was consulted. Relevant data were extracted and cross-checked. In cases in which important data were missing from the selected studies, the authors were contacted by email or phone.

Quality assessment The quality of the selected studies was assessed by the Jadad score, which ranges from 0 to 5. Articles with a Jadad score of more than 3 were included in our meta-analysis. Two researchers independently assessed the quality of the studies by applying the Jadad criteria. In cases of disagreement, a third member of the research team was consulted. All relevant data were subsequently extracted.

Statistical analysis Meta-analysis Meta-analysis was performed with the Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark). The I2 statistics was used in order to assess heterogeneity (clinical heterogeneity and statistical heterogeneity), the level of significance being set at p < 0.1. For studies showing clinical homogeneity and statistical homogeneity (i.e., p > 0.1 and I2 ≤ 50%), a fixed effect model was used; for those showing clinical homogeneity and statistical heterogeneity (i.e., p < 0.1 and I2 > 50%), a random effects model was used. In the presence of significant clinical heterogeneity, only descriptive 374

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statistics were used. Continuous variables included weighted mean difference and standardized mean difference, the effects being expressed as 95% CIs. The level of significance was set at p < 0.05. Funnel plots were used in order to determine whether there was significant publication bias.

Heterogeneity test Heterogeneity was analyzed by the method of subgroup analysis, which consists of dividing the data into smaller units and comparing the subgroups. On the basis of the AHI, body mass index (BMI), SBP, DBP, total duration of CPAP treatment, mean daily duration of CPAP treatment, Epworth Sleepiness Scale (ESS) score, and geographic location of the institutions, we divided the study sample into eight subgroups in order to analyze potential factors leading to heterogeneity.

Sensitivity analysis Sensitivity analysis was performed by excluding studies that might affect the analysis and by using different correlation coefficients to observe the stability of the results. RESULTS A total of 423 articles were initially retrieved, and a total of 308 remained after duplicate entries were removed. Of the remaining articles, 6(13-18) were included in our meta-analysis (Figure 1). The 6 included articles were randomized controlled trials (RCTs) and comprised a total of 479 patients. Of those, 245 had been control group patients and 234 had been treatment group patients. The basic characteristics of the 6 RCTs included in the meta-analysis are shown in Table 1. Table 2 shows the baseline AHI, ESS score, BMI, SBP (as assessed by 24-h ABPM), and DBP (as assessed by 24-h ABPM) in the 6 RCTs included in our meta-analysis. All 6 RCTs examined the effects of CPAP treatment on mean SBP (as assessed by 24-h ABPM) in patients with OSA and resistant hypertension. The pooled estimate of the change in mean SBP was −5.40 mmHg (95% CI: −9.17 to −1.64; p = 0.005; I2 = 74%). Five of the 6 RCTs examined the effects of CPAP treatment on mean DBP (as assessed by 24-h ABPM) in patients with OSA and resistant hypertension. The pooled estimate of the change in mean DBP was −3.86 mmHg (95% CI: −6.41 to −1.30; p = 0.003; I2 = 82%). There was significant heterogeneity among the studies, and a random effects model was therefore used in order to analyze the results (Figures 2 and 3). Five studies examined the effects of CPAP treatment on mean daytime and nocturnal SBP in patients with OSA and resistant hypertension. The pooled estimates of the changes in mean daytime SBP and mean nocturnal SBP were −4.11 mmHg (95% CI: −9.06 to −0.84; p = 0.10; I2 = 85%) and −3.17 mmHg (95% CI: −6.25 to −0.09; p = 0.04; I2 = 90%), respectively (Table 3). The pooled estimates of the changes in mean daytime

Lei Q, Lv Y, Li K, Ma L, Du G, Xiang Y, Li X

30 articles retrieved from PubMed 9 articles retrieved from the Cocharane Library 329 articles retrieved from ScienceDirect 51 articles retrieved from the Web of Science

4 articles identified by contacting researchers through ResearchGate

308 articles remained after duplicate entries were removed

inappropriate study design (n = 169) nonresistant hypertension (n = 65) inappropriate comparasion (n = 36) no explicitly reported outcome (n = 27) baseline comorbidity (n = 5)

Studies for which aggregate data were abailable (n = 6) Participants (n = 479)

6 studies included in the meta-analysis, comprising a total of 234 treatment group patients and 245 control group patients Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the process of including studies in our meta-analysis. Table 1. Basic characteristics of the six studies included in the meta-analysis.

Author

Year Number of patients

Muxfeldt 2015 et al.(17)

46 (CPAP)

Male gender, % 37.9

Mean CPAP Type Treatment Method Country Jadad age ± compliance, of duration of BP score SD, h study measurement years 60.8 ± 8.0 4.8 RCT 6 months ABPM Brazil 3

60 (Control) de Oliveira et al.(13)

2014

24 (CPAP)

59.5 ± 7.3

≥4

RCT

8 weeks

ABPM

Brazil

72.4

58.7 ± 9.5

5.7 ± 1.5

RCT

3 months

ABPM

Spain

57 ± 2a

6.01 ± 0.20

RCT

6 months

ABPM

Brazil

72.4

56.0 ± 9.5

5 ± 1.9

RCT

3 months

ABPM

Spain

75.9

59.2 ± 8.7

5.6 ± 1.5

RCT

3 months

ABPM

Spain

23 (Control) Lloberes et al.(14)

2014

27 (CPAP) 29 (Control)

Pedrosa et al.(18)

2013

19 (CPAP) 16 (Control)

Martínez- 2013 García et al.(16)

98 (CPAP) 96 (Control)

Lozano et al.(15)

2010

20 (CPAP) 21 (Control)

CPAP: continuous positive airway pressure; BP: blood pressure; RCT: randomized controlled trial; and ABPM: ambulatory blood pressure monitoring. aData expressed as mean ± SE. J Bras Pneumol. 2017;43(5):373-379

375

DBP and mean nocturnal DBP were −2.11 mmHg (95% CI: −4.16 to −0.05; p = 0.04; I2 = 0%) and −1.55 mmHg (95% CI: −2.81 to −0.29; p = 0.02; I2 = 0%), respectively (Table 4). Because there was significant heterogeneity among the studies regarding mean daytime SBP/DBP, a random effects model was used in order to analyze the results. Because there was no significant heterogeneity among the studies regarding mean nocturnal SBP/DBP, a fixed effect model was used in order to analyze the results. Subgroup analysis was used in order to explore potential factors leading to heterogeneity. With regard to changes in mean SBP (as assessed by 24-h ABPM) before and after CPAP therapy, no heterogeneity was found among the eight subgroups for an AHI ≥ 30; an AHI < 30; a baseline SBP/DBP > 145/85 mmHg; a baseline SBP/DBP < 145/85 mmHg; a

BMI < 32 kg/m2; a CPAP treatment duration ≤ 3 months; a European location; or a study sample size ≥ 25 (Table 3). With regard to changes in mean DBP (as assessed by 24-h ABPM) before and after CPAP therapy, it was unlikely that an AHI ≥ 30, a BMI < 32 kg/m2, a CPAP treatment duration ≤ 3 months, an ESS score of < 10, a European location, or a study sample size of < 25 were the factors leading to heterogeneity (Table 4). Meta-regression analysis showed that the ESS score, BMI, AHI, and age were not the factors leading to heterogeneity in mean SBP as assessed by 24-h ABPM. In contrast, there was a significant correlation between age and heterogeneity in mean DBP as assessed by 24-h ABPM (Table 5). A sensitivity analysis was performed by removing one study at a time from the combined effects model

Table 2. Baseline apnea-hypopnea index, Epworth Sleepiness Scale score, body mass index, systolic blood pressure (as assessed by 24-h ambulatory blood pressure monitoring), and diastolic blood pressure (as assessed by 24-h ambulatory blood pressure monitoring).a

Study

AHI 41 (21)

Muxfeldt et al.(17) de Oliveira et al.(13) Lloberes et al.(14) Pedrosa et al.(18) Martínez-García et al.(16) Lozano et al.(15)

ESS score 11 (6)

BMI 33.4 (5.3)

SBP 129 (16)

DBP 75 (12)

20 (18-31)b

10 (6-15)b

29.8 ± 4.4c

148 ± 17

88 ± 13

50.1 ± 20.6

6.76 ± 3.7

31.4 (4.9)

139.2 ± 11.5

80.8 ± 10.8

29 (24-48)b

10 ± 1c

32 (28-39)b

162 ± 4

97 ± 2

40.4 (18.9)

9.1 (3.7)

34.1 (5.4)

144.2 (12.5)

83.0 (10.5)

52.67 ± 21.5

6.14 ± 3.30

30.8 ± 5.0

129 (16)

75 (12)

AHI: apnea-hypopnea index; ESS: Epworth Sleepiness Scale; BMI: body mass index; SBP: systolic blood pressure; and DBP: diastolic blood pressure. aValues expressed as n (%) or mean ± SD, except where otherwise indicated. b Data expressed as median (range). cData expressed as mean ± SE.

CPAP Treatment Conventional Treatment Study or Subgroup Garcia 2013 Lloberes 2014 Lozano 2010 Muxfeldt 2015 Oliveira 2014 Pedrosa 2013

Mean SD Total -4.7 10.92 98 -2.3 10.8 27 -7.6 10.9 20 0.8 14.13 46 -10 14.68 24 -6.5 3.3 19

Mean Difference IV. Random. Mean SD Total Weight 95% Cl -1.2 12.78 96 20.9% -3.50 [-6.85,-0.15] 2.35 11.9 29 15.4% -4.65 [-10.60, 1.30] -0.6 13.7 21 12.5% -7.00 [-14.56, 0.56] -0.4 13.45 60 16.7% 1.20 [-4.12, 6.52] -0.7 13.88 23 11.5% -9.30 [-17.47, -1.13] 3.1 3.3 16 23.1% -9.60 [-11.79, -7.41]

234

Total (95% Cl)

245

100.0% -5.40 [-9.17, -1.64]

Heterogenety Tau = 14.77; Chi = 19.55, df = 5 (P = 0.002); I2 = 74% Test for overall effect: z = 2.81 (P = 0.005) 2

Mean Difference IV. Random. 95% Cl

-100

-50

Favours [experimental]

100

Favours [control]

Figure 2. Forest plot of the mean change in systolic blood pressure as assessed by 24-h ambulatory blood pressure monitoring and its 95% CI. CPAP Treatment Conventional Treatment Study or Subgroup Garcia 2013 Lloberes 2014 Lozano 2010 Muxfeldt 2015 Pedrosa 2013 Total (95% Cl)

Mean -3.9 -4.4 -4.9 -0.2 -4.5

SD Total 7.38 98 6 27 6.4 20 7.32 46 1.9 19 210

Mean -0.5 0.25 0.1 -0.5 2.1

SD Total Weight 5.8 96 22.7% 6.7 29 18.0% 7.3 21 15.2% 5.45 60 20.6% 2.7 16 23.5% 222

Mean Difference IV. Random. 95% Cl -3.40 [-5.27, 1.53] -4.65 [-7,98, -1.32] -5.00 [-9.20, -0.80] 0.30 [-2.23, 2.83] -6.60 [-8.17, -5.03]

Mean Difference IV. Random. 95% Cl

100.0% -3.86 [-6.41, -1.30]

Heterogenety Tau2 = 16.58; Chi2 = 21.98, df = 4 (P = 0.002); I2 = 82% Test for overall effect: z = 2.96 (P = 0.003)

-100 -50 0 50 100 Favours [experimental] Favours [control]

Figure 3. Forest plot of the mean change in diastolic blood pressure as assessed by 24-h ambulatory blood pressure monitoring and its 95% CI.

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Lei Q, Lv Y, Li K, Ma L, Du G, Xiang Y, Li X

in order to observe mean changes in effects and determine whether there were any differences between the combined effects model and the original model regarding heterogeneity and CIs. One study was found to have led to heterogeneity. Different standard deviations and correlation coefficients were used, but the results were not significantly different. Funnel plots showed no significant publication bias (Begg’s test, p = 0.707; Egger’s test, p = 0.347).

DISCUSSION OSA has been acknowledged as an independent risk factor for hypertension,(11,19,20) being an adverse clinical factor that makes it impossible to control hypertension; in addition, OSA is the most common factor leading to resistant hypertension.(21) Given that CPAP performs extraordinarily well in maintaining continuous positive pressure in the respiratory tract and that it can effectively reduce the AHI, cardiovascular morbidity,

Table 3. Subgroup analysis of mean changes in systolic blood pressure as assessed by 24-h ambulatory blood pressure monitoring.

Subgroup

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

SBP (as assessed by 24-h ABPM) Mean net 95% CI p; I2 (%) change −3.07 −5.50 to −0.65 p = 0.01; I2 = 22% −9.58 −11.70 to −7.46 p < 0.00001; I2 = 0% −9.58 −11.70 to −7.46 p < 0.00001; I2 = 0% −3.07 −5.50 to −0.65 p = 0.01; I2 = 22% −6.81 −8.55 to −5.08 p < 0.00001; I2 = 89% −6.47 −10.53 to −2.42 p = 0.002; I2 = 0% −7.47 −9.18 to −5.76 p < 0.00001; I2 = 70% 1.20 −4.12 to 6.52 p = 0.66; I2 = 0% −8.03 −10.06 to −6.00 p < 0.00001; I2 = 93% −4.71 −7.29 to −2.12 p = 0.0004; I2 = 0% −5.89 −13.33 to 1.55 p = 0.12; I2 = 85% −4.19 −6.92 to −1.47 p = 0.003; I2 = 0% −4.19 -6.92 to −1.47 p = 0.003; I2 = 0% −8.10 −10.07 to −6.13 p < 0.00001; I2 = 85% −0.20 −0.41 to −0.01 p = 0.06; I2 = 36%

−0.96

No. of studies AHI

≥ 30 > 30 Baseline SBP/DBP, mmHg > 145/85 < 145/85 ≥ 32 BMI, kg/m2 < 32 CPAP compliance, h >5 ≤5 Treatment duration, months > 3 ≤3 ESS score ≥ 10 < 10 Location Europe South America Study sample size ≥ 25 < 25

−1.36 to −0.57

p < 0.00001; I2 = 88%

SBP: systolic blood pressure; DBP: diastolic blood pressure; ABPM: ambulatory blood pressure monitoring; AHI: apnea-hypopnea index; BMI: body mass index; CPAP: continuous positive airway pressure; and ESS: Epworth Sleepiness Scale. Table 4. Subgroup analysis of mean changes in diastolic blood pressure as assessed by 24-h ambulatory blood pressure monitoring.

Subgroup

AHI

≥ 30 < 30 Baseline SBP/DBP, mmHg > 145/85 < 145/85 ≥ 32 BMI, kg/m2 < 32 CPAP compliance, h >5 ≤5 Treatment duration, months >3 ≤3 ESS score ≥ 10 < 10 Location Europe South America Study sample size ≥ 25 < 25

No. of studies 4 1 1 4 3 2 4 1 2 3 2 3 3 2 3 2

DBP (as assessed by 24-h ABPM) Mean net 95% CI p; I2 (%) change −2.76 −4.06 to −1.46 p < 0.0001; I2 = 64% −6.60 −8.17 to −5.03 p < 0.00001; I2 = 0% −6.60 −8.17 to −5.03 p < 0.00001; I2 = 0% −2.76 −4.06 to −1.46 p < 0.0001; I2 = 64% −4.24 −5.32 to −3.15 p < 0.00001; I2 = 91% −4.79 −7.39 to −2.18 p = 0.0003; I2 = 0% −5.18 −6.28 to −4.09 p < 0.00001; I2 = 55% 0.30 −2.23 to 2.83 p = 0.82; I2 = 0% −4.67 −6.00 to −3.33 p < 0.00001; I2 = 95% −3.87 −5.39 to −3.35 p < 0.00001; I2 = 0% −4.67 −6.00 to −3.33 p < 0.00001; I2 = 95% −3.87 −5.39 to −2.35 p < 0.00001; I2 = 0% −3.87 −5.39 to −2.35. p < 0.00001; I2 = 0% −4.67 −6.00 to −3.33 p < 0.00001; I2 = 95% −2.53 −3.89 to −1.16 p = 0.0003; I2 = 72% −6.40 −7.88 to −4.93 p < 0.00001; I2 = 0%

DBP: diastolic blood pressure; SBP: systolic blood pressure; ABPM: ambulatory blood pressure monitoring; AHI: apnea-hypopnea index; BMI: body mass index; CPAP: continuous positive airway pressure; and ESS: Epworth Sleepiness Scale. J Bras Pneumol. 2017;43(5):373-379

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Table 5. Meta-regression of 24-h ambulatory blood pressure monitoring data.

Explanatory variable ESS score BMI AHI Age

SBP No. of studies 6 6 6 6

DBP p 0.74 0.14 0.22 0.47

No. of studies 5 5 5 5

p 0.44 0.25 0.70 < 0.0001

SBP: systolic blood pressure; DBP: diastolic blood pressure; ESS: Epworth Sleepiness Scale; BMI: body mass index; and AHI: apnea-hypopnea index.

and cardiovascular mortality,(22,23) it is currently one of the most effective ways to treat mild, moderate, and severe OSA. However, there is still controversy as to whether CPAP can effectively control blood pressure. The present meta-analysis showed that, in patients with OSA and resistant hypertension undergoing CPAP treatment, mean SBP and DBP (as assessed by 24-h ABPM) decreased by 5.40 mmHg and 3.86 mmHg, respectively. In addition, mean nocturnal SBP and DBP decreased value after CPAP treatment (2.11 mmHg and 1.55 mmHg, respectively). Although mean daytime SBP and DBP decreased by 4.11 mmHg and 3.17 mmHg, respectively, after CPAP treatment, the combined effects of CPAP on SBP were statistically significant. We found two observational studies showing the effects of CPAP treatment on blood pressure in patients with OSA and resistant hypertension. Dernaika et al.(24) found that mean arterial pressure decreased by 5.6 mmHg after CPAP therapy (95% CI: 2.0-8.7; p = 0.03). Frenţ et al.(25) suggested that long-term CPAP treatment can significantly control blood pressure in patients with OSA and resistant hypertension. The findings of the two aforementioned studies are consistent with those of the present study. Durán-Cantolla et al.(26) found that mean SBP and DBP (as assessed by 24-h ABPM) decreased by 2.1 mmHg (95% CI: 0.4-3.7; p = 0.01) and 1.3 mmHg (95% CI: 0.2-2.3; p = 0.02), respectively. Barbé et al.(27) found that, after CPAP treatment, mean SBP and DBP decreased by 1.89 mmHg (95% CI: −0.11 to 3.9; p = 0.0654) and 2.19 mmHg (95% CI: 0.93-3.46; p = 0.0008), respectively. Therefore, it can be inferred that CPAP treatment has significant effects on the blood pressure of patients with OSA and resistant hypertension. Iftikhar et al.(28) performed a meta-analysis of the effects of CPAP on blood pressure in patients with resistant hypertension and OSA and reported that the risk of target organ damage and cardiovascular complications is higher in patients with resistant hypertension than in those with nonresistant hypertension, having found that CPAP treatment resulted in a favorable reduction in blood pressure in the former. In the present study, we performed a combined effects analysis of mean daytime SBP/DBP, and the results of the heterogeneity test revealed a fairly large heterogeneity in daytime SBP/DBP across the studies. A sensitivity analysis revealed that the heterogeneity was mainly due to a study conducted by Pedrosa et al.,(18) who concluded that CPAP treatment cannot significantly improve mean nocturnal SBP/DBP but 378

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can significantly improve mean daytime SBP/DBP. This finding is similar to those of the present meta-analysis. We found two studies in which patients received CPAP treatment, conventional antihypertensive therapy, or a combination of the two. Lozano et al.(15) found that the combined use of CPAP treatment and conventional antihypertensive therapy resulted in a more significant reduction in mean DBP (as assessed by 24-h ABPM) than did the use of conventional antihypertensive therapy alone. The results obtained by Litvin et al.(29) are consistent with those obtained by Lozano et al.,(15) the former group of authors having found that the combined use of CPAP and conventional antihypertensive therapy resulted in a more significant reduction in blood pressure. Therefore, patients with resistant hypertension should receive a combination of antihypertensive therapy and CPAP treatment, the effects of which are more significant than are those of antihypertensive therapy alone. Our subgroup analysis revealed that the AHI, BMI, and ESS score were in the subgroup at risk of developing OSA and might be factors leading to heterogeneity. This is possibly due to the fact that the severity of OSA has an impact on the treatment of hypertension. The present meta-analysis has some advantages over two earlier meta-analyses.(28,30) First, all 6 studies included in our meta-analysis are RCTs. Second, we compiled a more comprehensive literature set, our results therefore being more convincing. Finally, in order to explore as many factors leading to heterogeneity as possible and provide a better explanation for the observed results, we adopted a variety of approaches to testing heterogeneity. The present study has limitations. First, because of the limitations of our method of literature retrieval, it is possible that relevant studies were left out. Second, the number of RCTs included in our meta-analysis was rather small. Third, we did not control for confounding factors such as mean patient age, type of antihypertensive medication, degree of obesity, and genetic factors. Finally, the control groups were not homogeneous across studies. Despite these limitations, the results of the present study can be used in order to inform future studies. In conclusion, CPAP treatment has an effect on patients with OSA and resistant hypertension. When treating patients with hypertension, physicians can prescribe CPAP treatment or CPAP treatment in combination with conventional antihypertensive therapy for those with concomitant OSA.

Lei Q, Lv Y, Li K, Ma L, Du G, Xiang Y, Li X

REFERENCES 1. Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, et al. Clinical guideline for the evaluation, management and longterm care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5(3):263-76 2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-5. https://doi.org/10.1056/ NEJM199304293281704 3. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365(9464):1046-53. https://doi. org/10.1016/S0140-6736(05)74229-X 4. Parati G, Lombardi C, Hedner J, Bonsignore MR, Grote L, Tkacova R, et al. Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea. J Hypertens. 2012;30(4):633-46. https://doi. org/10.1097/HJH.0b013e328350e53b 5. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034-41. https://doi.org/10.1056/ NEJMoa043104 6. Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2011;122(4):352-60. https://doi. org/10.1161/CIRCULATIONAHA.109.901801 7. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52. https://doi. org/10.1161/01.HYP.0000107251.49515.c2 8. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510-26. https://doi. org/10.1161/CIRCULATIONAHA.108.189141 9. Gonçalves SC, Martinez D, Gus M, de Abreu-Silva EO, Bertoluci C, Dutra I, et al. Obstructive sleep apnea and resistant hypertension: a case-control study. Chest. 2007;132(6):1858-62. https://doi. org/10.1378/chest.07-1170 10. Calhoun DA, Nishizaka MK, Zaman MA, Harding SM. Aldosterone excretion among subjects with resistant hypertension and symptoms of sleep apnea. Chest. 2004;125(1):112-7. https://doi.org/10.1378/ chest.125.1.112 11. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ. 2000;320(7233):479-82. https://doi.org/10.1136/bmj.320.7233.479 12. Khan A, Patel NK, O’Hearn DJ, Khan S. Resistant hypertension and obstructive sleep apnea. Int J Hypertens. 2013;2013:193010. https:// doi.org/10.1155/2013/193010 13. de Oliveira AC, Martinez D, Massierer D, Gus M, Gonçalves SC, Ghizzoni F, et al. The antihypertensive effect of positive airway pressure on resistant hypertension of patients with obstructive sleep apnea: a randomized, double-blind, clinical trial. Am J Respir Crit Care Med. 2014;190(3):345-7. https://doi.org/10.1164/rccm.2014030479LE 14. Lloberes P, Sampol G, Espinel E, Segarra A, Ramon MA, Romero O, et al. A randomized controlled study of CPAP effect on plasma aldosterone concentration in patients with resistant hypertension and obstructive sleep apnea. J Hypertens. 2014;32(8):1650-7; discussion 1657. https://doi.org/10.1097/HJH.0000000000000238 15. Lozano L, Tovar JL, Sampol G, Romero O, Jurado MJ, Segarra A, et al. Continuous positive airway pressure treatment in sleep apnea

patients with resistant hypertension: a randomized, controlled trial. J Hypertens. 2010;28(10):2161-8. https://doi.org/10.1097/ HJH.0b013e32833b9c63 16. Martínez-García M, Capote F, Campos-Rodríguez F, Lloberes P, Díaz de Atauri MJ, Somoza M, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: the HIPARCO randomized clinical trial. JAMA. 2013;310(22):2407-15. https://doi.org/10.1001/jama.2013.281250 17. Muxfeldt ES, Margallo V, Costa LM, Guimarães G, Cavalcante AH, Azevedo JC, et al. Effects of continuous positive airway pressure treatment on clinic and ambulatory blood pressures in patients with obstructive sleep apnea and resistant hypertension: a randomized controlled trial. Hypertension. 2015;65(4):736-42 https://doi. org/10.1161/HYPERTENSIONAHA.114.04852 18. Pedrosa RP, Drager LF, de Paula LK, Amaro AC, Bortolotto LA, Lorenzi-Filho G. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest. 2013;144(5):148794. https://doi.org/10.1378/chest.13-0085 19. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378-84. https://doi.org/10.1056/ NEJM200005113421901 20. Marin JM, Agusti A, Villar I, Forner M, Nieto D, Carrizo SJ, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012;307(20):2169-76. https://doi. org/10.1001/jama.2012.3418 21. Oliveras A, Schmieder RE. Clinical situations associated with difficultto-control hypertension. J Hypertens. 2013;31 Suppl 1:S3-8. https:// doi.org/10.1097/HJH.0b013e32835d2af0 22. Mannarino MR, Di Filippo F, Pirro M. Obstructive sleep apnea syndrome. Eur J Intern Med. 2012;23(7):586-93. https://doi. org/10.1016/j.ejim.2012.05.013 23. Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011;58(5):811-7. https://doi.org/10.1161/ HYPERTENSIONAHA.111.179788 24. Dernaika TA, Kinasewitz GT, Tawk MM. Effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. J Clin Sleep Med. 2009;5(2):103-7. 25. Frenţ ŞM, Tudorache VM, Ardelean C, Mihăicuţă S. Long-term effects of nocturnal continuous positive airway pressure therapy in patients with resistant hypertension and obstructive sleep apnea. Pneumologia. 2014;63(4):204, 207-11. 26. Durán-Cantolla J, Aizpuru F, Montserrat JM, Ballester E, Terán-Santos J, Aguirregomoscorta JI, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ. 2010;341:c5991. https://doi.org/10.1136/bmj.c5991 27. Barbé F, Durán-Cantolla J, Capote F, de la Peña M, Chiner E, Masa JF, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med. 2010;181(7):718-26. https://doi.org/10.1164/rccm.200901-0050OC 28. Iftikhar IH, Valentine CW, Bittencourt LR, Cohen DL, Fedson AC, Gíslason T, et al. Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis. J Hypertens. 2014;32(12):2341-50; discussion 2350. https://doi.org/10.1097/HJH.0000000000000372 29. Litvin AY, Sukmarova ZN, Elfimova EM, Aksenova AV, Galitsin PV, Rogoza AN, et al. Effects of CPAP on “vascular” risk factors in patients with obstructive sleep apnea and arterial hypertension. Vasc Health Risk Manag. 2013;9:229-35. 30. Liu L, Cao Q, Guo Z, Dai Q. Continuous Positive Airway Pressure in Patients With Obstructive Sleep Apnea and Resistant Hypertension: A Meta-Analysis of Randomized Controlled Trials. J Clin Hypertens (Greenwich). 2016;18(2):153-8. https://doi.org/10.1111/jch.12639

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SPECIAL ARTICLE

Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey 1. Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma “Tor Vergata”, Roma, Italia. 2. ProxAgen OOD, Sofia, Bulgaria. 3. WHO Collaborating Centre for TB and Lung Diseases, Maugeri Care and Research Institute, Tradate, Italia. 4. Public Health Consulting Group SAGL, Lugano, Switzerland. 5. Clínica en Tuberculosis y Enfermedades Pleurales, Instituto Nacional de Enfermedades Respiratorias – INER – Ciudad de México, México. 6. Instituto de Doenças do Tórax, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro (RJ) Brasil. 7. Faculty of Medicine, University of Southampton, Southampton, United Kingdom. 8. Department of Paediatric Infectious Diseases and Immunology, Evelina London Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. 9. Great Ormond Street Hospital Institute of Child Health, University College London, London, United Kingdom. 10. SA MRC Centre for TB Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 11. National Institute of Hygiene, Rabat, Morocco. 12. Unità di Ricerca Translazionale, Dipartimento di Epidemiologia e Ricerca Preclinica, Istituto Nazionale per le Mallatie Infettive – INMI – Lazzaro Spallanzani, Roma, Italia. 13. Homerthon University Hospital, London, United Kingdom. A. Posthumous publication. Submitted: 29 June 2017. Accepted: 3 September 2017. Study carried out under the auspices of the TB Diagnostic Survey Working Group.

Massimo Amicosante1,2A, Lia D’Ambrosio3,4, Marcela Munoz5, Fernanda Carvalho de Queiroz Mello6, Marc Tebruegge7,8,9, Novel Njweipi Chegou10, Fouad Seghrouchni11, Rosella Centis3, Delia Goletti12, Graham Bothamley13, Giovanni Battista Migliori3; TB Diagnostic Survey Working Group ABSTRACT Objective: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. Methods: A multilingual survey was disseminated online between July and November of 2016. Results: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle- and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle- and lowincome countries. Conclusions: Second-generation molecular assays have become more widely available in high- and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users. Keywords: Tuberculosis/diagnosis; Surveys and questionnaires; Income; Mycobacterium tuberculosis/isolation & purification; Molecular diagnostic techniques/methods; Serologic tests/methods. INTRODUCTION Tuberculosis continues to be one of the most prevalent human infections worldwide, the World Health Organization (WHO) reporting that an estimated 10.4 million new tuberculosis cases occurred in 2015.(1) In approximately one third of those cases, the affected individuals are sputum smear-positive (i.e., have active tuberculosis) and could therefore transmit the disease.(1) A core aspect of tuberculosis control is the rapid identification and effective treatment of individuals transmitting the Mycobacterium tuberculosis complex, the causative agent of tuberculosis.(1-8) However, in most settings, more than half of all active tuberculosis cases are not confirmed through laboratory testing or the diagnosis is delayed because reliable diagnostic tools are not available.(1,3,8) The most common microbiological test to detect M. tuberculosis is microscopic examination of sputum or other clinical material stained for AFB, commonly referred to as smear microscopy,(9) in which a positive result is defined as 5,000-10,000 stained bacilli/mL. Therefore, its sensitivity is variable, depending on several factors, and can be as low as 20-30% in some settings.(9) In contrast, culture for M. tuberculosis, which is still considered the gold standard, can detect positivity on

Correspondence to:

Giovanni Battista Migliori. WHO Collaborating Centre for TB and Lung Diseases, Maugeri Care and Research Institute, Tradate, Italia. Tel.: 39 0331 829404. Fax: 39 0331 829402. E-mail: giovannibattista.migliori@fsm.it Financial support: None.

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the basis of only 10-100 viable bacilli/mL of specimen, thus identifying M. tuberculosis in more than 80% of active tuberculosis cases, with a specificity greater than 98%. However, liquid cultures can take two to four weeks to produce a positive result and, due to the growth characteristics of M. tuberculosis, solid cultures can take up to eight weeks.(9) Rapid M. tuberculosis culture methods and molecular assays could play an important role in hastening the diagnosis of tuberculosis and generally have high specificity.(10,11) However, the implementation of these methods is not possible in all clinical settings.(10-17) In addition, although molecular assays for the diagnosis of tuberculosis—such as the Xpert MTB-RIF assay for the identification of M. tuberculosis and the detection of rifampin resistance (hereafter referred to as the Xpert assay)—are becoming more widely available, they are still quite costly, especially at facilities where their use is not supported by external funding sources. (18) Serology-based tuberculosis tests potentially have the necessary characteristics to overcome these problems. They can be performed rapidly at a low cost and could be used as point-of-care tests, even in low-resource clinical settings.(8,18) However, the commercial serological tests for active tuberculosis that are currently available have suboptimal sensitivity and specificity,(19) as well as low reproducibility.(20) Due to those limitations, the WHO does not recommend the use of any of the currently available commercial serological tests for the diagnosis of tuberculosis.(21) Based on the considerations above and with the aim of improving tuberculosis control worldwide, the WHO has recently released a document outlining the indications for and desirable characteristics of novel tuberculosis tests.(8) That document also defined stringent sensitivity and specificity criteria for novel rapid diagnostic tests for tuberculosis, known as target product profiles (TPPs).(8) There are four such TPPs, three of which are focused on the rapid identification of tuberculosis cases(8,22): a triage test and a biomarker-based test (both suitable for point-of-care use); and a rapid sputum-based test for detecting M. tuberculosis at the microscopy-center level. Although the target sensitivity level varies among these test types, depending on the form of tuberculosis, it is estimated to be > 90% for all three.(22) Similarly (with the exception of the triage screening test), the target specificity is quite high, ideally in excess of 98%.(22) However, an effective novel test for tuberculosis might yet encounter further barriers to its acceptance and implementation, including costs and infrastructure requirements.(17,18,22) Currently, there is limited knowledge on the perceptions and attitudes of end users toward novel tests for tuberculosis, which could represent an additional hurdle for incorporating novel assays into the clinical diagnostic routine. This study aimed to determine the current use of existing tuberculosis tests, as well as the acceptability of future tuberculosis tests, among experts involved in tuberculosis diagnostics worldwide.

METHODS

Survey design and data collection The survey was based on a structured questionnaire, designed to elicit feedback, that included a total of 52 questions, organized into 18 sections: section 1, General expertise; section 2, Specific expertise in tuberculosis field; section 3, Diagnostic tests in current use; sections 4-9, Previous experience with diagnostic tests for tuberculosis; sections 10-16, Acceptability of novel diagnostic tests for tuberculosis; section 17, Accepted performance characteristics of novel diagnostic tests for tuberculosis; and section 18, Current price of the diagnostic tests and potential acceptability of pricing for novel tests. Participation in the survey was voluntary. Data were collected anonymously, no personal data, except for respondent ages or electronic tracking (Internet protocol address or other encoding identification) of the survey submission data, being recorded. Respondents were aware that they were participating in research and that the results would be published. Respondents were given the opportunity to provide their e-mail address in order to be informed of the project results toward the end of the survey. In addition, respondents were given the opportunity to provide their name and institution at the end of the survey in the event that they wished to be named as a project collaborator in the resulting publications. According to the current standards set by European Directive 2001/20/EC and their implementation in national regulations (e.g., UK National Research Ethics Service regulations, Governance Arrangements for Research Ethics Committees, paragraph 2.3.13), research ethics committee review is not required for research involving healthcare staff recruited as research participants, by virtue of their professional role. To maximize its accessibility to tuberculosis experts worldwide, the questionnaire was offered in English, Spanish, and French. The multilingual questionnaires were accessible online on a Google platform for a 4-month period extending from 16 July 2016 to 16 November 2016. The English-language version of the survey instrument is available online (https://docs.google.com/forms/d/188ZEQjuNaYeKlIEzMBzGwhzSuHm00loTcf0m_wHths/ edit?usp=sharing). The survey links were distributed, by e-mail, to various groups of tuberculosis experts, including the tuberculosis experts registered with the Global Laboratory Initiative of the WHO (via its “listserv” mailing list); the Mycobacteriology Working Group of the Italian Society of Clinical Microbiology; the European Society of Mycobacteriology; the Paediatric Tuberculosis Network European Trials Group; and the laboratory specialists of the Tuberculosis Network European Trialsgroup Clinical Research Collaboration. This study was conducted within the framework established jointly by the Latin-American Thoracic Association and European Respiratory Society. It was supported by the Brazilian Thoracic Society and guided by the tenets of the Latin-American Thoracic Association/ J Bras Pneumol. 2017;43(5):380-392

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European Respiratory Society SinTB project, which is focused on eliminating tuberculosis in Latin America.

Statistical analysis, primary data stratification, and characteristics of the survey population

variables among groups, ANOVA was used, whereas the chi-square test and logistic regression were used for the comparison of dichotomous and categorical variables. After multiple comparisons, Bonferroni correction was used if required. Values of p ≤ 0.05 after Bonferroni correction were considered statistically significant.

Data from individual language databases were pooled into a single file for the purpose of analysis. The information provided for the entry “Country of work” was used in order to define the WHO region, as well as the World Bank classification and stratification of the country by its 2015 gross national income (GNI) per capita, according to the Atlas method calculation (in US dollars: http://data.worldbank.org/indicator/ NY.GNP.PCAP.CD?order=wbapi_data_value_2014 ± wbapi_data_value ± wbapi_data_value-last&sort=desc). Those two parameters were used for the primary stratification of the survey data. Each country was classified as low-income (GNI per capita ≤ US$1,025); lower middle-income (GNI per capita of US$1,026–4,035); upper middle-income (GNI per capita of US$4,036–12,475); or high-income (GNI per capita ≥ US$12,476). Data were available for all entry countries, although not for Palestine, which was therefore not included in any of the sub-stratification analyses.

A total of 723 respondents from 114 countries and territories participated in the survey. Figure 1 shows the geographical location of the survey respondents. For 15 countries—including most of the countries on the WHO list of high tuberculosis burden countries(1)—there were 10 or more respondents; for 27 countries, there was only one respondent. Table 1 summarizes the characteristics of the respondents, including age, level of education, place of work, work experience, and expertise. The three largest groups of professional respondents included those with expertise in infectious diseases, those with expertise in pulmonology, and those with expertise in microbiology, collectively comprising nearly two thirds (64.45%) of the study population, with no significant differences among respondents in terms of their background in clinical or laboratory work (p = 0.1075).

Analyses were carried out with the SPSS Statistics software package for Windows, version 19.0 (SPSS Italia SRL, Bologna, Italy), Prism 6 (Graphpad Software, San Diego, CA, USA), and the Real Statistics add-in for Excel (available at http://www.real-statistics. com/). Continuous variables are expressed as mean ± standard deviation, whereas dichotomous and categorical variables are expressed as absolute and relative frequencies. For the comparison of continuous

In agreement with the general global trend reported by the United Nations,(23) the age of the survey respondents was significantly lower in low-income countries than in high-income and upper middle-income countries (p < 0.0001 for both comparisons). As can be seen in Table 1, respondent ages were also lower in the lower middleincome countries than in the high-income countries (p = 0.0003). In addition, the survey respondents in high-income countries included a significantly higher

RESULTS

Legend 1-2 replies 5 replies 10 replies 20 replies 30 replies > 40 replies Figure 1. Geographic distribution of the survey respondents, by country. A graded color scale (bottom left) indicates the density of respondents in each country.

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Table 1. Characteristics of the survey respondents.a

Variable

Income level of the countries (World Bank classification) High Upper Lower Low middle middle (n = 191) (n = 263) (n = 172) (n = 96) 26.4 36.4 23.8 13.3 48.2 ± 9.9 46.3 ± 11.0 44.3 ± 10.3 42.2 ± 10.2

Proportional distribution, % Age (years), mean ± SD Age range (years) 21-30 31-40 41-50 51-60 ≥ 61 Total

5 (2.6) 38 (19.9) 74 (38.7) 54 (28.3) 20 (9.4) 191 (100.0)

16 (6.1) 77 (29.3) 63 (24.0) 81 (30.8) 26 (9.8) 263 (100.0)

14 (8.1) 56 (32.6) 54 (31.4) 39 (22.7) 9 (5.1) 172 (100.0)

7 (7.3) 43 (44.8) 27 (28.1) 15 (15.6) 4 (4.1) 96 (100.0)

Total

2 (1.0) 24 (12.6) 35 (18.3) 85 (44.5) 45 (23.6) 191 (100.0)

2 (0.8) 79 (30.0) 76 (28.9) 65 (24.7) 41 (15.6) 263 (100.0)

2 (1.2) 37 (21.5) 69 (40.1) 42 (24.4) 22 (12.8) 172 (100.0)

1 (1.0) 22 (22.9) 49 (51.0) 19 (19.8) 5 (5.2) 96 (100.0)

25 (13.1) 42 (22.0) 83 (43.5) 41 (21.5) 191 (100.0)

48 (18.3) 53 (20.2) 75 (28.5) 87 (33.1) 263 (100.0)

30 (17.4) 51 (29.7) 62 (36.0) 29 (16.9) 172 (100.0)

23 (24.0) 28 (29.2) 32 (33.3) 13 (13.5) 96 (100.0)

94 (49.2) 54 (28.3) 19 (9.9) 5 (2.6) 5 (2.6) 14 (7.3) 191 (100.0)

163 (62.0) 44 (16.7) 23 (8.7) 24 (9.1) 2 (0.8) 7 (2.7) 263 (100.0)

82 (47.7) 30 (17.4) 15 (8.7) 12 (7.0) 1 (0.6) 32 (18.6) 172 (100.0)

51 (53.1) 15 (15.6) 14 (14.6) 2 (2.1) 1 (1.0) 13 (13.5) 96 (100.0)

78 (40.8) 30 (15.7) 83 (43.5) 0 (0.0) 191 (100.0)

128 (48.7) 3 (1.1) 129 (49.0) 3 (1.1) 263 (100.0)

42 (24.4) 20 (11.6) 107 (62.2) 3 (1.7) 172 (100.0)

22 (22.9) 4 (4.2) 69 (71.9) 1 (1.0) 96 (100.0)

58 (30.4) 39 (20.4) 1 (0.5) 10 (5.2) 43 (22.5) 10 (5.2) 10 (5.2) 4 (2.1) 16 (8.4) 191 (100.0)

57 (21.7) 72 (27.4) 34 (12.9) 2 (0.8) 44 (16.7) 12 (4.6) 8 (3.0) 9 (3.4) 25 (9.5) 263 (100.0)

35 (20.3) 33 (19.2) 11 (6.4) 7 (4.1) 30 (17.4) 7 (4.1) 19 (11.0) 5 (2.9) 25 (14.5) 172 (100.0)

32 (33.3) 11 (11.5) 12 (12.5) 3 (3.1) 11 (11.5) 3 (3.1) 12 (12.5) 0 (0.0) 12 (12.5) 96 (100.0)

Highest level of education High school Undergraduate degree Masters degree Doctorate Postgraduate work Experience in tuberculosis 1-5 years 6-9 years 10-20 years > 20 years Total Main employer Public health Academic institution Other publicly funded institute Private healthcare facility Industry Other private concern Total Main focus in tuberculosis Adult Pediatric Adult and pediatric No answer provided Total Main area of expertise Infectious diseases Pulmonology General medicine (adult) Pediatrics Microbiology Immunology Laboratory medicine Basic science Other Total

Total

(n = 723b) 100.0 < 0.00001 45.8 ± 10.6 < 0.00001 < 0.00001 42 (5.8) 215b (29.7) 218 (30.2) 189 (26.1) 54 (8.2) 723b (100.0) < 0.00001 7 (1.0) 163b (22.5) 229 (31.7) 211 (29.2) 113 (15.6) 723b (100.0) < 0.00001 127b (17.6) 174 (24.1) 252 (34.9) 170 (23.5) 723b (100.0) < 0.00001 391b (54.1) 143 (19.8) 71 (9.8) 43 (5.9) 9 (1.2) 66 (9.1) 723b (100.0) < 0.00001 271 (37.5) 57 (7.9) 388 (53.7) 7 (1.0) 723b (100.0) < 0.00001 183b (25.3) 155 (21.4) 58 (8.0) 22 (3.0) 128 (17.7) 32 (4.4) 49 (6.8) 18 (2.5) 78 (10.8) 723b (100.0)

a Values expressed as n (%), except where otherwise indicated. bIncludes one respondent working in a country that could not be classified according to the World Bank classification. *ANOVA or chi-square test, with Bonferroni correction.

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Table 1. Continued...

Variable

Area of interest in tuberculosis (multiple answers allowed) Clinical Laboratory Research Policy Maker Test Producer Other Industry Other Total

Income level of the countries (World Bank classification) High Upper Lower Low middle middle (n = 191) (n = 263) (n = 172) (n = 96)

Total

(n = 723b) 0.0542

126 (66.0) 89 (46.6) 105 (55.0) 25 (13.1) 12 (6.3) 1 (0.5) 11 (5.8) 191 (100.0)

184 (70.0) 133 (50.6) 146 (55.5) 53 (20.2) 34 (12.9) 2 (0.8) 11 (4.2) 263 (100.0)

93 (54.1) 84 (48.8) 98 (57.0) 40 (23.3) 8 (4.7) 2 (1.2) 10 (5.8) 172 (100.0)

54 (56.3) 45 (46.9) 71 (74.0) 36 (37.5) 6 (6.3) 3 (3.1) 9 (9.4) 96 (100.0)

458b (63.3) 351 (48.5) 420 (58.1) 154 (21.3) 60 (8.3) 8 (1.1) 41 (5.7) 723b (100.0)

proportion of respondents with graduate degrees and professorships (p < 0.0001 for all comparisons), although no such differences were detected among the other subgroups (Table 1). The distribution of the respondents by their years of experience in the area of tuberculosis was comparable between lower middle-income and low-income countries (p = 0.59), whereas the number of respondents with long-term experience in tuberculosis was significantly higher in high-income and upper middle-income countries than in lower middle-income and low-income countries (p < 0.0001 for all comparisons), as shown in Table 1. Stratification of the survey data by GNI per capita (the World Bank classification) allowed an assessment of the differences between countries with different tuberculosis testing needs, as well as different tuberculosis incidence rates. The main differences observed regarding age and expertise were considered for correction in the subsequent analyses.

Laboratory throughput and current tests for the diagnosis of active tuberculosis Of the 723 survey respondents, 690 (95.4%) had access to or were regularly performing laboratory tests for tuberculosis. Table 2 shows the number of diagnostic tests for tuberculosis performed per year and the range of tests to which the survey respondents stated they had access. More than half of the survey respondents had access to laboratory facilities performing more than 1,000 diagnostic tests for tuberculosis per year. As expected, the proportion of respondents with access to a laboratory performing more than 5,000 diagnostic tests for tuberculosis per year was higher among respondents working in low-income countries than among those working in high-income and upper middle-income countries (p < 0.05 for both comparisons). Among assays for the diagnosis of active tuberculosis, AFB staining was the most widely available test (available to 90.8% of the survey respondents), followed by 384

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solid culture (73.7%). In high-income countries, liquid culture was more widely available than was solid culture (Table 2). As expected, molecular assays were more widely available in high-income countries than in other countries, comparisons being made for commercial molecular assays (p < 0.00001 for all comparisons), in-house molecular assays (p < 0.02 for all comparisons), and any molecular assay (p < 0.00001 for all comparisons). However, the data show that more than two thirds of the respondents in low- and lower middle-income countries had access to molecular assays (Table 2). This contrasts with the availability of interferon-gamma release assays (IGRAs) among survey respondents, which was strongly correlated with the country income classification (p = 0.0026). We found that IGRAs were more widely available in laboratories located in high-income countries than in those located in other countries (p < 0.00001 for all comparisons). Finally, although the use of the currently available commercial serological tests for tuberculosis has been strongly discouraged by the WHO since 2010,(21) the survey data suggest that they remain widely available in tuberculosis laboratories. More than a quarter of the survey respondents stated that either ELISA-based serological tests or lateral flow immunoassays were in use in their laboratories, with no significant differences between countries by income (p = 0.0723 for all comparisons), as shown in Table 2.

Prices of rapid diagnostic tests for tuberculosis In the multivariate analysis of the responses (Table 3), the prices of rapid tuberculosis assays were found to be associated with the availability of commercial molecular assays and with the availability of AFB staining only, regardless of the country income classification (p < 0.002 for all comparisons). In contrast, the type of employing institution, number of tests performed per year, years of experience in the area of tuberculosis, level of education, and decision-making capacity were

Amicosante M, Dâ&#x20AC;&#x2122;Ambrosio L, Munoz M, Mello FC, Tebruegge M, Chegou NN, Seghrouchni F, Centis R, Goletti D, Bothamley G, Migliori GB

Table 2. Diagnostic tuberculosis tests in current use and total annual throughput as stated by the respondents.a

Variable

Total

(n = 690b) Proportional distribution, % Tuberculosis tests per year < 100 100-1,000 1,000-5,000 > 5,000 Not known Type of test (multiple answers) AFB staining Solid culture Liquid culture First-line drug susceptibility Second-line drug susceptibility â&#x20AC;&#x153;In-houseâ&#x20AC;? molecular assay Commercial molecular assay IGRA ELISA-based assay (serology) LFIA Other Any serological test (ELISA+LFIA) Any molecular assay

Income level of the countries (World Bank classification) High Upper Lower Low middle middle (n = 179) (n = 257) (n = 162) (n = 91) 25.94 37.25 23.48 13.19

0.023 70 (10.14) 175 (25.36) 187 (27.10) 196 (28.41) 62 (8.99)

25 (13.97) 36 (20.11) 56 (31.28) 49 (27.37) 13 (7.26)

28 (10.89) 77 (29.96) 68 (26.46) 64 (24.90) 20 (7.78)

13 (8.02) 41 (25.31) 42 (25.93) 52 (32.10) 14 (8.64)

3 (3.30) 21 (23.08) 21 (23.08) 31 (34.07) 15 (16.48)

627c (90.87) 509c (73.77) 468c (67.83) 500 (72.46) 317 (45.94) 193 (27.97) 413 (59.86) 264 (38.26) 124 (17.97) 75 (10.87) 20 (2.90) 175 (25.36) 488 (70.72)

158 (88.27) 142 (79.33) 151 (84.36) 140 (78.21) 102 (56.98) 70 (39.11) 145 (81.01) 144 (80.45) 31 (17.32) 26 (14.53) 8 (4.47) 50 (27.93) 157 (87.71)

228 (88.72) 187 (72.76) 155 (60.31) 174 (67.70) 99 (38.52) 58 (22.57) 131 (50.97) 76 (29.57) 63 (24.51) 26 (10.12) 9 (3.50) 76 (29.57) 154 (59.92)

155 (95.68) 111 (68.52) 103 (63.58) 121 (74.69) 78 (48.15) 44 (27.16) 90 (55.56) 37 (22.84) 18 (11.11) 12 (7.41) 3 (1.85) 27 (16.67) 115 (70.99)

85 (93.41) 68 (74.73) 58 (63.74) 65 (71.43) 38 (41.76) 21 (23.08) 47 (51.65) 7 (7.69) 12 (13.19) 11 (12.09) 0 (0.00) 22 (24.18) 62 (68.13)

< 0.00001

0.0723 < 0.00001

IGRA: interferon-gamma release assay; and LFIA: lateral flow immunoassay. aValues expressed as n (%), except where otherwise indicated. bIncludes data only from respondents who stated that they were performing tests. c Includes one respondent working in a country that could not be classified according to the World Bank classification. *Chi-square test, with Bonferroni correction.

not associated with the stated prices for the tests (p > 0.09 for all comparisons, data not shown). As can be seen in Table 3, more than a third of the survey respondents did not know the current prices (i.e., the costs, excluding labor and overhead) of rapid tests for the diagnosis of tuberculosis. The prices stated by the respondents working in high-income countries were generally higher than the prices stated by those working in the other countries (p < 0.0055 for all comparisons). Similarly, the stated prices were higher in upper middle-income countries than in lower middle- and low-income countries (p < 0.00001 for all comparisons). As expected, the use of commercial molecular assays represented the main reason for high prices of tests for the diagnosis of active tuberculosis. As can be seen in Table 3, the survey respondents who had access only to AFB staining stated lower prices than did those who had access to AFB staining plus molecular assays and those who had access only to molecular assays (p < 0.05 for all comparisons).

Impact of the Xpert assay on the availability and pricing of molecular tests For survey respondents working in lower middle- and low-income countries where molecular assays were available, the price range most often indicated for rapid tests was US$ 10-20 (Table 3). This is in accordance

with the pricing negotiated by the Foundation for Innovative New Diagnostics for the Xpert assay in low-resource settings. Therefore, we attempted to ascertain whether access to that specific test plays a significant role in determining the rapid test price range indicated in lower middle- and low-income countries. Among 413 survey respondents who reported having access to commercial molecular assays, 193 (46.7%) reported using the Xpert assay alone or in combination with other molecular assays for the diagnosis of tuberculosis. As shown in Table 4, the proportions of respondents using Xpert assays were higher than those of respondents using other molecular assays in the lower middle- and low-income countries, and that ratio was lower in the high-income and upper middle-income countries (p < 0.05 for all comparisons). Table 5 shows the reported prices for rapid tests among molecular assay users, stratified by the use of Xpert assays. Apart from the differences observed among countries by income, no significant differences were observed between the prices reported for the Xpert assay and those reported for other molecular assays in each income subgroup. This suggests that manufacturers of other commercial molecular assays have adjusted the pricing of their assays to match that of the Xpert assay. Table 6 shows the level of experience of the survey respondents with molecular J Bras Pneumol. 2017;43(5):380-392

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Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey

Table 3. Price ranges (in US$), declared by the survey respondents, of rapid tests for the diagnosis of active tuberculosis, excluding labor and overhead.a

Parameter Price range (US$) 1-10 11-20 20-30 30-50 > 50 Subtotal Not known Total Price range (US$) 1-10 11-20 20-30 30-50 > 50 Subtotal Not known Total Price range (US$)

1-10 11-20 20-30 30-50 > 50 Subtotal Not known Total

Total

Income level of the countries (World Bank classification) High Upper middle Lower middle Low Users of AFB staining only 123 (25.68) 16 (14.04) 30 (17.44) 47 (36.43) 30 (46.88) 146 (30.48) 17 (14.91) 51 (29.65) 54 (41.86) 24 (37.50) 59 (12.32) 23 (20.18) 22 (12.79) 9 (6.98) 5 (7.81) 57 (11.90) 25 (21.93) 18 (10.47) 11 (8.53) 3 (4.69) 94 (19.62) 33 (28.95) 51 (29.65) 8 (6.20) 2 (3.13) 479 114 172 129 64 77 (40.31) 91 (34.60) 43 (25.00) 32 (33.33) 244b (33.75) 191 263 172 96 723b Users of molecular assays only 64 (20.71) 9 (9.57) 14 (13.46) 28 (35.90) 13 (39.39) 99 (32.04) 14 (14.89) 34 (32.69) 36 (46.15) 15 (45.45) 38 (12.30) 19 (20.21) 13 (12.50) 5 (6.41) 1 (3.03) 40 (12.94) 20 (21.28) 14 (13.46) 3 (3.85) 3 (9.09) 68 (22.01) 32 (34.04) 29 (27.88) 6 (7.69) 1 (3.03) 309 94 104 78 33 104 (25.18) 51 (35.17) 27 (20.61) 12 (13.33) 14(29.79) 413 145 131 90 47 Users of AFB staining and commercial molecular assays Total AFB staining AFB staining only Commercial plus commercial molecular assays molecular assays only 113 (25.11) 64 (21.84) 49 (34.75) 0 (0.00) 134 (29.78) 91 (31.06) 35 (24.82) 8 (50.00) 56 (12.44) 35 (11.95) 18 (12.77) 3 (18.75) 55 (12.22) 37 (12.63) 15 (10.64) 3 (18.75) 92 (20.44) 66 (22.53) 24 (17.02) 2 (12.50) 450 293 141 16 202 (30.98) 95 (24.48) 98 (41.00) 9 (36.00) 652 388 239 25

< 0.00001

0.0262

Values expressed as n (%), except where otherwise indicated. bIncludes one respondent working in a country that could not be classified according to the World Bank classification.

tests, stratified by use of the Xpert assay and other molecular assays.

Acceptability of novel rapid diagnostic tests for tuberculosis The level of acceptability (an indirect indicator of the need for novel rapid diagnostic tests for tuberculosis) was determined for two different prototype assays: a novel molecular assay in line with the WHO TPP for a rapid sputum-based test for detecting M. tuberculosis; and a novel serological test in line with the WHO TPP for a biomarker-based triage test. Table 7 summarizes the results regarding the acceptability of the two assays among the survey respondents. More than 80% of the respondents would accept either novel test, provided that certain criteria were met, and there was no statistical difference between the two tests in terms of their acceptability (p = 0.084). With regard to novel molecular assays, responses regarding general acceptability did not differ significantly among countries stratified by World Bank classification income level (p = 0.0825). The level of acceptance was 386

J Bras Pneumol. 2017;43(5):380-392

significantly associated with a higher level of respondent education, defined as a doctorate or professorship (p < 0.002, data not shown), although not with the respondent having a decision-making role, respondent age, or respondent years of experience in the area of tuberculosis (p > 0.05 for all comparisons). It is noteworthy that the conditional acceptance based on validation differed between country types by income (p < 0.0025): survey respondents working in highincome countries were most likely to accept a test still undergoing validation (p < 0.05 for all comparisons), as shown in Table 7. Acceptance of a molecular assay still undergoing validation was positively associated with a higher level of respondent education (p < 0.003, data not shown) and expertise in immunology (p < 0.002, data not shown), whereas it showed no association with the respondent having a decision-making role, respondent age, or respondent years of experience in the area of tuberculosis (p > 0.05, data not shown). In contrast to the responses regarding the general acceptability of molecular assays, those regarding that of a novel serological assay differed significantly among

Amicosante M, D’Ambrosio L, Munoz M, Mello FC, Tebruegge M, Chegou NN, Seghrouchni F, Centis R, Goletti D, Bothamley G, Migliori GB

Table 4. Declared use of molecular assays among the survey respondents.a

Test used

Income level of the countries (World Bank classification)

Total High

Xpert MTB/RIF Other molecular assays Total

Upper middle Lower middle

193 (46.73) 220 (53.27)

52 (35.86) 92 (63.45)

55 (41.98) 76 (58.02)

50 (55.56) 41 (45.56)

413

145

131

Low 36 (76.60)

< 0.00001

11 (23.40) 47

Xpert MTB/RIF: rapid molecular assay for the identification of Mycobacterium tuberculosis and the detection of rifampin resistance. aValues expressed as n (%), except where otherwise indicated. Table 5. Rapid tuberculosis test prices, as reported by the molecular assay users surveyed, stratified by use of the Xpert assay and other molecular assays.a

Price range (US$)

Total

Molecular assay use Xpert Other 1-10 40 24 (26.32) (15.29) 11-20 54 45 (35.53) (28.66) 20-30 17 21 (11.18) (13.38) 30-50 12 28 (7.89) (17.83) > 50 29 39 (19.08) (24.84) Subtotal 152 157 p 0.0621 Do not know 40 64 (20.83) (28.96) Total 192 221

Income level of the countries High Upper middle Molecular assay Molecular assay use use Xpert Other Xpert Other 5 4 6 8 (12.20) (7.55) (13.33) (13.56) 7 7 17 17 (17.07) (13.21) (37.78) (28.81) 10 9 5 8 (24.39) (16.98) (11.11) (13.56) 6 14 4 10 (14.63) (26.42) (8.89) (16.95) 13 19 13 16 (31.71) (35.85) (28.89) (27.12) 41 53 45 59 0.5569 0.7336 12 39 10 17 (22.64) (42.39) (18.18) (22.37) 53 92 55 76

(World Bank classification) Lower middle Low Molecular assay Molecular assay use use Xpert Other Xpert Other 18 10 11 2 (43.90) (27.03) (44.00) (25.00) 19 17 11 4 (46.34) (45.95) (44.00) (50.00) 1 4 1 0 (2.44) (10.81) (4.00) (0.00) 0 3 2 1 (0.00) (8.11) (8.00) (12.50) 3 3 0 1 (7.32) (8.11) (0.00) (12.50) 41 37 25 8 0.1354 0.3818 9 3 9 5 (18.00) (7.50) (26.47) (38.46) 50 40 34 13

Xpert: rapid molecular assay for the identification of Mycobacterium tuberculosis and the detection of rifampin resistance. aValues expressed as n (%), except where otherwise indicated.

countries by income level (p = 0.0283). As can be seen in Table 7, fewer than three quarters of respondents working in high-income countries stated that such a test would be acceptable, which was significantly lower than that found for respondents working in other countries (p < 0.05 for all comparisons). Additional analyses revealed no association between acceptability and the level of education of the respondent, respondent age, and respondent years of experience in the area of tuberculosis (p > 0.05 for all comparisons, data not shown), whereas the respondent having a decisionmaking role showed borderline significance (p = 0.05 for all comparisons, data not shown).

Acceptability of novel rapid diagnostic tests for tuberculosis in relation to their performance characteristics Although more than 80% of the 723 survey respondents indicated general acceptance of a novel rapid diagnostic test for tuberculosis—622 (86.0%) indicating acceptance of a molecular test and 591 (81.7%) indicating acceptance of a serological test—391 (54.1%) indicated that their acceptance depended on test accuracy. The results regarding the acceptability

of novel tuberculosis tests based on their performance characteristics are summarized in Table 8. Nearly two thirds of the respondents indicated that they would expect a minimum sensitivity of > 90% (i.e., within the range of optimal sensitivity for the WHO TPPs for biomarker-based tests and rapid sputum-based tests). Fewer than 7% of the respondents indicated that they would be satisfied with a test sensitivity ≤ 80%. The expected sensitivity stated by respondents was not found to be associated with variables related to the respondent (years of experience in the area of tuberculosis, age, level of education, having a decision-making role, main area of expertise, and field of interest within the area of tuberculosis) or with the country income level (p > 0.05 for all comparisons, data not shown). Only 10.6% of the respondents stated that a specificity of 80-90%, the target specificity level stated in the WHO TPP for a triage test for active tuberculosis, would be acceptable. More than two thirds of the respondents stated that a novel test should have a minimum specificity of 95%. As with sensitivity, the level of specificity expected was not found to be associated with variables related to the respondent J Bras Pneumol. 2017;43(5):380-392

387

Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey

Table 6. Experience with molecular tests among survey respondents, stratified by use of the Xpert assay and other molecular assays.a

Test used

Income level of the countries (World Bank classification) High income Upper middle Lower middle Low-income income income Years of experience with molecular assays 1-10 > 10 1-10 > 10 1-10 > 10 1-10 > 10

Xpert MTB/RIF 23 (46.94) 26 (53.06) 46 (86.79) 7 (13.21) 42 (84.00) 8 (16.00) 30 (88.24) 4 (11.76) < 0.00001 Other molecular 29 (35.80) 52 (64.20) 45 (66.18) 23 (33.82) 20 (74.07) 7 (25.93) 6 (75.00) 2 (25.00) 0.003 assays p* 0.2846 0.0742 0.3891 0.3923 Values expressed as n (%), except where otherwise indicated. *Corrected for respondent age.

Table 7. Acceptability of a novel rapid sputum-based molecular assay and a novel serological assay.a

Acceptability

Not acceptable Acceptable Do not know Total Acceptable only if fully validated Acceptable even if still being validatedc Acceptable (manufacturerâ&#x20AC;&#x2122;s assurance sufficient)

Total

38 (5.26) 622b (86.03) 63 (8.71) 723b 355 (57.07) 227 (36.50) 40b (6.43)

Income level of the countries (World Bank classification) High Upper Lower Low middle middle Novel rapid molecular assay (prototype of a sputum-based assay) 9 (4.71) 12 (4.56) 7 (4.07) 10 (10.42) 157 (82.20) 235 (89.35) 153 (88.95) 76 (79.17) 25 (13.09) 16 (6.08) 12 (6.98) 10 (10.42) 191 263 172 96 70 (44.59) 140 (59.57) 101 (66.01) 44 (57.89) 78 (49.68) 81 (34.47) 41 (26.80) 27 (35.53) 9 (5.73)

14 (5.96)

11 (7.19)

0.0825

0.0025

5 (6.58)

Novel serological assay (prototype of a biomarker-based triage test) Not acceptable 61 (8.44) 20 (10.47) 19 (7.22) 17 (9.88) 5 (5.21) 82 (85.42) Acceptable 591b (81.74) 141 (73.82) 227 (86.31) 140 (81.40) Do not know 71 (9.82) 30 (15.71) 17 (6.46) 15 (8.72) 9 (9.38) 191 263 172 96 Total 723b 144 (63.44) 100 (71.43) 55 (67.07) Acceptable only if fully validated and 378b (63.96) 78 (55.32) in line with WHO indications 193 (32.66) 59 (41.84) 73 (32.16) 36 (25.71) 25 (30.49) Acceptable even if still being validated,c provided it was developed in line with WHO indications Acceptable (manufacturerâ&#x20AC;&#x2122;s 20 (3.38) 4 (2.84) 10 (4.41) 4 (2.86) 2 (2.44) assurance sufficient)

0.0383

0.1250

Values expressed as n (%), except where otherwise indicated. bIncludes one respondent working in a country that could not be classified according to the World Bank classification. cIf sufficiently independent peer-reviewed data are available. a

(years of experience in the area of tuberculosis, age, level of education, having a decision-making role, main area of expertise, and field of interest within the area of tuberculosis) or with the country income level (p > 0.05 for all comparisons, data not shown). DISCUSSION Tuberculosis control policies(1,2) are intimately related to the availability of effective tests for the diagnosis of active tuberculosis and for the identification of latent tuberculosis infection. Improved tuberculosis diagnostics, together with other interventions, are key to reaching the goal of entering the pre-elimination 388

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phase by 2035 in countries with a low incidence of the disease.(2,3,5) In this context, the WHO released indications for the TPP for tuberculosis tests in 2014, with the specific aim of setting the agenda for the development of rapid tests for the diagnosis of active tuberculosis.(8) However, policy application and the acceptance of novel tests could face additional barriers, including the perceptions and needs of tuberculosis specialists. In this paper, we have reported the results of a large global survey on tuberculosis diagnostics, including tests in current use and novel tests, establishing end-user acceptance based upon performance characteristics, the availability of validation data, and pricing, taking

Amicosante M, Dâ&#x20AC;&#x2122;Ambrosio L, Munoz M, Mello FC, Tebruegge M, Chegou NN, Seghrouchni F, Centis R, Goletti D, Bothamley G, Migliori GB

Table 8. Minimum sensitivity and specificity expected by survey respondents for novel tests for the diagnosis of active tuberculosis.a

Parameter

Total

Expected sensitivity > 50% 2 (0.51) > 60% 4 (1.03) > 70% 21 (5.40) > 80% 104 (26.74) > 90% 243 (62.47) Do not know 15 (3.86) Total 389 Expected specificity > 99% 99 (25.65) > 95% 174 (45.08) > 90% 58 (15.03) > 80% 41 (10.62) Do not know 14 (3.63) Total 386

Income level of the countries (World Bank classification) High Upper middle Lower middle Low

0 (0.00) 1 (0.76) 10 (7.63) 38 (29.01) 78 (59.54) 4 (3.05) 131

0 (0.00) 1 (0.74) 6 (4.41) 42 (30.88) 84 (61.76) 3 (2.21) 136

1 (1.35) 0 (0.00) 2 (2.70) 19 (25.68) 48 (64.86) 4 (5.41) 74

1 (2.08) 2 (4.17) 3 (6.25) 5 (10.42) 33 (68.75) 4 (8.33) 48

0.0976

31 (23.66) 66 (50.38) 20 (15.27) 10 (7.63) 4 (3.05) 131

34 (25.37) 57 (42.54) 25 (18.66) 16 (11.94) 2 (1.49) 134

23 (31.08) 29 (39.19) 10 (13.51) 8 (10.81) 4 (5.41) 74

11 (23.40) 22 (46.81) 3 (6.38) 7 (14.89) 4 (8.51) 47

0.2970

Values expressed as n (%), except where otherwise indicated.

the WHO TPPs into account. The survey respondents comprised 723 tuberculosis specialists from 114 countries and territories, with good coverage of regions with a high incidence of tuberculosis (Figure 1), and we therefore believe that the data collected are representative. To our knowledge, this is the largest study to date on the opinions and perceptions of the end users of tuberculosis tests regarding novel tuberculosis diagnostics. Our data show that AFB staining continues to be the most widely available test for tuberculosis, more than 90% of the survey respondents having access to this test. However, only three quarters of the respondents had access to culture and drug-susceptibility tests to properly identify the pathogen and determine the resistance pattern by phenotypic assays, which are still considered the gold standard. Our data also indicate that IGRAs are largely used by professionals for the diagnosis of tuberculosis infection mainly in high-income countries. Replacing tuberculin skin tests with IGRAs in middle- and low-income countries has been discouraged by the WHO, because IGRAs are technically complex and far more expensive, as well as because, despite their higher costs (because IGRAs usually also require laboratory technicians trained in their use), their performance is comparable to that of tuberculin skin tests.(24) Despite their suboptimal performance,(24,25) as well as the limitations to their use in young children, the elderly, and immunocompromised patients,(26-30) IGRAs are still widely used in high-income countries. However, tuberculosis pre-elimination and elimination policies will require novel tests for the rapid identification of individuals infected with tuberculosis and of those progressing to active tuberculosis, ideally with high sensitivity, high specificity, and low costs.(31) More than 70% of the survey respondents stated that they had access to in-house or commercial molecular assays for the diagnosis of tuberculosis.

In high-income countries, the large majority of respondents had access to such molecular assays. Even in lower income countries, approximately two thirds of the respondents had access to such assays, likely as a reflection of the large-scale roll-out of the Xpert assay, driven by WHO policy and a preferential pricing structure for low resource settings.(10) In addition, we found that the introduction of the Xpert assay at a subsidized price(10,18,22) resulted in a general alignment of molecular assay prices. In fact, the prices of first-generation commercial molecular assays (e.g., Amplicor and GeneProbe) were in the range of US$30-50 per test during the 2000-2008 period.(32,33) The present survey indicates that the current molecular assays are mostly in the US$11-20 price range, with common geographic pricing policies and no significant differences in price ranges between the Xpert assay and other molecular assays. A policy of sustained support and implementation of efficient second-generation assays will likely contribute to further increasing access to high-quality diagnostics, especially in low-income countries. Due to the low reproducibility and poor specificity of the currently available serological tests for the diagnosis of active tuberculosis (lateral flow immunoessays in particular),(19,20) the WHO has issued a recommendation against their use.(21) It was therefore surprising to find that more than a quarter of the survey respondents stated that they were currently using such tests. This is a cause for concern, because the use of these poorly performing tests results not only in significant expenditures but also in inappropriate management of patients. However, given that serological tests for tuberculosis might have some key advantages (including short assay times and comparatively low prices), there is a need for further research on novel serological tests developed in line with the WHO TPPs. It was also of note that the clear majority of respondents stated that J Bras Pneumol. 2017;43(5):380-392

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they would find a novel serological assay acceptable, as long as sufficient supporting data were available. The survey results indicate that over 80% of tuberculosis specialists are likely to accept a novel test for the rapid diagnosis of active tuberculosis if it is offered at an affordable price. Our results suggest that there is a perceived need for rapid assays that are more efficient, as well as that the acceptability of such assays is influenced by cost, respondents wanting the prices to be lower than those of the existing assays. This underscores the fact that, even with the preferential pricing that is currently available to facilities in low-resource countries, the prices of the tests are still perceived as prohibitive by some tuberculosis experts. Although the WHO developed TPPs for rapid tests for the diagnosis of tuberculosis three years ago,(8) nearly half of the tuberculosis experts surveyed stated they would accept a novel test for the diagnosis of tuberculosis even in the absence of robust data on test performance (based on assurances from the manufacturer alone or on preliminary data obtained while the test is still undergoing validation). Our findings indicate that, in addition to setting policies, there is a need to educate the end users of rapid tests for the diagnosis of tuberculosis. ACKNOWLEDGMENTS We thank the Global Laboratory Initiative of the WHO, the Associazione Microbiologi Clinici Italiani (AMCLI, Italian Society of Clinical Microbiology), the European Society of Mycobacteriology (ESM), the Paediatric Tuberculosis Network European Trials Group (ptbnet), and the Tuberculosis Network European Trialsgroup (TBNET) Clinical Research Collaboration, for sharing the survey link among the tuberculosis specialists in their networks. We are also grateful to all of the survey respondents for kindly supporting this initiative. The authors are immensely grateful for the contribution that Prof. Massimo Amicosante made as a man and as a scientist in the fight against tuberculosis. May he rest in peace. The TB Diagnostic Survey Working Group members (in alphabetical order): Abdulraheem A. M. Al-Hattami (National TB Programme, Sana’a, Yemen); Abebaw Kebede (Ethiopian Public Health Institute, Addis Ababa, Ethiopia); Adrian Rendon (University Hospital of Monterrey UANL, Monterrey, Mexico); Alberto L. Garcia-Basteiro (Centro de Investigação em Saude de Manhiça, Manhiça, Mozambique); Aliyu Samuel Abdulmumuni (State Specialist Hospital Gombe, Gombe, Nigeria); Amos Nota (SADC HIV/ AIDS Cross Border Initiative, Chirundu, Zambia); Analita Pace-Asciak (Infectious Disease Prevention and Control Unit, Ministry of Health, La Valletta, Malta); Andre Loxton (Stellenbosch University, Cape Town, South Africa); Angshu Bhowmik (Homerton University Hospital, London, UK); Antonino Catanzaro (University of California San Diego, San Diego, CA, USA); Aschalew 390

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Worku (St Peter Hospital, Addis Ababa, Ethiopia); Basirudeen Syed Ahamed Kabeer (National Institute for Research in Tuberculosis, Chennai, India); Branislava Savic (National reference laboratory for TB, Institute of Microbiology and Immunology, University of Belgrade, Belgrade, Serbia); Brian Bakoko Nselebete (National TB Programme, Kinshasa, Democratic Republic of the Congo); Carla Montesano (University of Rome “Tor Vergata”, Rome, Italy); Carlotta Montagnani (Anna Meyer Children’s University Hospital, Florence, Italy); Caterina Mammina (University of Palermo, Palermo, Italy); Celine Nkenfou (Centre Chantal Byia, Yaounde, Cameroon), Charlotte Kvasnovsky (University of Maryland Medical Center, Baltimore, MD, USA); Cristina Braz (Brazilian Thoracic Society, Brasilia, Brazil); Daniel Blázquez-Gamero (12 de Octubre University Hospital, Madrid, Spain); Daniela M Cirillo (IRCCS San Raffaele Scientific Institute, Milan, Italy); Dawit Kebede Huluka (Addis Ababa University College of Health Sciences, Addis Ababa, Ethiopia); Diah Handayani (University Indonesia, Jakarta, Indonesia); Dimitrios Papaventsis (National Reference Laboratory for Mycobacteria, Sotiria Chest Diseases Hospital of Athens, Athens, Greece); Domingo Palmero (Hospital Muñiz, Buenos Aires, Argentina); Donald Catanzaro (University of Arkansas, Fayetteville, AR, USA); Duncan Chanda (University of Zambia School of Medicine, Lusaka, Zambia); Elmira Gurbanova (Main Medical Department of the Ministry of Justice, Baku, Azerbaijan); Eman Sobh (Al-Azhar University, Cairo, Egypt); Fikru Melaku Gebremariam (Oromia Public Health Research Laboratory, Oromia, Ethiopia); Florence Komurian Pradel (Fondation Mérieux, Lyon, France); Gaetano Brindicci (Santa Maria della Misericordia Hospital, Urbino, Italy); Giovanni Sotgiu (University of Sassari, Sassari, Italy); Giuseppina De Iaco (“Ospedali Riuniti Ancona”, Ancona, Italy); Grace Kahenya (University of Lusaka, Lusaka, Zambia); Grace Nwankwo (Federal Teaching Hospital, Abakaliki, Nigeria); Harald Hoffmann (Synlab MVZ Gauting, Gauting, Germany); Hebert Mutunzi (Ministry of Health and Child Care, Harare, Zimbabwe); Ilora Kenechukwu (Lyienu Mission Hospital, Ogidi, Nigeria); Ivan Pavic (Children’s Hospital Zagreb, Zagreb, Croatia); Jean-Pierre Mukeba (Coordination Provinciale Lepre et Tuberculose du Haut-Katanga, Lubumbashi, Democratic Republic of Congo); Jesse Wambugu (Foundation for Innovative New Diagnostics [FIND], Nairobi, Kenya); Kedir Abdella Abdulsemed (Jimma University Mycobacteriology Research Center, Jimma, Ethiopia); Kingsley Nnanna Ukwaja (Federal Teaching Hospital, Abakaliki, Nigeria); Lanfranco Fattorini (Italian National Institute of Health, Rome, Italy); Lorenzo Guglielmetti (Bligny Hospital, Paris, France); Lorenzo Zammarchi (University of Florence, Florence, Italy); Luis Anibarro (Unidad de Tuberculosis, Complexo Hospitalario de Pontevedra, Pontevedra, Spain); Lynn S. Zijenah (University of Zimbabwe College of Health Sciences, Harare, Zimbabwe); Marc Lipman (University College London, London, UK); Mariya Ivanovska (Medical University of Plovdiv, Plovdiv, Bulgaria); Maria Nikolova (National Center of Infectious and Parasitic

Amicosante M, D’Ambrosio L, Munoz M, Mello FC, Tebruegge M, Chegou NN, Seghrouchni F, Centis R, Goletti D, Bothamley G, Migliori GB

Diseases, Sofia, Bulgaria); Martin Castellanos Joya (Ministry of Health, Mexico City, Mexico); Maryline Bonnet (Institut de Recherche pour le Développement, INSERM U1175, Montpellier, France); Master Chisale (Mzuzu Central Hospital, Mzuzu, Malawi); Mathilde Frechet Jachym (Sanatorium Bligny, Briss Sous Forges, France); Mohamed Elmi (Ministry of Health, Mogadishu, Somalia); Muktar A. Gadanya (Aminu Kano Teaching Hospital/Bayero University, Kano, Nigeria); Muluwork Getahun (Ethiopian Public Health Institute, Addis Ababa, Ethiopia); Nicolas Veziris (Centre National de Référence des Mycobactéries, APHP, UPMC Paris, Paris, France); Nii Nortey Hanson-Nortey (National TB Programme, Accra, Ghana); Ogonna N.O. Nwankwo (University of Calabar teaching Hospital, Calabar, Nigeria); Paola Del Monte (University of Bologna, Bologna, Italy); Rachid Fourati (Direction de Soins de Sainte de Base, Tunis, Tunisia); Rafael Laniado-Laborín (Hospital General Tijuana, Tijuana, Mexico); Rakesh Lodha (All India Institute of Medical Sciences, New Delhi, India); Rebecca Wong (Society for Thoracic Disease, Beijing, China); Regina Bhebhe (National Tuberculosis Reference Laboratory, Harare, Zimbabwe); Roberto de la Tour (Medicine Sans Frontieres, OCG, Geneva, Switzerland); Roberto Targa Ferreira (Hospital N. S. da Conceição, Conceição, Brazil); Sambo Boy (National Center for Tuberculosis and Leprosy Control/WHO-Special Service Agreement

[CENAT/WHO-SSA], Phnom Penh, Cambodia); Samuel Eyanu (National TB Reference Laboratory, Kampala, Uganda); Sarman Singh (All India Institute of Medical Sciences, New Delhi, India); Silva Tafaj (University Hospital “Shefqet Ndroqi”, Tirana, Albania); Simone A Joosten (Leiden University Medical Center, Leiden, the Netherlands); Steven Callens (Ghent University Hospital, Ghent, Belgium); Sylvester Moyo (Clinton Health Access Initiative, Mbabane, Swaziland); Teklu Molie Tao (Dire Dawa Regional Health Bureau, Dire Dawa, Ethiopia); Tewodros Haile Gebremariam (Addis Ababa University College of Health Sciences, Addis Ababa, Ethiopia); Thomas Panwal Meshak (Institute of Human Virology, Abuja, Nigeria); Tomas Perez-Porcuna (Hospital Universitaria Mútua Terrassa, Barcelona, Spain); Tuula Vasankari (Filha and University of Turku, Turku, Finland); Valeria Cavalcanti Rolla (National Institute of Infectious Diseases Evandro Chagas - Fundação Oswaldo Cruz [Fiocruz, Oswaldo Cruz Foundation], Rio de Janeiro, Brazil); Varinder Singh (Lady Hardinge Medical College, New Delhi, India); Vinod H Ratageri (Karnataka Institute of Medical Sciences, Karnataka, India); Vladimir Milanov (University Hospital for Respiratory Diseases “St. Sofia”, Sofia, Bulgaria); Yuri Rosati (Ospedale Provinciale Macerata, Macerata, Italy); and Zhenia Fuentes-Alcala (Hospital Dr Jose Ignacio Baldo, El Algodonal, Caracas, Venezuela).

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Gagneux S, et al. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement. Int J Tuberc Lung Dis. 2016;20(1):24-42. https://doi.org/10.5588/ijtld.15.0221 12. Albert H, Nathavitharana RR, Isaacs C, Pai M, Denkinger CM, Boehme CC. Development, roll-out and impact of Xpert MTB/ RIF for tuberculosis: what lessons have we learnt and how can we do better? Eur Respir J. 2016;48(2):516-25. https://doi. org/10.1183/13993003.00543-2016 13. Barreto LB, Lourenço MC, Rolla VC, Veloso VG, Huf G. Use of amplified Mycobacterium tuberculosis direct test in respiratory samples from HIV-infected patients in Brazil. J Bras Pneumol. 2014;40(2):148-54. https://doi.org/10.1590/S1806-37132014000200008 14. Furini AA, Pedro Hda S, Rodrigues JF, Montenegro LM, Machado RL, Franco C, et al. Detection of Mycobacterium tuberculosis complex by nested polymerase chain reaction in pulmonary and extrapulmonary specimens. J Bras Pneumol. 2013;39(6):711-8. https://doi.org/10.1590/S1806-37132013000600010 15. Moreira Ada S, Huf G, Vieira MA, Fonseca L, Ricks M, Kritski AL. Performance comparison between the mycobacteria growth indicator tube system and Löwenstein-Jensen medium in the routine detection of Mycobacterium tuberculosis at public health care facilities in Rio de Janeiro, Brazil: preliminary results of a pragmatic clinical trial. J Bras Pneumol. 2013;39(3):365-7. https://doi. org/10.1590/S1806-37132013000300014 16. Telles MA, Menezes A, Trajman A. Bottlenecks and recommendations for the incorporation of new technologies in the tuberculosis laboratory network in Brazil. J Bras Pneumol. 2012;38(6):766-70. https://doi.org/10.1590/S1806-37132012000600013 17. Albert H, Nathavitharana RR, Denkinger CM, Isaacs C, Boehme CC. Tuberculosis prevention must integrate technological and basic care innovation. Eur Respir J. 2016;48(5):1531-1532. https://doi. org/10.1183/13993003.01601-2016 18. McNerney R, Cunningham J, Hepple P, Zumla A. New tuberculosis diagnostics and rollout. Int J Infect Dis. 2015;32:81-6. https://doi. org/10.1016/j.ijid.2015.01.012 19. Steingart KR, Flores LL, Dendukuri N, Schiller I, Laal S, Ramsay A, et al. Commercial serological tests for the diagnosis of active J Bras Pneumol. 2017;43(5):380-392

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pulmonary and extrapulmonary tuberculosis: an updated systematic review and meta-analysis. PLoS Med. 2011;8(8):e1001062. https:// doi.org/10.1371/journal.pmed.1001062 20. Steingart KR, Ramsay A, Dowdy DW, Pai M. Serological tests for the diagnosis of active tuberculosis: relevance for India. Indian J Med Res. 2012;135(5):695-702. 21. World Health Organization. Commercial serodiagnostic tests for diagnosis of tuberculosis. Policy Statement. Geneva: World Health Organization; 2001. 22. Migliori GB, Lienhardt C, Weyer K, van der Werf MJ, Blasi F, Raviglione MC. Ensuring rational introduction and responsible use of new TB tools: outcome of an ERS multisector consultation. Eur Respir J. 2014;44(6):1412-7. https://doi.org/10.1183/09031936.00132114 23. United Nations. Department of Economic and Social Affairs; Population Division. World Population Ageing 2015. New York City: United Nations; 2015. 24. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev. 2014;27(1):3-20. https:// doi.org/10.1128/CMR.00034-13 25. Losi M, Knights AJ, Mariani F, Altieri AM, Paone G, Loxton AG, et al. QuantiFERON-TB performance enhanced by novel Mycobacterium tuberculosis-specific antigens. Eur Respir J. 2016;47(2):660-4. https://doi.org/10.1183/13993003.01015-2015 26. Edwards A, Gao Y, Allan RN, Ball D, de Graaf H, Coelho T, et al. Corticosteroids and infliximab impair the performance of interferon-Îł release assays used for diagnosis of latent tuberculosis. Thorax. 2017;72(10):946-949. https://doi.org/10.1136/thoraxjnl-2016-209397 27. Tebruegge M, Ritz N, Curtis N, Shingadia D. Diagnostic Tests

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for Childhood Tuberculosis: Past Imperfect, Present Tense and Future Perfect? Pediatr Infect Dis J. 2015;34(9):1014-9. https://doi. org/10.1097/INF.0000000000000796 28. Tebruegge M, Dutta B, Donath S, Ritz N, Forbes B, CamachoBadilla K, et al. Mycobacteria-Specific Cytokine Responses Detect Tuberculosis Infection and Distinguish Latent from Active Tuberculosis. Am J Respir Crit Care Med. 2015;192(4):485-99. https://doi.org/10.1164/rccm.201501-0059OC 29. Tebruegge M, Ritz N, Koetz K, Noguera-Julian A, Seddon JA, Welch SB, et al. Availability and use of molecular microbiological and immunological tests for the diagnosis of tuberculosis in Europe. PLoS One. 2014;9(6):e99129. https://doi.org/10.1371/journal. pone.0099129 30. Tebruegge M, de Graaf H, Sukhtankar P, Elkington P, Marshall B, Schuster H, et al. Extremes of age are associated with indeterminate QuantiFERON-TB gold assay results. J Clin Microbiol. 2014;52(7):2694-7. https://doi.org/10.1128/JCM.00814-14 31. Petruccioli E, Scriba TJ, Petrone L, Hatherill M, Cirillo DM, Joosten SA, et al. Correlates of tuberculosis risk: predictive biomarkers for progression to active tuberculosis. Eur Respir J. 2016;48(6):17511763. https://doi.org/10.1183/13993003.01012-2016 32. Pinto M, Entringer AP, Steffen R, Trajman A. Cost analysis of nucleic acid amplification for diagnosing pulmonary tuberculosis, within the context of the Brazilian Unified Health Care System. J Bras Pneumol. 2015;41(6):536-8. https://doi.org/10.1590/s180637562015000004524 33. Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression. PLoS ONE. 2008;3(2):e1536. https://doi.org/10.1371/journal.pone.0001536

J Bras Pneumol. 2017;43(5):393-398 http://dx.doi.org/10.1590/S1806-37562016000000368

PICTORIAL ESSAY

Usual interstitial pneumonia: typical, possible, and “inconsistent” patterns Pedro Paulo Teixeira e Silva Torres1, Marcelo Fouad Rabahi2, Maria Auxiliadora Carmo Moreira2, Gustavo de Souza Portes Meirelles3, Edson Marchiori4 1. Multimagem Diagnósticos, Goiânia (GO) Brasil. 2. Universidade Federal de Goiás, Goiânia (GO) Brasil. 3. Grupo Fleury, São Paulo (SP) Brasil. 4. Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. Submitted: 4 December 2016. Accepted: 4 May 2017. Study carried out at Multimagem Diagnósticos and at the Universidade Federal de Goiás, Goiânia (GO) Brasil.

ABSTRACT Idiopathic pulmonary fibrosis is a severe and progressive chronic fibrosing interstitial lung disease, a definitive diagnosis being established by specific combinations of clinical, radiological, and pathological findings. According to current international guidelines, HRCT plays a key role in establishing a diagnosis of usual interstitial pneumonia (UIP). Current guidelines describe three UIP patterns based on HRCT findings: a typical UIP pattern; a pattern designated “possible UIP”; and a pattern designated “inconsistent with UIP”, each pattern having important diagnostic implications. A typical UIP pattern on HRCT is highly accurate for the presence of histopathological UIP, being currently considered to be diagnostic of UIP. The remaining patterns require further diagnostic investigation. Other known causes of a UIP pattern include drug-induced interstitial lung disease, chronic hypersensitivity pneumonitis, occupational diseases (e.g., asbestosis), and connective tissue diseases, all of which should be included in the clinical differential diagnosis. Given the importance of CT studies in establishing a diagnosis and the possibility of interobserver variability, the objective of this pictorial essay was to illustrate all three UIP patterns on HRCT. Keywords: Tomography, X-ray computed; Lung diseases, interstitial; Pulmonary fibrosis.

INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease that is usually progressive. Recently defined diagnostic criteria include exclusion of other known causes of interstitial lung disease, the presence of a usual interstitial pneumonia (UIP) pattern on HRCT, and specific combinations of HRCT and surgical lung biopsy patterns.(1,2) A typical UIP pattern on HRCT has been shown to be highly accurate for the presence of a UIP pattern on surgical lung biopsy (90-100%); reliable imaging features of UIP are currently considered to be diagnostic of a UIP pattern, without the need for a surgical lung biopsy.(1) Surgical lung biopsy is currently recommended when HRCT findings are not typical of UIP, a definitive diagnosis being established by specific combinations of imaging and histopathological findings.(1) Therefore, correct interpretation of HRCT findings is essential for a definitive diagnosis, particularly in view of the fact that antifibrotic agents have recently been approved for use in the treatment of IPF.(3) Current guidelines describe three UIP patterns based on HRCT findings: a typical UIP pattern (which eliminates the need for surgical lung biopsy); a pattern designated “possible UIP”; and a pattern designated “inconsistent with UIP”, surgical lung biopsy being required in patients presenting with either of the last two patterns.(1,2,4) The objective of the present study was to describe and illustrate

the criteria for classifying patients as having a typical UIP pattern, a possible UIP pattern, or an inconsistent with UIP pattern. HRCT FEATURES CHARACTERIZING UIP PATTERNS

Typical UIP pattern A typical UIP pattern on HRCT consists of predominantly basal and peripheral reticular opacities and honeycombing, with or without traction bronchiolectasis. In addition, all of the findings that are considered to be inconsistent with UIP must be absent (Figure 1).(1) When all of the aforementioned criteria are met, the findings are considered to be pathognomonic for UIP, eliminating the need for a surgical lung biopsy.(1) There is good interobserver agreement among radiologists for typical UIP findings.(5,6) It is of note that UIP and IPF are not synonyms, known causes of a UIP pattern including drug-induced interstitial lung disease, occupational diseases (e.g., asbestosis), hypersensitivity pneumonitis, and connective tissue diseases.(5)

Possible UIP pattern A possible UIP pattern consists of predominantly basal and peripheral reticular opacities and no honeycombing or any of the findings that are considered to be inconsistent with UIP (Figure 2).(1) A possible UIP pattern is less specific for UIP than is a typical UIP pattern, the main

Correspondence to:

Pedro Paulo Teixeira e Silva Torres. Rua 9, 326, Residencial Amaury Menezes, apto. 1502, Setor Oeste, CEP 74110-100, Goiânia, GO, Brasil. Tel.: 55 62 99291-8514. E-mail: pedroptstorres@gmail.com Financial support: None. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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differential diagnosis being with fibrotic nonspecific interstitial pneumonia (NSIP).(5) No honeycombing, extensive ground-glass opacity, subpleural sparing, and lower lobe volume loss are suggestive of NSIP.(7-9) Honeycombing is rare in cases of NSIP, having been found in less than 5% of the patients with idiopathic NSIP investigated in one study.(7)

Inconsistent with UIP pattern Findings that are considered to be inconsistent with UIP include a) longitudinal disease distribution in the middle and upper lung fields; b) peribronchovascular predominance of changes in the axial axis (Figure 3); c) extensive ground-glass opacity, the extent of which is greater than that of reticular opacities; d) bilateral scattered micronodules predominantly in the upper lung fields (Figure 4); e) cysts (multiple, bilateral, away from areas of fibrosis); f) a mosaic perfusion pattern/air trapping (bilateral, in three or more lobes; Figure 5); and g) consolidations. Several of the aforementioned findings are suggestive of chronic hypersensitivity pneumonitis (CHP), further investigation being required for a differential diagnosis.(5)

SPECIAL CONSIDERATIONS

Technical aspects Technically satisfactory image acquisition is required for a correct diagnosis, minimum technical requirements including a) images acquired at full inhalation, without motion artifacts; b) thin, sequential or volumetric axial images with a reconstruction interval ≤ 2 cm; c) slice thickness ≤ 2 mm; d) use of a high-resolution algorithm; e) a field of view optimized to include only lung parenchyma; f) images acquired during exhalation are useful for defining air trapping; g) use of the prone position in case of uncertainty regarding position-dependent opacities; and h) use of multiplanar reconstructions of volume acquisition CT images.(10) Inadequately performed inspiratory maneuvers can result in increased/heterogeneous lung attenuation and motion artifacts that can adversely affect CT studies (Figure 6). Suggestions for improving the quality of CT studies include the use of simple, clear instructions on how to perform inspiratory/expiratory maneuvers, patient training in different breathing levels before

Figure 1. A 77-year-old female patient presenting with a typical usual interstitial pneumonia pattern. In A, axial CT scans of the chest with lung window settings, showing reticular opacities, traction bronchiectasis, and extensive honeycombing. In B, coronal reformatted CT images showing an apicobasal gradient of involvement.

Figure 2. A 75-year-old male patient presenting with a possible usual interstitial pneumonia pattern. Axial CT scan of the chest with lung window settings (in A) and coronal reformatted CT image (in B) showing peripheral reticular opacities and traction bronchiolectasis (in A) and an apicobasal gradient (in B), without honeycombing.

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Torres PPTS, Rabahi MF, Moreira MAC, Meirelles GSP, Marchiori E

Figure 3. A 38-year-old female patient presenting with an inconsistent with usual interstitial pneumonia pattern and diagnosed with chronic hypersensitivity pneumonitis. Axial HRCT scan of the chest with lung window settings, showing diffuse reticular opacities with traction bronchiolectasis. Note severe peribronchovascular bundle involvement in the right upper lobe (arrow).

Figure 5. A 61-year-old female patient presenting with an inconsistent with usual interstitial pneumonia pattern and diagnosed with chronic hypersensitivity pneumonitis. Axial HRCT scans of the chest with lung window settings, showing diffuse reticular opacities, as well as areas of ground-glass attenuation associated with areas of decreased attenuation (arrows), characterizing a mosaic pattern.

Interobserver agreement was found to be only moderate for experienced general radiologists and thoracic radiologists, the difficulty in distinguishing among UIP patterns being attributed to discrepancies regarding the presence and distribution of honeycombing.

Atypical patterns and differential diagnosis

Figure 4. A 63-year-old female patient presenting with an inconsistent with usual interstitial pneumonia pattern and diagnosed with sarcoidosis. Axial HRCT scan of the chest with lung window settings, showing confluent, predominantly peribronchovascular reticular opacities with characteristics of micronodules with a perilymphatic distribution (arrows).

image acquisition, and the use of rest periods during sequential acquisitions.(10)

Diagnosis of honeycombing A correct CT diagnosis of honeycombing is a crucial step in identifying a typical UIP pattern and establishing a clinical and imaging diagnosis of IPF.(1) However, even among evaluators with extensive experience in interstitial lung disease, there is significant interobserver variability in attempts to detect honeycombing and differentiate it from other findings, such as traction bronchiectasis, cystic disease, and pulmonary emphysema (Figure 7).(11) Diagnostic criteria for honeycombing include predominantly subpleural cysts of 3-10 mm in diameter, sharing relatively thick (1-3 mm) walls and grouped on layers, and the exclusion of emphysema.(11,12)

Interobserver agreement: CT criteria for UIP patterns Walsh et al.(13) evaluated interobserver agreement for the current criteria for a UIP pattern on CT.

Although typical CT findings of UIP can predict a histopathological diagnosis of UIP, they are absent in up to 30% of patients.(14) Sverzellati et al.(14) studied histopathologically confirmed cases of UIP and found that radiologists made an alternative diagnosis in 62% of the cases. The aforementioned study(14) shows that, although CT is highly accurate in diagnosing UIP in typical situations, CT studies should not be used in order to exclude the possibility of UIP. In atypical cases, first-choice diagnoses include NSIP, CHP, sarcoidosis, and chronic organizing pneumonia.

Temporal evolution The clinical course of IPF is variable and unpredictable at the time of diagnosis; although most patients experience a slow progressive decline, some remain stable, whereas others experience a rapid decline.(1,15) With regard to the severity of HRCT findings, areas of ground-glass attenuation usually progress to reticular opacities, which in turn progress to honeycombing, the extent of which increases over time.(16) It is of note that CT interpretation changes over time, meaning that a possible UIP pattern can progress to a typical UIP pattern (Figure 8).

Future directions The risks of performing a surgical lung biopsy in patients with interstitial lung disease should be taken into consideration; in many cases, diagnosis and treatment are delayed because patient clinical status is a contraindication to biopsy.(17,18) Therefore, there is a growing interest in the noninvasive diagnosis of J Bras Pneumol. 2017;43(5):393-398

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Figure 6. Axial CT scans of the chest with lung window settings. In A, scan taken during an inadequately performed inspiratory maneuver, the resulting image resembling diffuse ground-glass opacity. In B, a new scan, taken during an adequately performed inspiratory maneuver.

Figure 7. In A, axial HRCT scan of the chest with lung window settings. In B, coronal reformatted CT image (minimum intensity projection). In A, images suggestive of a cluster of subpleural cysts (arrows), suspected of being honeycombing but found to be traction bronchiectasis (arrows) on oblique coronal reformatted CT images (in B).

IPF, particularly in cases of patients presenting with CT findings of possible UIP. Recent studies comparing IPF patients with a typical UIP pattern and those with a possible UIP pattern have shown clinical and functional similarities between the two groups of patients, as well as showing evidence of a comparable response to antifibrotic treatment with nintedanib. (19-21) Several studies investigating patients with IPF have shown high rates of biopsy-proven UIP in those with a possible UIP pattern.(22-25) Age at disease onset and the extent of fibrosis on initial HRCT scans have been significantly related to a high probability of IPF, a possible UIP pattern being suggestive of a clinical and radiological diagnosis of IPF in the following cases: a) typical clinical and demographic presentation (i.e., patients over 60 years of age presenting with dyspnea on exertion and pulmonary fibrosis of indeterminate etiology), as determined by a specialist in interstitial lung diseases; and b) imaging findings of possible UIP, according to a specialist in interstitial imaging.(24,26) It is of note that some of the studies suggesting that CT findings of possible UIP are sufficient for a 396

J Bras Pneumol. 2017;43(5):393-398

Figure 8. Axial HRCT scans of the chest with lung window settings, showing the right lower lobe. In A, initial CT findings meeting the criteria for possible usual interstitial pneumonia (UIP), i.e., reticular opacities and ground-glass attenuation, without honeycombing. In B, follow-up CT findings six years later, meeting the criteria for a typical UIP pattern, with disease progression and honeycombing.

diagnosis of IPF derived from clinical trials in which the prevalence of IPF was high, meaning that the results might have been overestimated.(23,24) In a study conducted by Brownell et al.,(25) it was found that a possible UIP pattern is highly specific for UIP on biopsy; however, the positive predictive value of that pattern is directly related to the prevalence of IPF in the study population. Therefore, according to the authors, a possible UIP pattern on HRCT should not be regarded as confirmatory of histopathological UIP in populations in whom the prevalence of IPF is low or indeterminate.(25) Given that the prevalence of CHP is high (i.e., as high as 15%) in Brazil, studies are needed in order to determine the prevalence of IPF in patients with possible UIP before a decision can be made regarding the need for biopsy in such patients.(27) Noninvasive diagnostic algorithms for CHP have been proposed, including a typical CT pattern, lymphocytosis in BAL fluid (lymphocyte count > 20-30%), and

Torres PPTS, Rabahi MF, Moreira MAC, Meirelles GSP, Marchiori E

identification of a causal relationship; such algorithms are extremely useful in the diagnosis of fibrotic interstitial lung diseases, given that the differential diagnosis between CHP and IPF is often difficult.(27,28) FINAL CONSIDERATIONS Of all idiopathic interstitial lung diseases, IPF is the most common; it has a poor prognosis in most cases, and the histopathological substrate of IPF is UIP.(29)

In a recent review of the diagnostic algorithm for IPF, HRCT was shown to play an indispensable role in characterizing UIP, typical findings being diagnostic of UIP and atypical findings requiring histopathological analysis.(1) For a definitive diagnosis, radiologists must be familiar with all UIP patterns and must be able to describe them accurately when writing radiological reports or participating in multidisciplinary meetings, particularly in view of current perspectives on the treatment of IPF, with the use of antifibrotic agents.

REFERENCES 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. https://doi. org/10.1164/rccm.2009-040GL 2. Baddini-Martinez J, Baldi BG, Costa CH, Jezler S, Lima MS, Rufino R. Update on diagnosis and treatment of idiopathic pulmonary fibrosis. J Bras Pneumol. 2015;41(5):454-66. https://doi.org/10.1590/S180637132015000000152 3. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015;192(2):e3-19. https://doi.org/10.1164/rccm.201506-1063ST 4. Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6),733-48. https://doi.org/10.1164/rccm.201308-1483ST 5. Hodnett PA, Naidich DP. Fibrosing interstitial lung disease. A practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature. Am J Resp Crit Care Med. 2013;188(2):141-9. https://doi.org/10.1164/ rccm.201208-1544CI 6. Flaherty KR, Thwaite EL, Kazerooni EA, Gross BH, Toews GB, Colby TV, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-8. https://doi. org/10.1136/thorax.58.2.143 7. Travis WD, Hunninghake G, King TE Jr, Lynch DA, Colby TV, Galvin JR, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008;177(12):1338-47. https://doi.org/10.1164/rccm.2006111685OC 8. Silva CI, Müller NL, Lynch DA, Curran-Everett D, Brown KK, Lee KS, et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. 2008;246(1):288-97. https:// doi.org/10.1148/radiol.2453061881 9. Sumikawa H, Jonkoh T, Fujimoto K, Arakawa H, Colby TV, Fukuoka J, et al. Pathologically proved nonspecific interstitial pneumonia: CT pattern analysis as compared with usual interstitial pneumonia CT pattern. Radiology. 2014;272(2):549-56. https://doi.org/10.1148/ radiol.14130853 10. Bankier AA, O’Donnell CR, Boiselle PM. Quality initiatives. Respiratory instructions for CT examinations of the lungs: a hands-on guide. Radiographics. 2008;28(4):919-31. https://doi. org/10.1148/rg.284085035 11. Watadani T, Sakai F, Johkon T, Noma S, Akira M, Fujimoto K, et al. Interobserver variability in the CT assessment of honeycombing in the lungs. Radiology. 2013;266(3):936-44. https://doi.org/10.1148/ radiol.12112516 12. Silva CI, Marchiori E, Souza Júnior AS, Müller NL; Comissão de Imagem da Sociedade Brasileira de Pneumologia e Tisiologia. Illustrated Brazilian consensus of terms and fundamental patterns in chest CT scans. J Bras Pneumol. 2010;36(1):99-123. https://doi. org/10.1590/S1806-37132010000100016 13. Walsh SL, Calandriello L, Sverzellati N, Wells AU, Hansell DM; UIP Observer Consort. Interobserver agreement for the ATS/ERS/JRS/ ALAT criteria for a UIP pattern on CT. Thorax. 2016;71(1):45-51.

https://doi.org/10.1136/thoraxjnl-2015-207252 14. Sverzellati N, Wells AU, Tomassetti S, Desai SR, Copley SJ, Aziz ZA, et al. Biopsy-proved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thin-section CT diagnoses. Radiology. 2010;254(3):957-64. https://doi.org/10.1148/radiol.0990898 15. Raghu G. Idiopathic pulmonary fibrosis. A rational clinical approach. Chest. 1987;92(1):148-54. https://doi.org/10.1378/chest.92.1.148 16. Misumi S, Lynch DA. Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of abnormalities, and temporal progression. Proc Am Thorac Soc. 2006;3(4):307-14. https://doi.org/10.1513/pats.200602-018TK 17. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. InHospital Mortality after Surgical Lung Biopsy for Interstitial Lung Disease in the United States. 2000 to 2011. Am J Resp Crit Care Med. 2016;193(10);1161-7. https://doi.org/10.1164/rccm.2015081632OC 18. Hutchinson JP, McKeever TM, Fogarty AW, Navaratnam V, Hubbard RB. Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997-2008. Eur Respir J. 2016;48(5):14531461. https://doi.org/10.1183/13993003.00378-2016 19. Raghu G, Wells AU, Nicholson AG, Richeldi L, Flaherty KR, Le Maulf F, ,et al. Effect of Nintendanib in Subgroups of Idiopathic Pulmonary Fibrosis by Diagnostic Criteria. Am J Respir Crit Care Med. 2017;195(1):78-85. https://doi.org/10.1164/rccm.201602-0402OC 20. Lee JW, Shehu E, Gjonbrataj J, Bahn YE, Rho BH, Lee MY, et al. Clinical Findings and outcomes in patients with possible usual interstitial pneumonia. Respir Med. 2015;109(4):510-6. https://doi. org/10.1016/j.rmed.2015.02.008 21. Gruden JF, Panse PM, Gotway MB, Jensen EA, Wellnitz CV, Wesselius L. Diagnosis of Usual Interstitial Pneumonitis in the Absence of Honeycombing: Evaluation of Specific CT Criteria With Clinical Follow-Up in 38 Patients. AJR Am J Roentgenol. 2016;206(3):472-80. https://doi.org/10.2214/AJR.15.14525 22. Gruden JF, Panse PM, Leslie KO, Tazelaar HD, Colby TV. UIP diagnosed at surgical lung biopsy, 2000-2009: HRCT patterns and proposed classification system. AJR Am J Roentgenol. 2013;200(5):W458-67. https://doi.org/10.2214/AJR.12.9437 23. Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, et al. CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis. Chest. 2015;147(2):450-459. https://doi.org/10.1378/chest.14-0976 24. Raghu G, Lynch D, Godwin JD, Webb R, Colby TV, Leslie KO, et al. Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial. Lancet Respir Med. 2014;2(4):277-84. https://doi.org/10.1016/S22132600(14)70011-6 25. Brownell R, Moua T, Henry TS, Elicker BM, White D, Vittinghoff E, et al. The use of pretest probability increases the value of highresolution CT in diagnosing usual interstitial pneumonia. Thorax. 2017;72(5):424-429. https://doi.org/10.1136/thoraxjnl-2016-209671 26. Salisbury ML, Xia M, Murray S, Bartholmai BJ, Kazerooni EA, Meldrum CA, et al. Predictors of idiopathic pulmonary fibrosis in absence of radiologic honeycombing: A cross sectional analysis in ILD patients undergoing lung tissue sampling. Respir Med. 2016;118:88-95. https://doi.org/10.1016/j.rmed.2016.07.016 27. Pereira CA, Gimenez A, Kuranishi L, Storrer K. Chronic hypersensitivity pneumonitis. J Asthma Allergy. 2016;9:171-181. eCollection 2016. J Bras Pneumol. 2017;43(5):393-398

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28. Salisbury ML, Myers JL, Belloli EA, Kazerooni EA, Martinez FJ, Flaherty KR. Diagnosis and Treatment of Fibrotic Hypersensitivity Pneumonia. Where We Stand and Where We Need to Go. Am J Respir Crit Care Med. 2016 Dec 21. [Epub ahead of print] https:// doi.org/10.1164/rccm.201608-1675PP 29. American Thoracic Society; European Respiratory Society. American

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Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165(2):277-304. https://doi.org/10.1164/ajrccm.165.2.ats01

J Bras Pneumol. 2017;43(5):399-399 http://dx.doi.org/10.1590/S1806-37562017000000162

IMAGING IN PULMONARY MEDICINE

Liquid silicone injection in the chest wall simulating cysticercosis Luiz Felipe Nobre1, Gláucia Zanetti2, Edson Marchiori2

A 37-year-old homosexual Brazilian man presented with fever, chest pain, and several small, palpable lumps in the anterior chest wall. Physical examination revealed numerous mobile subcutaneous and intramuscular nodules measuring 1-2 cm in the anterior chest wall, with signs of a local inflammatory process. Chest CT scanning showed numerous round and oval nodules, most of which had rim calcifications, in the anterior chest wall. The nodules were apparently related to the muscles of the region (Figure 1). Since the patient was from a cysticercosis endemic region, this infection was initially suspected. However, the CT findings were not suggestive of cysticercosis. The

characteristic morphology of the calcifications observed in cysticercosis is “rice like” (or “cigar shaped”), and the calcifications are orientated along the long axes of the muscles. In addition, nodules in cysticercosis are distributed diffusely throughout the muscles.(1) In our case, the calcifications presented with a rimmed aspect and occurred only in the anterior chest wall. Upon further discussion, the patient reported that he had undergone liquid silicone injection into the breasts, performed by an unskilled individual for soft-tissue augmentation, 12 years previously. In conclusion, sequelae of liquid silicone injection should be included in the differential diagnosis of chest wall calcifications.

Figure 1. Axial (in A) and coronal (in B) CT reconstruction scans showing various bilateral round and oval nodules with rim calcifications in the anterior chest wall. Three-dimensional coronal (in C) and oblique (in D) CT reconstruction images demonstrated that the nodules were apparently related to the muscles of the region.

REFERENCE 1. Liu H, Juan YH, Wang W, Liang C, Zhou H, Ghonge NP, et al. Intramuscular cysticercosis: starry sky appearance. QJM. 2014;107(6):459-61. https://doi. org/10.1093/qjmed/hct243

1. Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis (SC) Brasil. 2. Departamento de Radiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil. © 2017 Sociedade Brasileira de Pneumologia e Tisiologia

ISSN 1806-3713

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LETTER TO THE EDITOR

When is the use of contrast media in chest CT indicated? Bruno Hochhegger1,2,3, Robson Rottenfusser4,5, Edson Marchiori6

TO THE EDITOR: It is undeniable that CT plays an important role in the diagnosis and treatment of various clinical conditions involving the chest wall, mediastinum, pleura, pulmonary arteries, and lung parenchyma. The need for enhancement using i.v. contrast media depends on the specific clinical indication.(1-3) The most common contrast agents used with CT imaging are iodinated. Intravenous iodinated contrast agents are used for opacification of vascular structures. The major families of contrast agents are ionic and nonionic. Contrast agents can be further classified as high- or low-osmolality agents on the basis of the iodine concentration. Most centers use nonionic contrast agents (generally low-osmolality agents) for i.v. contrast studies.(1) The rate of major reactions (e.g., anaphylaxis and death) is the same for i.v. ionic and nonionic contrast agents—an estimate of 1 in 170,000 administrations—but nonionic contrast agents show a lower rate of minor reactions.(2) Approximately 5-12% of the patients who receive high-osmolality contrast media have adverse reactions, most of which are mild or moderate.(3-5) The use of low-osmolality contrast agents has been associated with a reduction in adverse effects. Children have a lower incidence of reactions to i.v. contrast agents, and most of these are mild (0.18% for low-osmolality agents).(3,4) Risk factors for contrast agent reactions include multiple drug allergies and asthma.(5) Although many radiology departments screen for shellfish allergy, there is no cross-reactivity between shellfish and iodinated contrast agents. Actually, in the vast majority of cases requiring CT scans of the chest is not required the use of contrast media for an accurate diagnosis. The most prevalent indications for CT, such as COPD, interstitial lung disease, pulmonary

nodule, small or large airway disease, and lung cancer screening, do not require the use of any contrast media. However, for the assessment of vascular disease, CT requires the use of an i.v. contrast agent to delineate the vessel lumen (e.g., aneurysm, dissection, and vascular tumor invasion). Pulmonary embolic disease is the third most common cause of acute cardiovascular disease.(3,5) Chest CT angiography is the most common way to assess for pulmonary embolic disease because, in addition to being accurate, fast, and widely available, it can assess alternate pathologies in cases of undifferentiated chest pain. Typically, the use of CT in order to investigate vascular disease or pleural pathology may include non-contrast-enhanced images to identify hemorrhage, enhancement, and calcifications. In addition, pleural enhancement is used in order to evaluate suspected or known exudative effusions and empyema.(2) It also aids in evaluating metastatic or primary malignancy of the pleura, particularly in cases of occult disease, as enhancement and thickening of the pleura are of diagnostic interest. The use of iodinated contrast agents in lung cancer is controversial. When there is suspected mediastinal invasion, the use of contrast media is indicated; however, other evaluations can be performed without it. In conclusion, the use of contrast-enhanced chest CT imaging is indicated to investigate vascular and pleural diseases, but most of the scans can be obtained without contrast enhancement. Also, the specific agent and the route of administration are based on clinical indications and patient factors. Clear communication between the physician and the radiologist is essential for obtaining the most appropriate study at the lowest cost and minimum risk to the patient.

REFERENCES 1. Utter DP. Survey of contrast media use in southeastern U.S. hospitals. Radiol Technol. 1997;68(5):386-90. https://doi.org/10.1148/ radiology.175.3.2343107 2. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology. 1990;175 (3):621-8. 3. American College of Radiology. ACR manual on contrast media: version

8. Reston (VA): American College of Radiology; 2012. 4. Dillman JR, Strouse PJ, Ellis JH, Cohan RH, Jan SC. Incidence and severity of acute allergic-like reactions to i.v. nonionic iodinated contrast material in children. AJR Am J Roentgenol. 2007;188(6):1643-7. Erratum in: AJR Am J Roentgenol. 2007;189(3):512. https://doi.org/10.2214/AJR.06.1328 5. Coakley FV, Panicek DM. Iodine allergy: an oyster without a pearl? AJR Am J Roentgenol. 1997;169(4):951-2. https://doi.org/10.2214/ ajr.169.4.9308442

1. Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre (RS) Brasil. 2. Santa Casa de Misericórdia de Porto Alegre, Porto Alegre (RS) Brasil. 3. Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. 4. Centro de Diagnósticos, Hospital da Cidade de Passo Fundo, Passo Fundo (RS) Brasil. 5. Programa de Pós-Graduação, Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS – Porto Alegre (RS) Brasil. 6. Departamento de Radiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro (RJ) Brasil.

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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, ISSN1806-3756), all articles will be made available in Spanish or Portuguese, as well as in English. Authors may submit color figures. However, the cost of printing figures in color, as well as any related costs, will be borne by the authors. For further clarification, please contact the Journal Secretary by e-mail or by telephone. The Jornal Brasileiro de Pneumologia upholds the World Health Organization (WHO) and International Committee of Medical Journal Editors (ICMJE) policies regarding the registration of clinical trials, recognizing the importance of these initiatives for the registration and international, open-access dissemination of information on clinical trials. Therefore, as of 2007, the Journal only accepts clinical trials that have been given an identification number by one of the clinical trials registries meeting the criteria established by the WHO and the ICMJE. This identification number must be included at the end of the abstract. Within this context, the Jornal Brasileiro de Pneumologia adheres to the definition of a clinical trial as described by the WHO, which can be summarized as “any study that prospectively assigns human beings to be submitted to one or more interventions with the objective of evaluation the effects that those interventions have on health-related outcomes. Such interventions include the administration of drugs, cells and other biological products, as well as surgical procedures, radiological techniques, the use of devices, behavioral therapy, changes in treatment processes, preventive care, etc

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

corresponding keywords in English. Keywords in Portuguese must be based on the Descritores em Ciência da Saúde (DeCS, Health and Science Keywords), published by Bireme and available at: http://decs.bvs.br, whereas keywords in English should be based on the National Library of Medicine Medical Subject Headings (MeSH), available at: http://www.nlm.nih.gov/mesh/MBrowser.html. Text: Original articles: For original articles, the text (excluding the title page, abstracts, references, tables, figures and figure legends) should consist of 2000 to 3000 words. Tables and figures should be limited to a total of five. The number of references should not exceed 30. Original articles should be divided into the following sections: Introduction, Methods, Results, Discussion, Acknowledgments, and References. The Methods section should include a statement attesting to the fact the study has been approved by the ethics in human research committee or the ethics in animal research committee of the governing institution. There should also be a section describing the statistical analysis employed, with the respective references. In the Methods and Results sections, subheadings may be used, provided that they are limited to a reasonable number. Subheadings may not be used in the Introduction or Discussion. Review and Update articles: Review and Update articles are written at the request of the Editorial Board, which may occasionally accept unsolicited manuscripts that are deemed to be of great interest. The text should not exceed 5000 words, excluding references and illustrations (figures or tables). The total number of illustrations should not exceed eight. The number of references should not exceed 60. Pictorial essays: Pictorial essays are also submitted only at the request of the Editors or after the authors have consulted and been granted permission by the Editorial Board. The text accompanying such essays should not exceed 3000 words, excluding the references and tables. No more than 12 illustrations (figures and tables) may be used, and the number of references may not exceed 30. Brief Communications: Brief communications should not exceed 1500 words, excluding references and tables. The total number of tables and figures should not exceed two, and the references should be limited to 20. The text should be unstructured. Letters to the Editor: Letters to the Editor should be succinct original contributions, not exceeding 800 words and containing a maximum of 6 references. Comments and suggestions related to previously published materials or to any medical theme of interest will be considered for publication. Correspondence: Authors may submit comments and suggestions related to material previously published in our journal. Such submissions should not exceed 500 words. Imaging in Pulmonary Medicine: Submissions should not exceed 200 words, including the title, text, and references (no more than three). Authors may include up to three figures, bearing in mind that the entire content will be published on a single page. Tables and Figures: All tables and figures should be in black and white, on separate pages, with legends and captions appearing at the foot of each. All tables and figures should be submitted as files in their original format. Tables should be submitted as Microsoft Word files, whereas figures should be submitted as Microsoft Excel, TIFF or JPG files. Photographs depicting surgical procedures, as well as those showing the results of exams or biopsies, in which staining and special techniques were used will be considered for publication in color, at no additional cost to the authors. Dimensions, units and symbols should be based on the corresponding guidelines set forth by the Associação Brasileira de Normas Técnicas (ABNT, Brazilian Association for the Establishment of Technical Norms), available at: http://www.abnt.org.br. Legends: Legends should accompany the respective figures (graphs, photographs and illustrations) and tables. Each legend should be numbered with an

Arabic numeral corresponding to its citation in the text. In addition, all abbreviations, acronyms, and symbols should be defined below each table or figure in which they appear. References: References should be listed in order of their appearance in the text and should be numbered consecutively with Arabic numerals. The presentation should follow the Vancouver style, updated in October of 2004, according to the examples below. The titles of the journals listed should be abbreviated according to the style presented by the List of Journals Indexed in the Index Medicus of the National Library of Medicine, available at: http://www. ncbi.nlm.nih.gov/entrez/journals/loftext.noprov.html. A total of six authors may be listed. For works with more than six authors, list the first six, followed by ‘et al.’ Examples: Journal Articles 1. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs AC et al. Prediction of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomized study. Eur Respir J. 1999;14(6):1204-13. Abstracts 2. Singer M, Lefort J, Lapa e Silva JR, Vargaftig BB. Failure of granulocyte depletion to suppress mucin production in a murine model of allergy [abstract]. Am J Respir Crit Care Med. 2000;161:A863. Chapter in a Book 3. Queluz T, Andres G. Goodpasture’s syndrome. In: Roitt IM, Delves PJ, editors. Encyclopedia of Immunology. 1st ed. London: Academic Press; 1992. p. 621-3. Official Publications 4. World Health Organization. Guidelines for surveillance of drug resistance in tuberculosis. WHO/Tb, 1994;178:1-24. Theses 5. Martinez TY. Impacto da dispnéia e parâmetros funcionais respiratórios em medidas de qualidade de vida relacionada a saúde de pacientes com fibrose pulmonar idiopática [thesis]. São Paulo: Universidade Federal de São Paulo; 1998. Electronic publications 6. Abood S. Quality improvement initiative in nursing homes: the ANA acts in an advisory role. Am J Nurs [serial on the Internet]. 2002 Jun [cited 2002 Aug 12]; 102(6): [about 3 p.]. Available from: http:// www.nursingworld.org/AJN/2002/june/Wawatch. htm Homepages/URLs 7. Cancer-Pain.org [homepage on the Internet]. New York: Association of Cancer Online Resources, Inc.; c2000-01 [updated 2002 May 16; cited 2002 Jul 9]. Available from: http://www.cancer-pain.org/ Other situations: In other situations not mentioned in these author instructions, authors should follow the recommendations given by the International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Updated October 2004. Available at http://www.icmje.org/. All correspondence to the Jornal Brasileiro de Pneumologia should be addressed to: Prof. Dr. Rogério Souza Editor-Chefe do Jornal Brasileiro de Pneumologia SCS Quadra 01, Bloco K, Salas 203/204 - Ed. Denasa. CEP: 70.398-900 - Brasília - DF, Brazil Telefones/Fax: 0xx61-3245-1030, 0xx61-3245-6218 Jornal Brasileiro de Pneumologia e-mail address: jpneumo@jornaldepneumologia.com.br (Assistente Editorial - Luana Campos) Online submission of articles: www.jornaldepneumologia.com.br

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

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