Brazilian Journal of Pulmonology - Volume 41, number 3, May/June - 2015

Published once every two months

J Bras Pneumol. v.41, number 3, p. 209-294 May/June 2015

EDITOR-IN-CHIEF Rogerio Souza - University of São Paulo, São Paulo, Brazil

Executive Editors

Associação Brasileira de Editores Científicos

Bruno Guedes Baldi - University of São Paulo, São Paulo, Brazil Caio Júlio Cesar dos Santos Fernandes - University of São Paulo, São Paulo, Brazil Carlos Roberto Ribeiro de Carvalho - University of São Paulo, São Paulo, Brazil Carlos Viana Poyares Jardim - University of São Paulo, São Paulo, Brazil

Publication Indexed in: Latindex, LILACS, Scielo Brazil, Scopus, Index Copernicus, ISI Web of Knowledge, MEDLINE and PubMed Central (PMC)

ASSOCIATE EDITORS

Available in Portuguese and English from: www.jornaldepneumologia.com.br or www.scielo.br/jbpneu.

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

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

EDITORIAL COUNCIL

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

Nestor Muller - Vancouver General Hospital, Vancouver, BC, Canadá Noé Zamel - University of Toronto, Toronto, ON, Canadá Paul Noble - Duke University, Durham, NC, USA Paulo Francisco Guerreiro Cardoso - Pavilhão Pereira Filho, Porto Alegre, RS Paulo Pego Fernandes - University of São Paulo, São Paulo, Brazil Peter J. Barnes - National Heart and Lung Institute, Imperial College, London, UK Renato Sotto-Mayor - Hospital Santa Maria, Lisbon, Portugal Richard W. Light - Vanderbili University, Nashville, TN, USA Rik Gosselink - University Hospitals Leuven, Bélgica Robert Skomro - University of Saskatoon, Saskatoon, Canadá Rubin Tuder - University of Colorado, Denver, CO, USA Sonia Buist - Oregon Health & Science University, Portland, OR, USA Talmadge King Jr. - University of California, San Francisco, CA, USA Thais Helena Abrahão Thomaz Queluz - São Paulo State University, Botucatu, Brazil Vera Luiza Capelozzi - University of São Paulo, São Paulo, Brazill

BRAZILIAN THORACIC SOCIETY Office: 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. Website: www.sbpt.org.br. E-mail: sbpt@sbpt.org.br

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

BTS Board of Directors (2013-2014 biennium): President: Dr. Renato Maciel - MG Secretary-General: Dr. Paulo Henrique Ramos Feitosa - DF Director, Professional Advocacy: Dr. Jose Eduardo Delfini Cançado - SP CFO: Dr. Saulo Maia Davila Melo - SE Scientific Director: Dr. Miguel Abidon Aide - RJ Director, Education and Professional Practice: Dr. Clystenes Odyr Soares Silva - SP Director, Communications: Dra. Simone Chaves Fagondes - RS President, BTS Congress 2016: Marcus Barreto Conde - RJ President Elect (2017/2018 biennium): Fernando Luiz Cavalcanti Lundgren - PE Chairman of the Board: Jairo Sponholz Araújo (PR) AUDIT COMMITTEE: Active Members: Clóvis Botelho (MT), Benedito Francisco Cabral Júnior (DF), Rafael de Castro Martins (ES) Alternates: Maurício Meireles Góes (MG), Alina Faria França de Oliveira (PE), Paulo Cesar de Oliveira (MG) COORDINATORS, BTS DEPARTMENTS: Programmatic Initiatives – Alcindo Cerci Neto (PR) Thoracic Surgery – Darcy Ribeiro Pinto Filho (RS) Sleep–disordered Breathing – Marcelo Fouad Rabahi (GO) Respiratory Endoscopy – Mauro Musa Zamboni (RJ) Pulmonary Function – John Mark Salge (SP) Imaging – Bruno Hochhegger (RS) Lung Diseases – Ester Nei Aparecida Martins Coletta (SP) Clinical Research – Oliver Augusto Nascimento (SP) Pediatric Pulmonology – Paulo Cesar Kussek (PR) Residency – Alberto Cukier (SP) COORDINATORS, BTS SCIENTIFIC COMMITTEES: Asthma – Emilio Pizzichini (SC) Lung Cancer – Teresa Yae Takagaki (SP) Pulmonary Circulation – Carlos Viana Poyares Jardim (SP) Advanced Lung Disease – Dagoberto Vanoni de Godoy (RS) Interstitial Diseases – José Antônio Baddini Martinez (SP) Environmental and Occupational Respiratory Diseases – Ana Paula Scalia Carneiro (MG) COPD – Roberto Stirbulov (SP) Epidemiology – Frederico Leon Arrabal Fernandes (SP) Cystic Fibrosis – Marcelo Bicalho of Fuccio (MG) Respiratory Infections and Mycoses – Mauro Gomes (SP) Pleura – Roberta Karla Barbosa de Sales (SP) International Relations – José Roberto de Brito Jardim (SP) Smoking – Luiz Carlos Corrêa da Silva (RS) Intensive Care – Marco Antônio Soares Reis (MG) Tuberculosis – Fernanda Carvalho de Queiroz Mello (RJ)

ADMINISTRATIVE SECRETARIAT OF THE BRAZILIAN JOURNAL OF PULMONOLOGY Address: SCS Quadra 01, Bloco K, Asa Sul, salas 203/204. Edifício Denasa, CEP 70398-900, Brasília, DF, Brazil. Tel. +55 61 3245-1030/+55 0800 616218.

Assistant Managing Editor: Luana Maria Bernardes Campos. E-mail: jpneumo@jornaldepneumologia.com.br Circulation: 1,100 copies Distribution: Free to members of the BTS and libraries Printed on acid-free paper SUPPORT:

Published once every two months

J Bras Pneumol. v.41, number 3, p. 209-294 May/June 2015

EDITORIAL 209 - Bringing the JBP and its readers closer together

O JBP mais próximo do leitor Rogério Souza

ARTIGOS ORIGINAIS / ORIGINAL ARTICLES 211 - Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study

Teste de caminhada de seis minutos e força muscular respiratória em pacientes com asma grave não controlada: um estudo piloto Luiz Fernando Ferreira Pereira, Eliane Viana Mancuzo, Camila Farnese Rezende, Ricardo de Amorim Côrrea

219 - Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal staging in lung cancer

Rendimiento diagnóstico de la ultrasonografía endobronquial con aspiración transbronquial por aguja fina en el estudio de etapificación mediastínica en pacientes con cáncer pulmonar Sebastián Fernández-Bussy, Gonzalo Labarca, Sofia Canals, Iván Caviedes, Erik Folch, Adnan Majid

225 - Mobility therapy and central or peripheral catheter-related adverse events in an ICU in Brazil

Realização de fisioterapia motora e ocorrência de eventos adversos relacionados a cateteres centrais e periféricos em uma UTI brasileira

Natália Pontes Lima, Gregório Marques Cardim da Silva, Marcelo Park, Ruy Camargo Pires-Neto 231 - Organizing pneumonia: chest HRCT findings

Pneumonia em organização: achados da TCAR de tórax

Igor Murad Faria, Gláucia Zanetti, Miriam Menna Barreto, Rosana Souza Rodrigues, Cesar Augusto Araujo-Neto, Jorge Luiz Pereira e Silva, Dante Luiz Escuissato, Arthur Soares Souza Jr, Klaus Loureiro Irion, Alexandre Dias Mançano, Luiz Felipe Nobre, Bruno Hochhegger, Edson Marchiori 238 - Risk factors for respiratory complications after adenotonsillectomy in children with obstructive sleep apnea

Fatores de risco para complicações respiratórias após adenotonsilectomia em crianças com apneia obstrutiva do sono Renato Oliveira Martins, Nuria Castello-Branco, Jefferson Luis de Barros, Silke Anna Theresa Weber

COMUNICAÇÃO BREVE / BRIEF COMMUNICATION 246 - Psychological criteria for contraindication in lung transplant candidates: a five-year study

Critérios psicológicos para contraindicação em candidatos a transplante pulmonar: um estudo de cinco anos

Elaine Marques Hojaij, Bellkiss Wilma Romano, André Nathan Costa, Jose Eduardo Afonso Junior, Priscila Cilene Leon Bueno de Camargo, Rafael Medeiros Carraro, Silvia Vidal Campos, Marcos Naoyuki Samano, Ricardo Henrique de Oliveira Braga Teixeira

EDUCAÇÃO CONTINUADA: IMAGEM / CONTINUING EDUCATION: IMAGING 250 - Small interstitial nodules

Pequenos nódulos intersticiais

Edson Marchiori, Gláucia Zanetti, Bruno Hochhegger

Published once every two months

J Bras Pneumol. v.41, number 3, p. 209-294 May/June 2015

ARTIGO DE REVISÃO / REVIEW ARTICLE 251 - Diagnosis of primary ciliary dyskinesia

Diagnóstico de discinesia ciliar primária

Mary Anne Kowal Olm, Elia Garcia Caldini, Thais Mauad 264 - PET/CT imaging in lung cancer: indications and findings

PET/TC em câncer de pulmão: indicações e achados

Bruno Hochhegger, Giordano Rafael Tronco Alves, Klaus Loureiro Irion, Carlos Cezar Fritscher, Leandro Genehr Fritscher, Natália Henz Concatto, Edson Marchiori

SÉRIE DE CASOS / CASE SERIES 275 - Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

Uso de sirolimo no tratamento de linfangioleiomiomatose: resposta favorável em pacientes com diferentes manifestações extrapulmonares Carolina Salim Gonçalves Freitas, Bruno Guedes Baldi, Mariana Sponholz Araújo, Glaucia Itamaro Heiden, Ronaldo Adib Kairalla, Carlos Roberto Ribeiro Carvalho

RELATO DE CASO / CASE REPORT 281 - Formation of multiple pulmonary nodules during treatment with leflunomide

Formação de múltiplos nódulos pulmonares durante tratamento com leflunomida

Gilberto Toshikawa Yoshikawa, George Alberto da Silva Dias, Satomi Fujihara, Luigi Ferreira e Silva, Lorena de Britto Pereira Cruz, Hellen Thais Fuzii, Roberta Vilela Lopes Koyama

IMAGENS EM PNEUMOLOGIA / IMAGES IN PULMONARY MEDICINE 285 - Intracavitary pulmonary aspergilloma: endoscopic aspects

Aspergiloma pulmonar intracavitário: aspectos endoscópicos

Evelise Lima, André Louis Lobo Nagy, Rodrigo Abensur Athanazio

CARTAS AO EDITOR / LETTER TO THE EDITOR 286 - Reversed halo sign in acute schistosomiasis

Sinal do halo invertido em esquistossomose aguda

Arthur Soares Souza Jr., Antonio Soares Souza, Luciana Soares-Souza, Gláucia Zanetti, Edson Marchiori 289 - Pulmonary large-cell neuroendocrine carcinoma presenting as multiple cutaneous metastases

Carcinoma neuroendócrino de grandes células do pulmão diagnosticado a partir de múltiplas metástases cutâneas Tiago Mestre, Ana Maria Rodrigues, Jorge Cardoso

292 - Nontuberculous mycobacteria in respiratory specimens: clinical significance at a tertiary care hospital in the north of Portugal

Micobactérias não tuberculosas em espécimes respiratórios: significado clínico em um hospital terciário no norte de Portugal

Hans Dabó, Vanessa Santos, Anabela Marinho, Angélica Ramos, Teresa Carvalho, Manuela Ribeiro, Adelina Amorim

Editorial Bringing the JBP and its readers closer together O JBP mais próximo do leitor

Rogério Souza1 There is no denying the role that a scientific journal plays in the dissemination of existing or newly acquired knowledge in a given area of expertise. In addition, an essential part of the mission of a scientific journal is to promote a discussion of controversial issues in order to give rise to new views and ideas that will encourage further research on a given topic.

However, publications with a narrower focus tend to have less visibility than do those with a broader scope. Nevertheless, scientific journals, particularly those that were originally regional journals, have another, less obvious, role.

The JBP was created as and continues to be the official organ of the Brazilian Thoracic Association (BTA).(1) The initial mission of the JBP was to disseminate knowledge in the field of pulmonology among the members of the BTA. However, the JBP, like the BTA itself, has grown and matured; in addition to disseminating knowledge, the JBP now reflects the growth and internationalization of respiratory research in Brazil and the world.(2) Nevertheless, the process of internationalization, which is common to many journals that are expanding their reach,(3) does not exempt the JBP from its fundamental role of disseminating and consolidating knowledge pertaining to the characteristics of the region from which it originates. This includes the publication of national guidelines on various diseases or clinical conditions,(4) the dissemination of specific epidemiological data, the dissemination of predicted values for healthy individuals,(5,6) the validation of Portuguese-language versions of instruments,(7) and the provision of support to emerging fields of research and research groups in Brazil.(8-10) Far from being trivial, this is a role that merits ongoing attention.

Scientific metrics, which do not necessarily reflect the full range of activities of a researcher, an institution, or even a journal, are currently overvalued.(11) The quest for growth and increased exposure sometimes results in distortions that

merit further reflection. Although objective quality analysis is desirable, indicators should not be analyzed without taking into consideration the methodology whereby they were created and their limitations. From an editorial standpoint, the impact factor, created by Eugene Garfield in 1955 as a tool for determining the representativeness of a journal, is currently the most widely used indicator. Its widespread acceptance was certainly a positive occurrence. However, the impact factor has become an absolute indicator of the quality of a journal. This is a conceptual error. The merits of a journal dedicated to a very specific area of knowledge can hardly be judged on the basis of the impact factor alone. This leads us back to the initial question: What is the true role of the JBP? In view of the aforementioned considerations, it is our desire to expand internationally without losing sight of our mission of meeting local needs. Regarding the impact factor of the JBP, there is undoubtedly room for improvement. Our 2014 impact factor, which will be published this year, is expected to decrease; however, it will increase again next year, further increasing our international exposure. Nevertheless, this should not be the focus of editorial work—albeit a direct consequence thereof—until a balance is struck between internationalization and local relevance.

In order to meet the aforementioned challenge, the print version of the JBP will now be published entirely in Portuguese, with the exception of articles submitted in Spanish. We therefore expect that all BTA members will read the print version of the JBP when it is published, once every two months. The Portuguese-language version of the JBP will also be available online (at www. jornaldepneumologia.com.br), together with a version entirely in English; therefore, readers from abroad who gain access to our articles via PubMed will continue to have direct access to English-language versions of all articles. In addition, the JBP now has two new sections: Imaging in Pulmonary Medicine and Continuing

1. Tenured Professor, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo; and Editor-in-Chief of the JBP, Brasília, Brazil.

http://dx.doi.org/10.1590/S1806-37132015000300001

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Education. The Imaging in Pulmonary Medicine section(12) is an idea that has been tried out by several former JBP editors and that is being put into practice again. The section will not be restricted to radiological results but will be used in order to showcase any images that might be of interest to readers, including those depicting endoscopic findings, radiological findings, or even unusual or well-documented preliminary clinical findings. The Continuing Education section is not exactly a section, but rather a heading under which certain series will be published in the JBP. The first such series, which begins in the current issue of the JBP, is designated “Continuing Education: Imaging” and is overseen by associate editors Edson Marchiori and Bruno Hochhegger. (13) In that series, practical aspects of routine radiological findings in the field of respiratory medicine will be discussed. Other Continuing Education series are under development and will address the many facets of the field of respiratory medicine.

The objective of the aforementioned changes is to bring the JBP and its readers—researchers, clinicians, surgeons, and even those who simply wish to stay up-to-date with the latest trends in the field of respiratory medicine—closer together.

We hope that all JBP readers can learn something from each issue; that is our ultimate goal!

References 1. Souza R. 2015--another step along the road in a 40-year journey... J Bras Pneumol. 2015;41(1):1-2. http://dx.doi. org/10.1590/S1806-37132015000100001 2. Carvalho CR, Baldi BG, Jardim CV, Caruso P, Souza R. New steps for the international consolidation of the Brazilian Journal of Pulmonology. J Bras Pneumol.

2014;40(4):325-6. http://dx.doi.org/10.1590/ S1806-37132014000400001

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3. Souza R, Carvalho CR. Brazilian Journal of Pulmonology and Portuguese Journal of Pulmonology: strengthening ties in respiratory science. Rev Port Pneumol. 2014;20(6):285-6. http://dx.doi.org/10.1016/j.rppneu.2014.11.001 4. Brazilian recommendations of mechanical ventilation 2013. Part 2. J Bras Pneumol. 2014;40(5):458-86. http:// dx.doi.org/10.1590/S1806-37132014000500003 5. Moreira GL, Manzano BM, Gazzotti MR, Nascimento OA, Perez-Padilla R, Menezes AM, et al. PLATINO, a nine-year follow-up study of COPD in the city of São Paulo, Brazil: the problem of underdiagnosis. J Bras Pneumol. 2014;40(1):30-7. http://dx.doi.org/10.1590/ S1806-37132014000100005 6. Dourado VZ, Guerra RL, Tanni SE, Antunes LC, Godoy I. Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses. J Bras Pneumol. 2013;39(2):190-7. http:// dx.doi.org/10.1590/S1806-37132013000200010 7. Valderramas S, Camelier AA, Silva SA, Mallmann R, de Paulo HK, Rosa FW. Reliability of the Brazilian Portuguese version of the fatigue severity scale and its correlation with pulmonary function, dyspnea, and functional capacity in patients with COPD. J Bras Pneumol. 2013;39(4):427-33. http://dx.doi.org/10.1590/S1806-37132013000400005 8. Corrêa Rde A, Silva LC, Rezende CJ, Bernardes RC, Prata TA, Silva HL. Pulmonary hypertension and pulmonary artery dissection. J Bras Pneumol. 2013;39(2):238-41. http://dx.doi.org/10.1590/S1806-37132013000200016 9. Gavilanes F, Alves JL Jr, Fernandes C, Prada LF, Jardim CV, Morinaga LT, et al. Left ventricular dysfunction in patients with suspected pulmonary arterial hypertension.

J Bras Pneumol. 2014;40(6):609-16. http://dx.doi. org/10.1590/S1806-37132014000600004 10. Polonio IB, Acencio MM, Pazetti R, Almeida FM, Silva BS, Pereira KA, et al. Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats. J Bras Pneumol. 2014;40(4):421-4. http://dx.doi. org/10.1590/S1806-37132014000400010 11. Casadevall A, Fang FC. Causes for the persistence of impact factor mania. MBio. 2014;5(2):e00064-14. Erratum in: MBio. 2014;5(3):e01342-14.

12. Lima E, Nagy AL, Athanazio RA. Intracavitary pulmonary aspergilloma: endoscopic aspects. J Bras Pneumol.

2015;41(3):285.

13. Marchiori E, Zanetti G, Hochhegger B. Small interstitial nodules. J Bras Pneumol. 2015;41(3):250.

http://dx.doi.org/10.1590/S1806-37132015000300001

Original Article Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study* Teste de caminhada de seis minutos e força muscular respiratória em pacientes com asma grave não controlada: um estudo piloto

Luiz Fernando Ferreira Pereira1, Eliane Viana Mancuzo2, Camila Farnese Rezende3, Ricardo de Amorim Côrrea4

Abstract Objective: To evaluate respiratory muscle strength and six-minute walk test (6MWT) variables in patients with uncontrolled severe asthma (UCSA). Methods: This was a cross-sectional study involving UCSA patients followed at a university hospital. The patients underwent 6MWT, spirometry, and measurements of respiratory muscle strength, as well as completing the Asthma Control Test (ACT). The Mann-Whitney test was used in order to analyze 6MWT variables, whereas the Kruskal-Wallis test was used to determine whether there was an association between the use of oral corticosteroids and respiratory muscle strength. Results: We included 25 patients. Mean FEV1 was 58.8 ± 21.8% of predicted, and mean ACT score was 14.0 ± 3.9 points. No significant difference was found between the median six-minute walk distance recorded for the UCSA patients and that predicted for healthy Brazilians (512 m and 534 m, respectively; p = 0.14). During the 6MWT, there was no significant drop in SpO2. Mean MIP and MEP were normal (72.9 ± 15.2% and 67.6 ± 22.2%, respectively). Comparing the patients treated with at least four courses of oral corticosteroids per year and those treated with three or fewer, we found no significant differences in MIP (p = 0.15) or MEP (p = 0.45). Conclusions: Our findings suggest that UCSA patients are similar to normal subjects in terms of 6MWT variables and respiratory muscle strength.

The use of oral corticosteroids has no apparent impact on respiratory muscle strength.

Keywords: Asthma; Exercise tolerance; Respiratory muscles.

Introduction Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness, variable airflow limitation, and symptoms such as dyspnea, wheezing, and cough, which improve spontaneously or with treatment.

The primary goals of asthma treatment include complete symptom control, optimal management of limitations in activities of daily living, and reducing future risks.(1,2) Most asthma patients have mild to moderate asthma, which is easily controlled with the use of inhaled corticosteroids (ICs) alone or in association with a long-acting β2 agonist (LABA).(3) However, among patients with severe asthma, there is a small subset of patients who remain symptomatic despite good

adherence to treatment, correct use of inhalers, appropriate management of comorbidities, and use of high-dose ICs in association with LABAs, oral corticosteroids, omalizumab, or any combination of the three.(4,5) Such patients are considered to have uncontrolled severe asthma (UCSA), which, according to current asthma guidelines, should be treated at specialized centers.(4,5) Patients with UCSA require high-dose ICs alone or in association with oral corticosteroids, the adverse effects of which include decreased protein synthesis and increased protein degradation and contribute to muscle atrophy.(6) In addition, increased airway resistance and lung hyperinflation also contribute to reducing inspiratory muscle

1. Preceptor. Pulmonology Outpatient Clinic, Federal University of Minas Gerais Hospital das Clínicas, Belo Horizonte, Brazil.

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

3. Resident in Pulmonology. Federal University of Minas Gerais Hospital das Clínicas, Belo Horizonte, Brazil.

4. Professor. Federal University of Minas Gerais School of Medicine, Belo Horizonte, Brazil. *Study carried out at the Pulmonology Outpatient Clinic and in the Pulmonary Function Laboratory, Federal University of Minas Gerais Hospital das Clínicas, Belo Horizonte, Brazil.

Correspondence to: Luiz Fernando F. Pereira. Avenida do Contorno, 4747, sala 610, Funcionários, CEP 30110-921, Belo Horizonte, MG, Brasil.

Tel. 55 31 3296-4041. E-mail: luizffpereira@uol.com.br Financial support: None.

Submitted: 1 December 2014. Accepted, after review: 10 April 2015.

http://dx.doi.org/10.1590/S1806-37132015000004483

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efficiency, resulting in increased muscle work and energy expenditure to overcome airflow limitation.(7) The aforementioned factors have yet to be well studied in patients with UCSA. The six-minute walk test (6MWT) is a submaximal exercise test that evaluates the overall and integrated responses of all body systems involved in physical exercise, including the pulmonary system, the cardiovascular system, peripheral and systemic circulation, blood, neuromuscular units, and muscle metabolism. (8,9) Respiratory muscle strength can be estimated from airway pressures generated by respiratory muscle contraction. Maximal static respiratory pressures are usually measured at the mouth during inhalation and exhalation, the former being designated MIP and the latter being designated MEP.(10) The role of the 6MWT in the evaluation and follow-up of patients with COPD, interstitial lung disease, pulmonary arterial hypertension, and heart failure is well established.(8) However, the only study evaluating the impact of severe asthma on the six-minute walk distance (6MWD) in adults was a study conducted by Canuto et al.,(11) who found that the 6MWD was significantly shorter in patients with difficult-to-control asthma (DCA) using oral corticosteroids than in healthy controls.

In addition, although respiratory muscle strength (particularly MIP) has been reported to be reduced in several studies involving asthma patients, it has yet to be evaluated in patients with UCSA.(12) The primary objective of the present study was to evaluate respiratory muscle strength and 6MWT variables in patients with UCSA. Secondary objectives were to evaluate the impact of oral corticosteroid use on respiratory muscle strength and to determine the correlation of the level of physical activity with the 6MWD and the level of asthma control in such patients.

Methods This was a cross-sectional study of UCSA patients over 18 years of age treated at the Difficult-to-Control Asthma Outpatient Clinic of the Federal University of Minas Gerais Hospital das Clínicas, in the city of Belo Horizonte, Brazil, between September and December of 2012. The research project was approved by the Research Ethics Committee of the Federal University of Minas Gerais (ETIC Ruling no. 156.403/2012).

All participants gave written informed consent.

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The diagnosis of severe asthma was based on the American Thoracic Society/European Respiratory Society (ATS/ERS) criteria,(13) as follows: • major criteria—use of oral corticosteroids for at least six months per year and continuous use of high-dose ICs (≥ 1,600 µg of budesonide or equivalent) in association with LABAs • minor criteria—FEV1 of < 80%; PEF variability > 20%; daily use of short-acting β2 agonists; use of more than three courses of oral corticosteroids per year; history of near-fatal asthma; one or more emergency room visits in the previous year; and rapid decline in lung function after a decrease in the dose of corticosteroid therapy The patients who were included in the present study received outpatient treatment for at least six months in order to control environmental factors and comorbidities, as well as to improve inhaler technique and treatment adherence. In addition, we included only patients assigned to Global Initiative for Asthma (GINA) and Brazilian Thoracic Association (BTA) asthma treatment step 4 or 5 (LABAs/high-dose ICs plus oral corticosteroids, anti-IgE treatment, or both)(1,2) and meeting two major ATS/ERS criteria or one major and two minor ATS/ERS criteria.(13) We excluded patients with severe heart disease; current smokers; former smokers who had a smoking history ≥ 10 pack-years or who had quit smoking less than one year prior; and patients who had had exacerbations requiring emergency room treatment/hospitalization, use of prednisone or equivalent at doses above 20 mg, use of antibiotics, or any combination of the three in the last four weeks.

The 6MWT was performed in a 25.6-m corridor with the use of a portable oximeter (Nonin Medical, Inc., Plymouth, MN, USA), in accordance with the recommendations of the ATS.(14) Each of the participants underwent two 6MWTs, at least 30 min apart. We evaluated the following parameters: SpO2, as measured by pulse oximetry; HR; RR; and patient perception of dyspnea and leg fatigue, as assessed by Borg scale scores at the beginning and end of each test. In addition, we determined the percentage of the predicted maximal HR (%HRmax) for adults, HR recovery at one minute after completion of the 6MWT (HRR1), and the 6MWD. Values of desaturation ≥ 4%,(8,14) %HRmax > 85% of predicted,(8,14) and http://dx.doi.org/10.1590/S1806-37132015000004483

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HRR1 > 12 bpm were considered significant.(15-17) The 6MWT during which the longest 6MWD was covered was considered valid; absolute and percent predicted 6MWD values were calculated by the reference equation for the 6MWD in the Brazilian population.(18) Spirometry was performed with a Koko spirometer (PDS Instrumentation Inc., Louisville, CO, USA). The tests were performed and the results were interpreted in accordance with the BTA guidelines.(10) All post-bronchodilator test results were reported as absolute values and as percentages of predicted values, in accordance with Pereira et al.(19) Respiratory muscle strength was evaluated in accordance with the BTA guidelines,(10) with a digital manometer (Warren E Collins Inc., Braintree, MA, USA), the signals being read and recorded through individual ducts. A 2-mm hole in the circuit prevented false measurements as a result of involuntary contractions of the cheeks. We measured MIP at RV and MEP at TLC. The results were expressed in cmH2O.(20) The level of asthma control was assessed with the Asthma Control Test (ACT), previously validated for use in Brazil,(21-23) a score of 25 points indicating clinical remission of symptoms or totally controlled asthma, a score of 20-24 points indicating adequately controlled asthma, and a score of < 20 points indicating uncontrolled asthma.

The level of physical activity was measured with the short version of the International Physical Activity Questionnaire (IPAQ), previously validated for use in Brazil.(24,25) The instrument consists of seven questions regarding the frequency (in number of days per week) and duration (in number of minutes per day) of vigorous physical activity, moderate physical activity, and walking activity.

On the basis of their IPAQ scores, individuals are classified as very active, active, irregularly active, or sedentary. In the present study, we divided the participants into two major groups: the group of very active/active individuals and the group of irregularly active/sedentary individuals.(24,25) All study participants underwent chest HRCT for the differential diagnosis of other diseases, such as COPD, bronchiectasis, and allergic bronchopulmonary aspergillosis.

Data analysis was performed with the Statistical Package for the Social Sciences, version 18 (SPSS Inc., Chicago, IL, USA), and Minitab http://dx.doi.org/10.1590/S1806-37132015000004483

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software, version 16 (Minitab Inc., State College, MA, USA). The Shapiro-Wilk test was used in order to evaluate the distribution of the data.

Categorical variables were expressed as absolute and relative frequencies, and continuous variables were expressed as mean and standard deviation (parametric distribution) or as median and range (nonparametric distribution). The Mann-Whitney test was used in order to evaluate the difference between the 6MWD recorded for the patients with UCSA and that predicted for healthy individuals, as well as to evaluate the association of physical activity levels (IPAQ scores) with the 6MWD, ACT scores, %HRmax, and HRR1. Spearman’s correlation test and the Kruskal-Wallis test were used in order to evaluate the association of oral corticosteroid use with MIP and MEP. Values of p < 0.05 were considered statistically significant.

On the basis of the longest 6MWD found in the literature (with a standard deviation of 90.44 m) and using a level of significance of 0.05 and an unpaired two-tailed Student’s t-test, we estimated that a sample size of 26 was needed in order to detect a difference of 50 m between the 6MWD found in the present study and that found in the literature.(26)

Results The initial sample consisted of 29 patients.

Three patients were excluded because of a probable overlap between asthma and COPD, and another one was excluded because of asthma exacerbation during the month of data collection.

The final sample consisted of 25 asthma patients (18 females and 7 males), their mean age being 49 years and their mean body mass index being 28.9 ± 7.9 kg/m2 (Table 1). All patients had ACT scores of < 15 points, 14 (56%) were classified as being irregularly active/sedentary, and 20 (80%) had exercise limitation in the period between asthma attacks. Ten patients (40%) had a history of exacerbations requiring ICU admission, and 7 (28%) had a history of exacerbations requiring mechanical ventilation.

All patients were receiving treatment with LABAs and high-dose ICs (≥ 1,600 µg of budesonide or equivalent), 6 (24%) had been using at least 10 mg/day of prednisone for more than one year, and 3 (12%) were using omalizumab.

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of centrilobular emphysema, in 11; mild right upper lobe fibrosis/atelectasis, in 1; and air trapping, in 1.

There was a predominance of obstructive lung disease (mean FEV1, 58.8 ± 21.8% of predicted), and 17 patients (68%) had positive bronchodilator test results. Although mean MIP and MEP were Table 1 - Baseline characteristics of the uncontrolled severe asthma patients studied.a Characteristic N = 25 Age, yearsb 49.8 ± 12.6 Female gender 18 (72) BMI,a kg/m2 28.9 ± 7.9 Former smokersc 4 (16) Activity limitations in the period between attacks No limitations 0 (0) Limitations in exercise performance 20 (80) Limitations in activities of daily living 3 (12) Limitations in self-care 2 (8) Limitations at rest 0 (0) Attacks in the previous yeard 5 (0-23) Systemic corticosteroid use during 9 (36) attacks (≥ 4 courses/year) Continuous oral corticosteroid use 6 (24) Total number of hospitalizationsd 15 (0-100) ICU admissions 10 (40) Need for mechanical ventilation 7 (28) History of CPA 1 (4) Comorbidities 21 (84) Chronic rhinosinusitis 22 (88) Nasal polyposis 2 (8) GERD 13 (52) Obesity 11 (44) SAH 2 (8) Diabetes mellitus 4 (16) Psychiatric disorder 4 (16) COPD 2 (8) Sequelae of tuberculosis 1 (4) ABPA 1 (4) ACTb 14.0 ± 3.9 Physical activities - IPAQ score Active or very active 11 (44) Irregularly active or sedentary 14 (56) BMI: body mass index; CPA: cardiopulmonary arrest; GERD: gastroesophageal reflux disease; SAH: systemic arterial hypertension; ABPA: allergic bronchopulmonary aspergillosis; ACT: Asthma Control Test; and IPAQ: International Physical Activity Questionnaire. aValues expressed as n (%), except where otherwise indicated. bValues expressed as mean ± SD. cIndividuals who had a smoking history of ≤ 10 packyears at the time of smoking cessation or those who had quit smoking at least one year prior. dValues expressed as median (range).

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normal, 7 (28%) and 11 (44%) of the 25 patients studied had reduced MIP and MEP (of < 65% of predicted), respectively (Table 2). Of the 7 patients who had reduced MIP, only 2 had spirometric signs of lung hyperinflation.

There was no significant difference (p = 0.14) between the median 6MWD recorded for the UCSA patients in the present study—512 m (range, 307.2-597.3 m)—and that predicted for healthy individuals—534 m (range, 382.6-621.3 m)—(Figure 1).

None of the patients required supplemental oxygen and there was no significant decrease in mean SpO2 during the 6MWT; however, 5 patients experienced desaturation during the test. Of those, 2 experienced bronchospasm, which was reversed with the use of a shortacting β2 agonist, 2 had comorbidities (allergic bronchopulmonary aspergillosis and sequelae of pulmonary tuberculosis), and 1 had evidence of emphysema and air trapping on chest CT scans.

At the end of the 6MWT, perceived leg fatigue was mild and perceived dyspnea was mild to moderate. All patients had a significant decrease in HRR1 (Table 3).

When we compared the subset of patients treated with continuous oral corticosteroids or four or more courses of oral corticosteroids per year (n = 15) with that of those treated with three or fewer (n = 10), in order to investigate the association between the frequency of oral corticosteroid use and respiratory muscle strength, we found no statistically significant differences in median MIP—74.5% (range, 59.0-104.0%) and 72.5% (range, 43.0-104.0%; p = 0.15), respectively—or MEP—67.5% (range, 29.0-121.0%) and 63.5% (range, 34.0-121.0%; p = 0.45), respectively.

Table 2 - Spirometry results and maximal respiratory pressures in the uncontrolled severe asthma patients studied (N = 25).a Variable Result Pre-BD Post-BD FEV1,% of predicted 58.8 ± 21.8 66 ± 22.4 FEV1, L 1.61 ± 0.63 1.81 ± 0.62 FVC, % of predicted 83.4 ± 20.7 91.0 ± 19.1 FVC, L 2.79 ± 0.71 3.05 ± 0.65 FEV1/FVC 56.3 ± 12.0 MIP, cmH2O −87.2 ± 21.0 MIP, % of predicted 72.9 ±15.2 MEP, cmH2O 108.3 ± 42.9 MEP, % of predicted 67.6 ± 22.2 BD: bronchodilator. aValues expressed as mean ± SD.

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The 11 most physically active patients and the 14 least physically active patients were found to be similar in terms of their ACT scores, 6MWD, HRR1, and %HRmax during the 6MWT (Table 4).

Discussion Patients who do not achieve asthma control at GINA asthma treatment step 4 or 5 have historically been classified as having DCA.(1) However, debate over the most appropriate terminology has been ongoing for more than two decades because of the different criteria used in order to define severe asthma, DCA, refractory asthma, therapy-resistant asthma, and, more recently, UCSA. In 2000, the ATS proposed criteria for defining DCA, and those criteria contributed to resolving part of the controversy.(13) However, it was only after the publication of the 2013 ATS/ERS task force guidelines—ratified and cited in the 2014 GINA guidelines—that the classification of severe asthma became clearer.(4,5) According to the aforementioned guidelines, the term “difficult-to-treat asthma” should be reserved for asthma in patients who are able to achieve better disease control after improving environmental hygiene, inhaler technique, treatment adherence, or comorbidity management.

However, the same guidelines defined patients with “severe asthma” as those who, despite the aforementioned measures, required drugs assigned to GINA asthma treatment steps 4 and 5 in the last 12 months or systemic corticosteroids for at least 6 months in the last 12 months in order to maintain asthma control or those in whom the disease remained inadequately 650 600

Meters

550 500 450 400

*

350 300

** 6MWD-UCSA

6MWD-HA

Figure 1 - Distribution of the six-minute walk distance (6MWD) in 25 patients with uncontrolled severe asthma (6MWD-UCSA) in comparison with the 6MWD predicted for healthy adults in Brazil (6MWD-HA).(18)a *Outliers. a Values expressed in median.

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controlled despite treatment.(4,5) Patients defined as having UCSA are those who, in addition to having poorly controlled asthma, meet at least one of the following criteria(4,5): an ACT score of < 20 points or an equivalent score on any other validated instrument for assessing asthma control; two or more exacerbations requiring systemic corticosteroid use in the last year; severe exacerbation requiring hospitalization in the last year; and persistent airflow limitation despite GINA asthma treatment step 4 or 5.(4,5) Therefore, it is increasingly important to characterize UCSA patients and identify outcomes that can aid in evaluating the impact of interventions on such patients. Among such outcomes are exercise capacity and respiratory muscle strength.

In our study, the 6MWD recorded for the patients with UCSA was similar to that predicted for healthy Brazilians.(18) In addition, the patients with UCSA had normal post-6MWT SpO2, HRR1, and respiratory muscle strength.

It is known that the 6MWT provides indicators of functional capacity (the 6MWD), pulmonary gas exchange (SpO2), cardiovascular stress (HR), cardiac automaticity (HRR1), and sensory stress (dyspnea scores).(8) Although our patients were irregularly active or sedentary and had moderate obstructive lung disease and uncontrolled asthma, their mean 6MWD was 512 ± 72 m. In addition, mean desaturation was less than significant during the test (SpO2 having decreased < 4% from baseline).

We found that %HRmax was achieved in approximately 71% of the study participants, a Table 3 - Six-minute walk test in the uncontrolled severe asthma patients studied (N = 25).a Variable Before the After the 6MWT 6MWT SpO2, % 96.1 ± 1.1 93.7 ± 3.5 HR, bpm 81.8 ± 16.7 117.8 ± 20.3 RR, breaths/min 18.5 ± 2.6 30.4 ± 5.5 Borg scale score 0.1 ± 0.4 2.9 ± 2.6 (leg fatigue) Borg scale score 0.9 ± 1.2 4.7 ± 1.9 (dyspnea) 6MWD, m 512 ± 4.2 HRR1, bpm 21.7 ± 8.3 HRmax, % 71 ± 11 6MWT: six-minute walk test; 6MWD: six-minute walk distance; HRR1: HR recovery at one minute after completion of the 6MWT; and HRmax: predicted maximal HR. aValues expressed as mean ± SD.

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Table 4 - Association of the level of physical activity with the level of asthma control and six-minute walk test variables in the uncontrolled severe asthma patients studied (N = 25).a Variable Level of physical activity (IPAQ score) p Very active or active Irregularly active or sedentary (n = 11) (n = 14) 6MWD, m 537.6 (320.0-597.3) 490.0 (307.2-588.6) 0.308 HRR1, bpm 19.0 (11.0-37.0) 19.5 (10.0-36.0) 0.935 HRmax, % 72 (53-89) 73 (50-84) 0.621 ACT score 15 (7-17) 13 (6-24) 0.144 IPAQ: International Physical Activity Questionnaire; 6MWD: six-minute walk distance; HRR1: HR recovery at one minute after completion of the six-minute walk test; HRmax: predicted maximal HR; and ACT: Asthma Control Test. aValues expressed as median (range).

finding that indicates efficient gas exchange and adequate cardiovascular stress. Mean HRR1 (21.7 ± 8.3 bpm) was significant, suggesting normal cardiac automaticity, although perceived leg fatigue and perceived dyspnea after completion of the 6MWT were moderate and somewhat strong, respectively. After reviewing the literature, we found only one study evaluating adults with severe asthma during the 6MWT.(11) In that study, the 6MWD was significantly shorter in the group of patients with DCA than in the controls.(11) However, the mean 6MWD in the group of patients with DCA was 435 m,(11) which is approximately 112 m shorter than the 6MWD recorded for our sample of patients with UCSA. It is of note that the patients in that study were older than those in the present study (52.3 ± 8.3 years vs. 49.8 ± 14.4 years), had more severe obstruction, as shown by percent predicted FEV1 (44.0 ± 15.9% vs. 58.8 ± 21.8%), and used drugs that were more potent, such as oral corticosteroids (64% vs. 24%) and omalizumab (47% vs. 12%).

At the end of the 6MWT, there was a decrease in SpO2 in 5 of the 25 UCSA patients investigated in the present study. In 2, this was attributed to bronchospasm, which was rapidly reversed by rest and by using short-acting β2 agonists. The remaining 3 had comorbidities (bronchiectasis due to sequelae of tuberculosis, allergic bronchopulmonary aspergillosis, and pulmonary emphysema with air trapping, respectively).

These results suggest that, in the absence of bronchospasm, the presence of desaturation during the 6MWT in patients with UCSA should raise the suspicion of comorbidities.

According to one group of authors,(27) the reasons for exercise limitation in patients with UCSA should be investigated and include asthma itself, alveolar hyperventilation, exercise-induced bronchoconstriction, physical deconditioning, J Bras Pneumol. 2015;41(3):211-218

submaximal test, and cardiac ischemia. The authors noted that, after the reasons for exercise limitation have been identified, treatment can be revised, particularly the use of high-dose corticosteroids in patients without pulmonary limitation.(27) Respiratory muscle strength measurements (mean MIP and MEP) in the UCSA patients investigated in the present study were no different from those in healthy individuals. An increase in functional residual capacity (caused by lung hyperinflation) flattens the diaphragm and alters respiratory mechanics, resulting in a mechanical disadvantage, which can be inferred by a reduction in respiratory muscle strength.

(7,28) However, asthma patients with mild or moderate obstructive lung disease might not have significant lung hyperinflation resulting in changes in diaphragm position.(29,30) The fact that the patients in the present study had moderate airway obstruction might explain why their MIPs and MEPs were similar to those in healthy individuals.

We found no significant differences in mean MIP and MEP between the asthma patients who often used oral corticosteroids and those who did not (i.e., those who were treated with three or fewer courses of oral corticosteroids per year).

However, only 6 patients (24%) were using oral corticosteroids continuously. One group of authors found that inspiratory muscle strength was lower in oral corticosteroid-dependent asthma patients than in asthma patients using high-dose ICs, the level of lung hyperinflation being similar between the two groups of patients.(28) It should be noted that MIP and MEP were found to be reduced in 28% and 48% of the patients, respectively.

A reduction in respiratory muscle strength can occur, particularly in obese females, as a result of respiratory muscle dysfunction. Respiratory http://dx.doi.org/10.1590/S1806-37132015000004483

Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study

muscle activity can also be negatively affected by increased elastic resistance caused by the presence of excess adipose tissue in the rib cage and abdomen, which results in a mechanical disadvantage to the muscles.(31,32) In our study, 72% of the patients were female, their mean body mass index being 28 kg/m2.

Although the results of the present study should be interpreted with caution, particularly because of the lack of a control group, the small sample size, the cross-sectional study design, and the single-center nature of the study, they are relevant because of the lack of studies examining exercise capacity in patients with severe asthma and because of the difficulties in investigating exercise capacity in such patients. In addition, the present study is relevant because it examined a sample of patients treated at a referral center in a university hospital and because of its high statistical power (of 81%).

In conclusion, the 6MWD recorded for the UCSA patients in the present study was found to be similar to that predicted for healthy Brazilians.

The fact that there was a decrease in SpO2 in 5 of the 25 patients studied can be explained by the presence of bronchospasm and comorbidities.

Respiratory muscle strength measurements (mean MIP and MEP) were found to be above the predicted lower limit, regardless of the use of oral corticosteroids. Further studies, involving a larger number of patients and including a control group, are needed in order to gain a better understanding of exercise capacity in patients with severe asthma and determine its role in the management of the disease.

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Original Article Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal staging in lung cancer* Rendimiento diagnóstico de la ultrasonografía endobronquial con aspiración transbronquial por aguja fina en el estudio de etapificación mediastínica en pacientes con cáncer pulmonar

Sebastián Fernández-Bussy1, Gonzalo Labarca2, Sofia Canals3, Iván Caviedes4, Erik Folch5, Adnan Majid6

Abstract Objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive diagnostic test with a high diagnostic yield for suspicious central pulmonary lesions and for mediastinal lymph node staging. The main objective of this study was to describe the diagnostic yield of EBUS-TBNA for mediastinal lymph node staging in patients with suspected lung cancer. Methods: Prospective study of patients undergoing EBUS-TBNA for diagnosis. Patients ≥ 18 years of age were recruited between July of 2010 and August of 2013. We recorded demographic variables, radiological characteristics provided by axial CT of the chest, location of the lesion in the mediastinum as per the International Association for the Study of Lung Cancer classification, and definitive diagnostic result (EBUS with a diagnostic biopsy or a definitive diagnostic method). Results: Our analysis included 354 biopsies, from 145 patients. Of those 145 patients, 54.48% were male. The mean age was 63.75 years. The mean lymph node size was 15.03 mm, and 90 lymph nodes were smaller than 10.0 mm. The EBUS-TBNA method showed a sensitivity of 91.17%, a specificity of 100.0%, and a negative predictive value of 92.9%. The most common histological diagnosis was adenocarcinoma. Conclusions: EBUS-TBNA is a diagnostic tool that yields satisfactory results in the staging of neoplastic mediastinal lesions.

Keywords: Lung neoplasms; Bronchoscopy; Endosonography; Neoplasm staging.

Introduction Early diagnosis and staging of pulmonary lesions are central to the treatment and survival of patients with suspected lung cancer, especially of those with suspected non-small cell lung cancer. (1) Among the available alternatives, surgery by mediastinoscopy, video-assisted thoracoscopy, or other techniques remains the reference standard for diagnosis and mediastinal staging. However, assessment by minimally invasive techniques, such as flexible

bronchoscopy with bronchial or transbronchial biopsy, endobronchial ultrasound (EBUS) with transbronchial needle aspiration (TBNA), virtual navigation, and electromagnetic navigation bronchoscopy, has made it possible to obtain representative histologic and cytologic samples with greater speed and a lower rate of complications.(1,2) Linear EBUS involves the use of a bronchoscope with a convex ultrasound transducer at its distal

1. Physician. Division of Interventional Pulmonology, Clinica Alemana of Santiago, Universidad del Desarrollo, Santiago, Chile.

2. Resident in Internal Medicine. Pontifical Catholic University of Chile School of Medicine, Santiago, Chile.

3. Physician. Clinica Alemana of Santiago, Universidad del Desarrollo, Santiago, Chile.

4. Physician. Division of Pulmonology, Clinica Alemana of Santiago, Universidad del Desarrollo, Santiago, Chile.

5. Staff Physician. Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 6. Director. Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. *Study carried out at the Clinica Alemana of Santiago, Universidad del Desarrollo, Santiago, Chile.

Correspondence to: Sebastián Fernández-Bussy. Avenida Manquehue Norte, 1410, Vitacura, Santiago, Chile.

Tel. 56 2 2210-1111. Fax: 56 2 575-4972. E-mail: sfernandezbussy@alemana.cl Financial support: None.

Submitted: 31 October 2014. Accepted, after review: 20 April 2015.

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end to confirm the location of the lesion in real time, which allows fine-needle aspiration of the lesion contents (i.e., TBNA), significantly increasing the diagnostic yield. This method was first used in early 2000 by Herth et al.(3,4) The diagnostic yield of EBUS-TBNA has been studied in different types of airway lesions, as well as in central and peripheral lesions. The procedure has proven to be useful in lesions adjacent to central airway structures, reportedly yielding a sensitivity of 90% and a specificity of 100%. A systematic review and meta-analysis,(5) which included 11 studies involving 1,299 patients referred for EBUS for mediastinal staging in non-small cell lung cancer, found a sensitivity of 93% (95% CI, 91%-94%) and a specificity of 100% (95% CI, 99%-100%). However, this diagnostic method is not sufficiently accurate to locate all mediastinal lymph node stations, especially stations 5, 6, 8, and 9 of the mediastinal lymph node map developed by the International Association for the Study of Lung Cancer (IASLC).(3,6) The objective of the present study was to describe the diagnostic yield of EBUS-TBNA as a diagnostic and staging method for secondary mediastinal nodal involvement in patients with non-small cell lung cancer.

Methods This was a prospective descriptive study of patients undergoing EBUS-TBNA for diagnosis of operable non-small cell lung cancer and referred for mediastinal nodal staging. All procedures performed in outpatients and inpatients of the Clinica Alemana of Santiago, Santiago, Chile, between July of 2010 and August of 2013 were included. Patients ≥ 18 years of age with a presumptive diagnosis of lung cancer or non-small cell lung cancer who met criteria for surgery were consecutively selected on the basis of clinical history and imaging studies (chest X-ray and CT scans). Lung cancer patients with distant metastasis (M1, as per the tumor-node-metastasis classification)(7) were excluded, as were patients undergoing restaging after chemotherapy and those who refused the procedure.

This study was reviewed and approved by the Research Ethics Committee of the Clinica J Bras Pneumol. 2015;41(3):219-224

Alemana of Santiago, Universidad del Desarrollo, Santiago, Chile.

All procedures were performed with a flexible video bronchoscope (BF-Q180; Olympus Corp., Miami, FL, USA) and a flexible ultrasound bronchoscope (BF-UC180F; Olympus Corp.) by an endoscopist. The procedures were performed in accordance with standard recommendations, with monitoring and sedation under anesthesia. (2) All patients had to sign a written informed consent before undergoing the procedure. The airway and mediastinal lymph node stations were thoroughly inspected with a flexible bronchoscope.

Subsequently, the lymph nodes were identified by radiological imaging study and linear transducer ultrasound. Mediastinal lymph nodes with suspected neoplastic involvement—defined as enlargement (10 mm in size), irregular borders, and irregular shape—that was not confirmed by imaging was aspirated at least six times using a transbronchial needle.

We recorded demographic variables such as age and gender, as well as lesion characteristics on axial CT of the chest, classifying them in accordance with the affected lymph node; location of the lesion in the mediastinum as per the IASLC lymph node map(6); lymph node morphology (round, oval, triangular, or other); lesion borders (defined or irregular); lesion size; and complications associated with the procedure.

The anatomopathological study of the samples was carried out at the Department of Pathology by an operator who was blinded to the clinical history and to the diagnostic result of the previous procedure. A sample that was positive for lung cancer was considered to be diagnostic, dispensing with another surgical biopsy. In cases in which bronchoscopy was nondiagnostic, the definitive diagnostic procedure that is defined as the reference standard (surgery by videoassisted thoracoscopy or by mediastinoscopy) was resorted to within 2 months, whereas in cases in which the lesion sample was nondiagnostic by all (bronchoscopic or surgical) methods, a 12-month or longer, chest CT follow-up was defined as the reference standard.

Data were recorded in a database designed in Microsoft Office Excel 2010. The working definitions used for this study were as follows: http://dx.doi.org/10.1590/S1806-37132015000004466

Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal staging in lung cancer

true positive (TP) = an EBUS-TBNA sample positive for lung cancer; true negative (TN) = an EBUS-TBNA sample negative for lung cancer and a surgical sample negative for lung cancer, or axial chest CT follow-up showing no significant changes; false negative (FN) = an EBUS-TBNA sample negative for lung cancer and a surgical sample positive for lung cancer.

In addition, diagnostic yield was defined as the sum of EBUS-TBNA results that were diagnostically positive for cancer and EBUSTBNA results that were negative for cancer and were confirmed by the reference standard (TP + TN).

On the basis of the results obtained, we assessed sensitivity—defined as TP/(TP + FN)— specificity—defined as TN/(TN + FP)—positive predictive value—defined as TP/(TP + FP)—and negative predictive value—defined as TN/(TN + FN). Once the diagnostic yield results were obtained, we calculated the positive and negative likelihood ratios for EBUS-TBNA.

Results Our analysis included 354 mediastinal lymph node biopsies, from 145 consecutive patients. Of those 145 patients, 54.48% were male. The mean age was 63.75 years (range, 20 to 88 years). The mean lymph node size was 15.03 mm, and 90 lymph nodes were smaller than 10.0 mm. The demographic and lesion characteristics of the patients included in this study are summarized in Table 1.

Lesions were located as follows: 40.96% in the lower or upper paratracheal region; 27.96% in the hilar region; 26.55% in the subcarinal region; and 4.53% in the interlobar, lobar, and subsegmental regions. Regarding the ultrasound characteristics of the lymph nodes, 35.0% were oval, 16.6% were triangular, and 51.41% had regular borders, whereas the location of the lesion in the mediastinum as per the IASLC lymph node map and biopsy diagnostic yield is summarized in Tables 2 and 3. The EBUS-TBNA method showed a sensitivity of 91.17%, a specificity of 100.0%, a positive predictive value of 100.0%, and a negative predictive value of 92.9%. The likelihood ratio for a positive diagnostic result http://dx.doi.org/10.1590/S1806-37132015000004466

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was 93.9, whereas the likelihood ratio for a negative diagnostic result was 0.06.

Analysis of the diagnostic yield of EBUS according to lesion size revealed that the result of 1/90 biopsies was false negative in those lesions smaller than 10 mm, with sensitivity being 90.0% and specificity being 100.0% for this group, whereas, in those lesions greater than 10 mm, the yield was 91.25%.

A definitive diagnosis was established by EBUSTBNA in 164 cases, by surgical techniques in 15 cases, and by radiological follow-up in 175 cases. Of the EBUS-TBNA samples that were negative, 15 corresponded to false negatives (pulmonary adenocarcinoma, in 11; squamous neoplasia, in 4).

Of all pulmonary lesions that were diagnosed by any method, 170 were found to be consistent with lung cancer, whereas 9 were of benign etiology. The prevalence of lung cancer in our series was 48.02%. The histologic results are summarized in Table 4.

Finally, in our series, there was one episode of pneumomediastinum that was considered related to the procedure and occurred after biopsy sampling of the pretracheal region, which was performed as part of mediastinal lymph node assessment. Management of this complication was medical, without major complications, with a 2-day hospital stay.

Discussion Assessment of pulmonary lesions by minimally invasive techniques plays an increasingly important Table 1 - Demographic characteristics of and lymph node size in the patients included in the study (N = 145).

Characteristic n % Females 66 45.51 Males 79 54.48 Mean age, years 63,75 20-88a Total number of biopsies 354 Size, mm <5 6 1.64 5-9 84 22.75 10-14 157 41.39 15-19 50 17.01 >20 57 17.21 a

Range.

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Table 2 - Location of the lymph nodes in the mediastinum as per the IASLC classification and biopsy results.

Location Samples Positive biopsies Negative biopsies False-negative biopsies 1 1 1 0 0 2L 3 2 1 0 2R 11 7 4 1 4L 45 21 24 0 4R 85 37 48 6 7 94 44 50 5 10L 45 15 30 1 10R 54 17 37 2 11R 11 9 2 0 11L 2 0 2 0 12R 3 2 1 0 Total 354 155 199 15 IASLC: International Association for the Study of Lung Cancer.

Table 3 - Ultrasound characteristics of the lymph nodes aspirated (N = 354) under EBUS guidance for mediastinal staging.

Characteristic n % Shape Oval 124 35.02 Round 148 41.8 Triangular 59 16.66 Other 23 6.49 Borders Regular 182 51.41 Irregular 172 48.58 EBUS: endobronchial ultrasound.

Table 4 - Definitive histologic results for the EBUSTBNA samples.

Histologic result % Neoplasia (n = 170) Adenocarcinoma 69.41 Squamous disease 18.82 Metastasis 1.76 Small cell disease 7.64 Neuroendocrine disease 2.35 Non-Hodgkinâ&#x20AC;&#x2122;s lymphoma Benign lesion (n = 9) Sarcoidosis granuloma 4.70 Tuberculosis granuloma 11.1 EBUS-TBNA: endobronchial ultrasound-guided transbronchial needle aspiration.

role as diagnostic yields are increased. EBUS has been used as a method that allows TBNA of pulmonary lesions to be performed reliably and safely. Methodologically, studies analyzing the J Bras Pneumol. 2015;41(3):219-224

diagnostic yield of pulmonary lesions suggestive of cancer do not have the reference standard applied to all positive histologic results. The main reason for this is that it is complicated to perform another diagnostic surgical procedure in patients diagnosed with lung cancer.

Another application of EBUS-TBNA is its ability to stage lung cancer in the mediastinum, mainly because the technique allows easy access to most lymph node stations, except for stations 5, 6, 8, and 9 (IASLC classification), from which it is not possible to obtain histologic or cytologic samples by using this technique; in such cases, EBUS-TBNA can be complemented with ultrasound-guided endoscopy.(8) However, the yield of EBUS-TBNA is significantly decreased in peripherally located pulmonary lesions.(3,8) The diagnostic yield of mediastinal staging by EBUS-TBNA is high, with a reported sensitivity of approximately 90% and a specificity of 100%. In a recently published randomized clinical trial,(9) the yield of EBUS-TBNA as the first-choice minimally invasive method for the staging and diagnosis of lung cancer in lesions adjacent to the central airways was compared with that of commonly used techniques. The group randomized to EBUS-TBNA had a decrease in the number of unnecessary thoracotomies and complications, as well as a decrease in the time required to confirm or rule out the diagnosis of lung cancer and make therapeutic decisions. In that study, EBUS-TBNA had a sensitivity of 92% and a specificity of 100%. http://dx.doi.org/10.1590/S1806-37132015000004466

Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal staging in lung cancer

In our series, the diagnostic yield of EBUSTBNA was high, especially because all lesions were located in the central airway, with lesions visualized by EBUS. We evaluated the yield of EBUS-TBNA and found that, in small lesions (those smaller than 10 mm), it remained satisfactory.

This finding is a contribution to the assessment of solitary pulmonary nodules and lymph nodes between 5 and 10 mm, given that lesions smaller than 7 mm are not seen on imaging studies such as positron emission tomography-CT, whereas, by using ultrasound, those lesions can be found and aspirated transbronchially, with a diagnostic yield of 90% or more.

Tedde et al.,(10) the only available reference regarding EBUS-TBNA in South America, included 50 patients who underwent a total of 201 EBUSTBNA biopsies of 81 lymph nodes or mediastinal masses for diagnosis and staging. In that series, the diagnosis of cancer was confirmed in 57% of the patients in whom EBUS-TBNA was diagnostic.

A negative point in that study was that, in 13 of the 50 patients, the cytologic material was not optimal for anatomopathological examination.

Complications associated with EBUS-TBNA are rare and usually minor. In our series, there was one case of pneumomediastinum—a complication with a reported rate of less than 1%—that was managed medically, without other major complications.

In the literature, complications are infrequent, with self-limited bleeding being reported in less than 5% of the procedures, whereas the rate of pneumothorax is 1% with no fatal events,(8,11) similar to what was found in our series.

This study has some limitations. First, the study design: the protocol for studies of diagnostic yield should be in accordance with the recommendations of the STARD statement.(12) In our study, those diagnostic procedures that were positive for lung cancer by histology were not confirmed by surgical biopsy or surgical histology (the gold standard), and therefore it is not possible to determine the proportion of false positives.

However, given that a positive histologic result for cancer is confirmatory, it should not be a confounding variable. Second, the prevalence found in our study was lower than that reported in other series of lung cancer patients, in which prevalence rates range from 70% to 75%. Third, http://dx.doi.org/10.1590/S1806-37132015000004466

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this study was conducted in a single center, with the same operator. Diagnostic yield is a learning curve-dependent variable, and this can reduce result applicability to other centers with less experience in EBUS-TBNA. In conclusion, EBUS-TBNA is a diagnostic tool with a high diagnostic yield, has few associated complications, and should be considered an option for mediastinal nodal staging in patients with lung cancer, especially in those with non-small cell lung cancer.

References 1. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

Chest. 2013;143(5 Suppl):e142S-65S. 2. Ernst A, Silvestri GA, Johnstone D; American College of Chest Physicians. Interventional pulmonary procedures: Guidelines from the American College of Chest Physicians.

Chest. 2003;123(5):1693-717. http://dx.doi.org/10.1378/ chest.123.5.1693 3. Anantham D, Koh MS, Ernst A. Endobronchial ultrasound.

Respir Med. 2009;103(10):1406-14. http://dx.doi. org/10.1016/j.rmed.2009.04.010 4. Dincer HE. Linear EBUS in staging non-small cell lung cancer and diagnosing benign diseases. J Bronchology Interv Pulmonol. 2013;20(1):66-76. http://dx.doi. org/10.1097/LBR.0b013e31827d1514 5. Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45(8):1389-96. http://dx.doi.org/10.1016/j.ejca.2008.11.043 6. Rusch VW, Asamura H, Watanabe H, Giroux DJ, RamiPorta R, Goldstraw P, et al. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4(5):568-77. http://dx.doi.org/10.1097/ JTO.0b013e3181a0d82e 7. Tanoue LT, Detterbeck FC. New TNM classification for non-small-cell lung cancer. Expert Rev Anticancer Ther.

2009;9(4):413-23. http://dx.doi.org/10.1586/era.09.11 8. Vilmann P, Puri R. The complete ‘’medical’’ mediastinoscopy (EUS-FNA + EBUS-TBNA). Minerva Med. 2007;98(4):331-8.

9. Navani N, Nankivell M, Lawrence DR, Lock S, Makker H, Baldwin DR, et al.; Lung-BOOST trial investigators.

Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an openlabel, pragmatic, randomised controlled trial. Lancet Respir Med. 2015;3(4):282-9. http://dx.doi.org/10.1016/ S2213-2600(15)00029-6 10. Tedde ML, Figueiredo VR, Terra RM, Minamoto H, Jatene FB. Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis and staging of mediastinal lymphadenopathy: initial experience in Brazil. J Bras Pneumol. 2012;38(1):33-40.

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11. von Bartheld MB, van Breda A, Annema JT. Complication rate of endosonography (endobronchial and endoscopic ultrasound): a systematic review.

Respiration. 2014;87(4):343-51. http://dx.doi. org/10.1159/000357066

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12. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration.

Ann Intern Med. 2003;138(1):W1-12. http://dx.doi. org/10.7326/0003-4819-138-1-200301070-00010

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Original Article Mobility therapy and central or peripheral catheter-related adverse events in an ICU in Brazil* Realização de fisioterapia motora e ocorrência de eventos adversos relacionados a cateteres centrais e periféricos em uma UTI brasileira

Natália Pontes Lima, Gregório Marques Cardim da Silva, Marcelo Park, Ruy Camargo Pires-Neto

Abstract Objective: To determine whether mobility therapy is associated with central or peripheral catheter-related adverse events in critically ill patients in an ICU in Brazil. Methods: A retrospective analysis of the daily medical records of patients admitted to the Clinical Emergency ICU of the University of São Paulo School of Medicine Hospital das Clínicas Central Institute between December of 2009 and April of 2011. In addition to the demographic and clinical characteristics of the patients, we collected data related to central venous catheters (CVCs), hemodialysis (HD) catheters and indwelling arterial catheters (IACs): insertion site; number of catheter days; and types of adverse events. We also characterized the mobility therapy provided. Results: Among the 275 patients evaluated, CVCs were used in 49%, HD catheters were used in 26%, and IACs were used in 29%. A total of 1,268 mobility therapy sessions were provided to patients while they had a catheter in place. Catheterrelated adverse events occurred in 20 patients (a total of 22 adverse events): 32%, infection; 32%, obstruction; and 32%, accidental dislodgement. We found that mobility therapy was not significantly associated with any catheter-related adverse event, regardless of the type of catheter employed: CVC—OR = 0.8; 95% CI: 0.7-1.0; p = 0.14; HD catheter—OR = 1.04; 95% CI: 0.89-1.21; p = 0.56; or IAC—OR = 1.74; 95% CI: 0.94-3.23; p = 0.07. Conclusions: In critically ill patients, mobility therapy is not associated with the incidence of adverse events involving CVCs, HD catheters, or IACs. Keywords: Physical therapy modalities; Intensive care units; Catheters; Early ambulation.

Introduction Early rehabilitation in intensive care unit (ICU) patients helps to prevent and minimize the deleterious effects of immobility, to improve functional capacity, and to reduce the duration of mechanical ventilation and length of hospital stay, as well as improving the quality of life of such patients.(1-4) However, the literature describes some barriers that limit or preclude this rehabilitation. Some examples are disease severity, level of sedation, use of vasoactive drugs, and presence of catheters, whether central or peripheral.(5,6) The use of central or peripheral catheters for drug administration and monitoring in critically

ill patients is common. In patients with difficult access, with multiple access sites, or with a bleeding disorder, partial or total confinement to bed to prevent catheter dislodgement or loss is still common. In addition, there is the concern about maintaining blood flow in patients undergoing continuous renal replacement therapy.(7) Recent studies have shown that mobilization of patients with catheters is safe and is not associated with access-related or catheter-related adverse events.(6,8,9) However, some centers still consider the presence of catheters a barrier to mobilization, delaying the start of rehabilitation.(5,10)

1. Physical Therapist. Department of Physical Therapy, Hospital das Clínicas Central Institute, University of São Paulo School of Medicine, São Paulo, Brazil.

2. Physician. Intensive Care Unit, Department of Clinical Emergencies, University of São Paulo School of Medicine Hospital das 3. Clínicas Central Institute, São Paulo, Brazil.

Physical Therapist. Department of Pathology, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. *Study carried out at the Hospital das Clínicas Central Institute, University of São Paulo School of Medicine, São Paulo, Brazil.

Correspondence to: Natália Pontes Lima. Faculdade de Medicina, USP, Avenida Dr. Arnaldo, 455, sala 1155, CEP 01246-903, São Paulo, SP, Brasil.

Tel. 55 11 2266-6470. E-mail: nataliaponteslima@yahoo.com.br Financial support: None.

Submitted: 9 June 2014. Accepted, after review: 10 February 2015.

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Given that the literature on this topic is controversial and that most studies were conducted in centers in the United States and Australia, all of which provide physical therapy that is different from that provided in Brazil, the objective of the present study is to determine whether mobility therapy is associated with central or peripheral catheter-related adverse events in critically ill patients in an ICU in Brazil. Our hypothesis is that there is no association between mobility therapy and central or peripheral catheter-related adverse events such as accidental dislodgement or removal and infection.

Methods This study was approved by the Human Research Ethics Committee of the Faculdade de Medicina da Universidade de São Paulo (FMUSP, University of São Paulo School of Medicine).

We performed a retrospective analysis of the daily medical and physical therapy records of patients admitted to the 6-bed ICU of the Department of Clinical Emergencies of the FMUSP Instituto Central do Hospital das Clínicas (ICHC, Hospital das Clínicas Central Institute) between December of 2009 and April of 2011. The daily record forms were developed prior to the study, were completed electronically, and had been in use for at least one year in the ICU. Therefore, data on all study variables were available through an electronic medical records system.

Physical therapy in the ICU was characterized by respiratory therapy and by mobility therapy.

In brief, respiratory therapy was based on airway clearance maneuvers (including aspiration), lung expansion techniques, adjustment of oxygen therapy, and inhalation therapy (the last of these being administered as medically prescribed). In addition, if the patient was mechanically ventilated, the physical therapist also assisted in adjustment of ventilator settings and in patient extubation.

Mobility therapy consisted of upper limb, lower limb, and trunk exercises, in passive, active, and resistive modes. Exercise was performed with the patient lying on the bed, sitting on the bed, or sitting in an armchair, depending on the ability of the patient and at the discretion of the physical therapist. In addition, exercise in the standing position and ambulation around the bed and in the hallway was recommended.

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1:6 resident in physical therapy/patient, and 1:10 senior physical therapist/patient. Physical therapy was available 12 hours a day (from 7:00 a.m. to 7:00 p.m.), and, during that period, each patient usually received two visits, which were tailored to the needs of each individual.

Data collection included demographic characteristics and clinical data, such as age, gender, clinical admission diagnosis, Simplified Acute Physiology Score (SAPS) 3, site of admission, duration of mechanical ventilation, length of ICU stay, and mortality. In addition, we collected data related to central venous catheters (CVCs), hemodialysis (HD) catheters, and indwelling arterial catheters (IACs): insertion site; number of catheter days; and number of mobility therapy sessions conducted with a catheter in situ. The catheter-related adverse events considered were obstruction, accidental dislodgement or removal, and infection. The data we collected on mobility therapy included the frequency and level of each activity (in-bed exercise, sitting on the edge of the bed or out of bed, standing, and walking). All data were entered into tables and were checked by two researchers.

Statistical analysis was performed with Statistical Package for the Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA). Descriptive analysis was performed using frequency of each event (percentage), mean (SD), or median (interquartile range [IQR]), when appropriate.

For each catheter type (CVC, HD catheter, and IAC), we determined the number of patients who experienced a catheter-related adverse event and the number of those who did not. Therefore, the patients were divided into two groups on the basis of presence or absence of catheter-related adverse events. We used the nonparametric MannWhitney test to compare the adverse event and non-adverse event groups in terms of number of catheter days and number of mobility therapy sessions, for each catheter type. Logistic regression analysis (including ORs and their 95% CIs) was performed to determine the association between adverse events and number of mobility therapy sessions. The association analysis was adjusted for number of catheter days (confounding variable).

For statistical analysis, the level of significance was set at 5% (p < 0.05). http://dx.doi.org/10.1590/S1806-37132015000004338

Mobility therapy and central or peripheral catheter-related adverse events in an ICU in Brazil

Results During the study period, 275 patients were admitted to the Clinical Emergency ICU of the ICHC-FMUSP, all of whom were included in the analysis. Patient demographic characteristics and clinical data are shown in Table 1. The mean age of the patients was 48 ± 18 years, and most patients (84%) were admitted for clinical decompensation. The remaining 16% were admitted for surgical reasons (postoperative period). In addition, of the 275 patients, 82 (30%) were admitted with a diagnosis of sepsis. The major source of origin was the emergency room (in 53%), followed by the ward because of clinical worsening (in 26%). The length of ICU stay was 5 [IQR: 7] days, and 44% of the patients required invasive mechanical ventilation during that period. Overall ICU mortality was 17%.

Of the 275 patients, 82% (n = 225) received at least one mobility therapy session (a total of 2,638 sessions) and 94% (n = 258) received at least one respiratory therapy session throughout their ICU stay. In addition, of those 275 patients, 31% (n = 86) sat in an armchair (i.e., out of bed) and 29% (n = 80) walked at least once during their ICU stay. Patients with orotracheal tubes (orotracheal intubation) or tracheostomy tubes (with or without mechanical ventilation) underwent a total of 1,428 mobility therapy sessions, in which the main activity was ambulation, in 237 Table 1 - Patient demographic characteristics.a Variable (n = 275) Age, years 48 ± 18 Male gender, n (%) 135 (49) SAPS3 38 ± 19 Diagnosis, n (%) Clinical 229 (84) Surgical 45 (16) Site of admission, n (%)b Emergency room 145 (53) Ward (clinical worsening) 72 (26) Operating room (PO) 45 (16) Others 12 (4) Mechanically ventilated patients, n (%) 122 (44) Duration of mechanical ventilation, daysc 3 [4] Length of ICU stay, daysc 5 [7] Mortality, n (%) 47 (17) SAPS: Simplified Acute Physiology Score; and PO: postoperative period. aValues expressed as mean ± SD, except where otherwise indicated. bInformation unavailable for four patients. cValues expressed as median [interquartile range].

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sessions; orthostasis, in 161 sessions; sitting in an armchair, in 91 sessions; sitting on the edge of the bed, in 60 sessions; and in-bed exercise, in 879 sessions. During those sessions, there were no reports of self-extubation or accidental extubation.

Table 2 shows the frequency of patients who experienced catheter-related adverse events by catheter type, as well as the number of catheter days, the frequency of mobility therapy sessions conducted with a catheter in situ, and the most successfully accomplished activity in those sessions, by catheter type and by absence or presence of catheter-related adverse events. Among the 275 patients evaluated, CVCs were used in 49%, HD catheters were used in 26%, and IACs were used in 29%. In addition, 86 patients (31%) required different types of catheters simultaneously.

The main insertion sites were the jugular and subclavian veins, for CVCs and HD catheters, and the radial artery, for IACs. A total of 1,268 mobility therapy sessions were conducted with a catheter in situ, and the most prevalent activity was in-bed limb mobilization (in passive, active, and resistive modes). Catheter-related adverse events occurred in 20 patients, and, in two of those 20 patients, there were two adverse events (a total of 22 catheter-related adverse events).

The adverse events were as follows: infection (n = 5, CVC; n = 2, HD catheter); obstruction (n = 5, HD catheter; n = 2, IAC); and accidental dislodgement or removal (n = 4, CVC; n = 1, HD catheter; n = 2, IAC). In one case, the cause of the adverse event was not recorded on the chart.

When comparing the adverse event and non-adverse event groups by catheter type, we found that the number of catheter days was greater in the former than in the latter—(median [IQR]) 8 [10] vs. 5 [4] days for CVCs (p < 0.05); and 7 [15] vs. 3 [4] days for IACs (p < 0.05)—as was the number of mobility therapy sessions per patient—(median [IQR]) 12 [19] vs. 4 [9] for HD catheters (p < 0.05). Logistic regression analysis for each catheter type, adjusted for number of catheter days, revealed that mobility therapy was not significantly associated with any catheterrelated adverse event, regardless of the type of catheter employed: CVC—OR = 0.862; 95% CI: 0.7-1.05; p = 0.146; HD catheter—OR = 1.046; 95% CI: 0.898-1.219; p = 0.562; or IAC—OR = 1.746; 95% CI: 0.942-3.237; p = 0.077.

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Table 2 - Characteristics of the catheters used and of the mobility therapy provided.

Variable CVC HD catheter IAC Adverse event Adverse event Adverse event Absent Present Absent Present Absent Present Patients, n (%) 126 (94) 8 (6) 63 (89) 8 (11) 75 (95) 4 (5) Catheter days, median [IQR] 5 [4] 8 [10]* 6 [7] 9 [16] 3 [4] 7 [15]* Mobility therapy sessions (n), median [IQR]a 4 [5] 6 [13] 4 [9] 12 [19]* 2 [3] 10 [22] Main insertion siteb,c Jugular vein, n 85 5 34 5 Subclavian vein, n 33 3 11 1 Femoral vein, n 6 1 17 2 Radial artery, n 50 3 Dorsalis pedis artery, n 15 0 Femoral artery, n 3 1 Most successfully accomplished activity Ambulation, n 23 2 125 0 3 0 Orthostasis, n 51 3 101 2 5 0 Sitting in an armchair, n 25 3 38 3 7 0 Sitting on the edge of the bed, n 36 2 39 8 5 1 Limb mobilization, n 533 42 382 59 227 20 CVC: central venous catheter; HD: hemodialysis; IAC: indwelling arterial catheter; and IQR: interquartile range. aMobility therapy sessions received by each patient with a catheter in situ. bThere can be more than one insertion site in each individual patient. cThe insertion site was not described on the chart in 3% (CVC); 4% (HD catheter), and 9% (IAC) of the cases. *p < 0.05 when compared with the respective non-adverse event group.

Discussion In the present study, we found that, of the 275 patients admitted to the Clinical Emergency ICU of the ICHC-FMUSP, 82% received mobility therapy, whereas 94% received respiratory therapy.

Of a total of 2,638 mobility therapy sessions, 1,268 were provided to patients while they had a catheter in place (CVC, IAC, or HD catheter), and we found that mobility therapy was not significantly associated with any catheter-related adverse event, regardless of the type of catheter employed. In addition, in 1,428 sessions provided during orotracheal intubation or during the use of a tracheostomy tube (with or without mechanical ventilation), there were no reported episodes of self-extubation or accidental extubation.

Recent cohort or prevalence studies have found that 34 to 62% of ICU patients receive mobility therapy.(9,11,12) In our study, 82% of the patients received at least one mobility therapy session. This difference in the proportion of treated patients can be explained by the large number of physical therapists in our ICU (1:10 senior physical therapist/patient and 1:6 resident in physical therapy/patient), unlike what occurs in ICUs in other countries, in which there is a strong presence of respiratory therapists.(13) J Bras Pneumol. 2015;41(3):225-230

However, the large number of physical therapists did not imply treatment aimed at more complex levels of mobilization, the most prevalent activity being in-bed exercise. One explanation for this finding is that early mobilization in ICUs in Brazil remains unusual, despite the constant, daily presence of the physical therapist. Another factor that can explain this situation is that only the activities conducted with a catheter in situ were analyzed, and patients with CVCs and IACs usually experience increased hemodynamic instability and increased disease severity.

In our study, we found no association between catheter-related adverse events and mobilization (mobility therapy) in the ICU. In addition, the incidence of catheter-related adverse events was 2% in our study (22 events in 1,268 sessions), being similar to the less than 5% incidence reported in other centers.(1,2,14-18) Damluji et al.,(6) when evaluating 101 patients who underwent 253 physical therapy sessions with a femoral catheter in situ, found that exercise was not associated with catheter-related adverse events.

Perme et al.,(8) when evaluating 77 patients with 92 femoral catheters (50 IACs, 15 CVCs, and 27 HD catheters), found that exercise was not associated with catheter-related thrombotic or obstructive complications. Likewise, we found http://dx.doi.org/10.1590/S1806-37132015000004338

Mobility therapy and central or peripheral catheter-related adverse events in an ICU in Brazil

no association between mobility therapy and catheter-related adverse events. However, unlike in the aforementioned studies, we assessed not only the femoral site but also the jugular and subclavian sites, for CVCs and HD catheters, and the radial and dorsalis pedis arteries, for IACs. In fact, the most common catheter insertion sites were the radial and jugular sites, given that catheter insertion into the femoral site is not the primary option in our ICU (Table 2).

Therefore, even when different insertion sites were used, exercise did not imply an increase in the number of catheter-related adverse events.

The present study has some limitations. First, this was a single-center study—direct comparison with other hospitals in Brazil should be conducted with caution. However, our findings are similar to those of studies conducted in countries where the difference in care is greater than that observed among hospitals in Brazil. Second, the study has a retrospective design—data were retrieved from a database and from patient charts. Therefore, we can establish only an association, not a causeand-effect relationship. In addition, information on catheter insertion site could not be obtained for all cases—that is, for 3% (CVC), 4% (HD catheter), and 9% (IAC)—nor was it possible to obtain information on one CVC-related adverse event. However, we believe that these factors do not alter the results of this study, because catheter insertion site was not used for analysis, being of descriptive value only. Third, the only factors used in our analysis were mobility therapy and number of catheter days. Thus, it was not possible to determine the effect of medical and nursing procedures (e.g., hygiene, transport, and tube passage) on our results. Catheter infection is known to be caused by multiple factors and can result from patient handling by healthcare workers. For this reason, the reported prevalence, which refers specifically to mobility therapy, might be overestimated relative to reality.

On the basis of the present study, we conclude that, in the study population, mobility therapy is not associated with the incidence of adverse events involving CVCs, HD catheters, or IACs.

References 1. Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373(9678):187482. http://dx.doi.org/10.1016/S0140-6736(09)60658-9

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2. Morris PE, Goad A, Thompson C, Taylor K, Harry B, Passmore L, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med. 2008;36(8):2238-43. http://dx.doi.org/10.1097/ CCM.0b013e318180b90e 3. Stiller K. Physiotherapy in intensive care: an updated systematic review. Chest. 2013;144(3):825-47. http:// dx.doi.org/10.1378/chest.12-2930 4. Kayambu G, Boots R, Paratz J. Physical therapy for the critically ill in the ICU: a systematic review and metaanalysis. Crit Care Med. 2013;41(6):1543-54. http:// dx.doi.org/10.1097/CCM.0b013e31827ca637 5. Leditschke IA, Green M, Irvine J, Bissett B, Mitchell IA. What are the barriers to mobilizing intensive care patients? Cardiopulm Phys Ther J. 2012;23(1):26-9.

6. Damluji A, Zanni JM, Mantheiy E, Colantuoni E, Kho ME, Needham DM. Safety and feasibility of femoral catheters during physical rehabilitation in the intensive care unit. J Crit Care. 2013;28(4):535.e9-15.

7. Morris PE. Moving our critically ill patients: mobility barriers and benefits. Crit Care Clin. 2007;23(1):1-20. http://dx.doi.org/10.1016/j.ccc.2006.11.003 8. Perme C, Lettvin C, Throckmorton TA , Mitchell K, Masud F. Early Mobility and Walking for Patients with Femoral Arterial Catheters in Intensive Care Unit : a Case Series. JACPT. 2011;2(1):32-6. http://dx.doi. org/10.1097/01592394-201102010-00004 9. Nydahl P, Ruhl AP, Bartoszek G, Dubb R, Filipovic S, Flohr HJ, et al. Early mobilization of mechanically ventilated patients: a 1-day point-prevalence study in Germany. Crit Care Med. 2014;42(5):1178-86. http:// dx.doi.org/10.1097/CCM.0000000000000149 10. Berney SC, Harrold M, Webb SA, Seppelt I, Patman S, Thomas PJ, et al. Intensive care unit mobility practices in Australia and New Zealand: a point prevalence study.

Crit Care Resusc. 2013;15(4):260-5.

11. Mendez-Tellez PA, Dinglas VD, Colantuoni E, Ciesla N, Sevransky JE, Shanholtz C, et al. Factors associated with timing of initiation of physical therapy in patients with acute lung injury. J Crit Care. 2013;28(6):980-4. http://dx.doi.org/10.1016/j.jcrc.2013.06.001 12. Sricharoenchai T, Parker AM, Zanni JM, Nelliot A, Dinglas VD, Needham DM. Safety of physical therapy interventions in critically ill patients: a single-center prospective evaluation of 1110 intensive care unit admissions. J Crit Care. 2014;29(3):395-400. http:// dx.doi.org/10.1016/j.jcrc.2013.12.012 13. Hodgin KE, Nordon-Craft A, McFann KK, Mealer ML, Moss M. Physical therapy utilization in intensive care units: results from a national survey. Crit Care Med. 2009;37(2):561-6; quiz 566-8 . http://dx.doi.org/10.1097/ CCM.0b013e3181957449 14. Needham DM, Korupolu R, Zanni JM, Pradhan P, Colantuoni E, Palmer JB, et al. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project. Arch Phys Med Rehabil. 2010;91(4):536-42. http://dx.doi.org/10.1016/j. apmr.2010.01.002 15. Bourdin G, Barbier J, Burle JF, Durante G, Passant S, Vincent B, et al. The feasibility of early physical activity in intensive care unit patients: a prospective observational one-center study. Respir Care. 2010;55(4):400-7.

16. Pohlman MC, Schweickert WD, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al. Feasibility of physical

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and occupational therapy beginning from initiation of mechanical ventilation. Crit Care Med. 2010;38(11):208994. http://dx.doi.org/10.1097/CCM.0b013e3181f270c3 17. Clark DE, Lowman JD, Griffin RL, Matthews HM, Reiff DA. Effectiveness of an early mobilization protocol in a trauma and burns intensive care unit: a retrospective

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cohort study. Phys Ther. 2013;93(2):186-96. http:// dx.doi.org/10.2522/ptj.20110417 18. Zanni JM, Korupolu R, Fan E, Pradhan P, Janjua K, Palmer JB, et al. Rehabilitation therapy and outcomes in acute respiratory failure: an observational pilot project. J Crit Care.

2010;25(2):254-62. http://dx.doi.org/10.1016/j.jcrc.2009.10.010

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Original Article Organizing pneumonia: chest HRCT findings* Pneumonia em organização: achados da TCAR de tórax

Igor Murad Faria1, Gláucia Zanetti2, Miriam Menna Barreto3, Rosana Souza Rodrigues4, Cesar Augusto Araujo-Neto5, Jorge Luiz Pereira e Silva5, Dante Luiz Escuissato6, Arthur Soares Souza Jr7, Klaus Loureiro Irion8, Alexandre Dias Mançano9, Luiz Felipe Nobre10, Bruno Hochhegger11, Edson Marchiori12

Abstract Objective: To determine the frequency of HRCT findings and their distribution in the lung parenchyma of patients with organizing pneumonia. Methods: This was a retrospective review of the HRCT scans of 36 adult patients (26 females and 10 males) with biopsy-proven organizing pneumonia. The patients were between 19 and 82 years of age (mean age, 56.2 years). The HRCT images were evaluated by two independent observers, discordant interpretations being resolved by consensus. Results: The most common HRCT finding was that of ground-glass opacities, which were seen in 88.9% of the cases. The second most common finding was consolidation (in 83.3% of cases), followed by peribronchovascular opacities (in 52.8%), reticulation (in 38.9%), bronchiectasis (in 33.3%), interstitial nodules (in 27.8%), interlobular septal thickening (in 27.8%), perilobular pattern (in 22.2%), the reversed halo sign (in 16.7%), airspace nodules (in 11.1%), and the halo sign (in 8.3%). The lesions were predominantly bilateral, the middle and lower lung fields being the areas most commonly affected.

Conclusions: Ground-glass opacities and consolidation were the most common findings, with a predominantly random distribution, although they were more common in the middle and lower thirds of the lungs.

Keywords: Cryptogenic organizing pneumonia; Respiratory tract diseases; Tomography, X-ray computed.

Introduction Organizing pneumonia (OP) is a clinical entity that is associated with nonspecific clinical findings, radiographic findings, and pulmonary function test results.(1) It corresponds to a histological pattern characterized by granulation tissue polyps within alveolar ducts and alveoli, with chronic inflammation of the adjacent lung parenchyma. Similar lesions can also be

observed in the respiratory bronchioles.(2,3) The term cryptogenic OP (COP) is more appropriate than the term bronchiolitis obliterans OP, which has been abandoned.(2) This is primarily due to the fact that the hallmark of COP is OP rather than bronchiolitis.(4) When the cause is unknown, OP is classified as primary or cryptogenic; when a causal connection

1. Master’s Student in Radiology. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

2. Professor. Graduate Program in Radiology, Federal University of Rio de Janeiro, Rio de Janeiro; and Professor of Clinical Medicine. Petrópolis School of Medicine, Petrópolis, Brazil.

3. Physician. Department of Radiological Diagnosis, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

4. Physician. Department of Radiological Diagnosis, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro; and Physician. D’Or Institute for Research and Education, Rio de Janeiro, Brazil.

5. Associate Professor. Department of Internal Medicine and Diagnostic Support, Universidade Federal da Bahia – UFBA, Federal University of Bahia – Salvador, Brazil.

6. Adjunct Professor of Radiology. Department of Clinical Medicine, Universidade Federal do Paraná – UFPR, Federal University of Paraná – Curitiba, Brazil.

7. Tenured Professor. São José do Rio Preto School of Medicine, São José do Rio Preto, Brazil.

8. Head. Department of Radiology, Royal Liverpool and Broadgreen University Hospital, Liverpool, United Kingdom.

9. Physician. Radiologia Anchieta, Hospital Anchieta, Taguatinga, Brazil.

10. Adjunct Professor of Radiology. Universidade Federal de Santa Catarina – UFSC, Federal University of Santa Catarina – Florianópolis, Brazil.

11. Adjunct Professor of Diagnostic Imaging. Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

12. Full Professor Emeritus. Fluminense Federal University, Niterói, Brazil. *Study carried out at the Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Edson Marchiori. Rua Thomaz Cameron, 438, Valparaíso, CEP 25685-120, Petrópolis, RJ, Brasil.

Tel. 55 24 2249-2777. Fax: 55 21 2629-9017. E-mail: edmarchiori@gmail.com Financial support: None.

Submitted: 24 January 2015. Accepted, after review: 10 March 2015.

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can be established, OP is classified as secondary.

The causes of OP are numerous and include infections, iatrogenic causes (a reaction to drugs and radiation therapy), illicit drug use, and autoimmune diseases.(1,2,5,6) The distinction between primary and secondary OP is extremely important because the treatment of patients with secondary OP includes treatment for OP itself and for the underlying disease or causative agent.(1) The literature does not provide sufficient data to determine whether COP and secondary OP are two distinct entities or the same entity, in which there is nonspecific lung injury and repair.(5) Although the diagnosis of OP is established by biopsy and histology, the clinical findings and imaging changes can suggest the diagnosis. In this context, HRCT is the imaging method of choice for diagnosing OP. In addition, HRCT allows us to evaluate the response to treatment and is useful for selecting the type of biopsy and the best site to perform it (when necessary). The objective of the present study was to determine the frequency of HRCT findings and their distribution in the lung parenchyma of patients with OP.

Methods The present study was approved by the Research Ethics Committee of the Fluminense Federal University Antonio Pedro University Hospital, located in the city of Niterói, Brazil. Because this was a retrospective study examining existing clinical data and involving no changes in the treatment or follow-up of patients, no written informed consent was required. This was a retrospective descriptive observational study of the HRCT scans of 36 patients with histologically confirmed OP. Of those 36 patients, 20 had primary OP and 16 had secondary OP. The HRCT scans were randomly collected by personally contacting pulmonologists and radiologists and by searching the image databases of 8 medical institutions in 6 different Brazilian states in the 2005-2013 period. Of the 36 patients, 26 (72.2%) were female and 10 (27.8%) were male. The patients were between 19 and 82 years of age (mean age, 56.2 years).

Given that multiple institutions were involved, different CT scanners were used for image acquisition. All patients underwent HRCT scans, which were taken from the lung apices to the lung bases. Thin (1- or 2-mm) scans were taken during inhalation, in increments of 5 or 10 mm, J Bras Pneumol. 2015;41(3):231-237

with the patients in the supine position and without intravenous injection of iodinated contrast material, a high spatial resolution filter (bone filter) being used for image reconstruction. The images were obtained and reconstructed with a 512 × 512 pixel matrix and were photographed for evaluation of the lung fields with a window opening of 1,200-2,000 HU and an opening level of −300 to −700 HU. For mediastinal evaluation, a window opening of 350-500 HU and an opening level of 10-50 HU were used.

The images were independently evaluated by two experienced observers. Discordant interpretations were resolved by consensus.

With regard to the HRCT findings, the following definitions were used: • ground-glass opacity—slightly increased attenuation of the lung parenchyma, unrelated to the obscuration of the vessels and adjacent airway walls • consolidation—increased attenuation of the lung parenchyma, resulting in obscuration of the vascular outlines and adjacent airway walls • peribronchovascular opacity—increased attenuation of the lung parenchyma adjacent to the peribronchovascular interstitium • reticulation—innumerable small linear opacities that, by summation, produce an appearance resembling a net • bronchiectasis—bronchial diameter greater than the diameter of the adjacent artery or absence of tapering of the bronchi and identification of a bronchus 1 cm from the pleural surface • interlobular septal thickening—thin linear opacities, which correspond to thickened interlobular septa • perilobular pattern—thick, irregular polygonal opacities in the periphery of the secondary pulmonary lobules • reversed halo sign—round, focal groundglass opacity surrounded by a ring-shaped peripheral consolidation • airspace nodules—ill-defined nodules smaller than 1 cm and tending to confluence • halo sign—ground-glass opacity surrounding a nodule or mass The criteria for the aforementioned findings are defined in the Fleischner Society Glossary of Terms,(7) and the terms used are those found in the Brazilian Thoracic Association Department http://dx.doi.org/10.1590/S1806-37132015000004544

Organizing pneumonia: chest HRCT findings

of Diagnostic Imaging consensus guidelines.(8,9) The scans were also evaluated for the presence of pleural effusion, lymph node enlargement, and associated findings.

On the basis of their distribution in the lung parenchyma, the findings were classified as follows: â&#x20AC;˘ left-sided, right-sided, or bilateral findings â&#x20AC;˘ findings in the upper third, middle third, or lower third of the lungs â&#x20AC;˘ central or peripheral findings In the craniocaudal axis, the lung was divided into upper third (from the lung apex to the level of the aortic arch), middle third (from the aortic arch to 2 cm below the carina), and lower third (from 2 cm below the carina to the costophrenic sulci). Lesions located predominantly in the middle third were defined as central lesions; those located predominantly in the upper and lower thirds were defined as peripheral lesions; and those with a predominantly random distribution were defined as random lesions.

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Figure 1 - Chest HRCT scan (lung window) at the level of the middle lung field of a 39-year-old male patient, showing ground-glass opacities predominantly in the lung periphery.

Results The most common HRCT findings (Table 1), in descending order, were as follows: groundglass opacities (Figure 1); consolidation (Figure 2); peribronchovascular opacities (Figure 3); reticulation (Figure 4); bronchiectasis; interstitial nodules; interlobular septal thickening; perilobular pattern (Figure 5); reversed halo sign; airspace nodules; and halo sign. There were signs of architectural distortion in 14 (38.9%) of the 36 patients studied.

Of the 36 patients studied, 33 (91.7%) had bilateral lung involvement. In 2 (5.6%), only the right lung was affected, and, in 1 (2.8%), Table 1 - Most common HRCT findings in 36 patients with organizing pneumonia.a HRCT findings Patients Ground-glass opacities 32 (88.9) Consolidation 30 (83.3) Peribronchovascular opacities 19 (52.8) Reticulation 14 (38.9) Bronchiectasis 12 (33.3) Interstitial nodules 10 (27.8) Interlobular septal thickening 10 (27.8) Perilobular pattern 8 (22.2) Reversed halo sign 6 (17.1) Airspace nodules 4 (11.1) Halo sign 3 (8.3) a

Values expressed as n (%).

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Figure 2 - Chest HRCT scan at the level of the lower lung field of a 53-year-old male patient, showing areas of consolidation with air bronchograms and peripheral distribution in the anterior lung regions.

Figure 3 - Chest HRCT scan (lung parenchymal window settings) of a 50-year-old male patient, showing bilateral consolidations with peribronchovascular distribution, interspersed with bronchiectasis.

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only the left lung was affected. With regard to the distribution of the lesions, the middle third of the lung was the most commonly affected area—in 33 (91.7%) of the 36 patients studied— followed by the lower third, in 28 (77.8%), and the upper third, in 21 (58.3%). In addition, the most common lesions were random lesions—in 26 (72.2%) of the 36 patients studied—followed by peripheral lesions, in 9 (25%), and central lesions, in 1 (2.8%).

Discussion Studies evaluating the distribution of patients with COP and secondary OP by gender have shown no significant difference between the two groups.(1,10,11) Of the 36 patients in the present study, 26 (72.2%) were female and 10 (27.8%) were male. With regard to age, studies have shown that OP is most common in the fifth

Figure 4 - Chest HRCT scan (lung parenchymal window settings) at the level of the lung bases of a 75-year-old male patient, showing bilateral reticular opacities in the posterior lung regions.

Figure 5 - Chest HRCT scan (lung parenchymal window settings) at the level of the upper lobes of a 47-year-old female patient, showing a perilobular pattern predominantly on the right. Note faint nodular opacities in the left lung.

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and sixth decades of life.(11,12) Although OP is rarely seen in children, there have been reports of OP in such individuals. In the present study, the patients were between 19 and 82 years of age (mean age, 56.2 years).

The initial symptoms of OP are nonspecific.

Fever, cough, asthenia, mild dyspnea, anorexia, and weight loss are the most common findings, mimicking influenza.(13) Therefore, an initial diagnosis of infectious disease is often made in patients with such findings. In addition, patients with such findings are often given empirical antibiotic therapy, which is ineffective. Fever can be absent in 50% of patients.(2) Therefore, the diagnosis is often delayed, being generally suspected 4-10 weeks after the onset of symptoms.

As the disease progresses, most of the initial symptoms can disappear, the exception being dyspnea, which sometimes worsens and becomes predominant. In some patients, the disease can progress rapidly, leading to severe dyspnea and even acute respiratory distress syndrome.(14) In general, there is no difference between the clinical manifestations of COP and those of secondary OP.(1,5) However, some clinical manifestations can provide important clues for the differential diagnosis. Severe arthralgia, myalgia, or both are more common in patients with OP associated with connective tissue disease.(15) Patient history taking is essential, given that it can aid in identifying a cause for the OP. Patients with a history of lung radiation therapy can present with symptoms and imaging changes suggestive of OP in the lung parenchyma several months after treatment.(16) In our sample, 20 patients (55.6%) had been diagnosed with primary (idiopathic) OP and 16 (44.4%) had been diagnosed with secondary OP on the basis of their clinical history and clinical examination findings. In studies involving larger samples of patients with OP, the proportion of patients with COP ranged from 52% to 65%,(1,10 ‑ 12) being similar to that found in the present study.

Of the 16 patients with secondary OP in the present study, 5 (31.2%) had OP associated with drugs (amiodarone, in 2, nitrofurantoin, in 1, bleomycin, in 1, and busulfan, in 1), 3 (18.8%) had OP associated with infections (influenza A (H1N1) infection, in 2, and cryptococcosis, in 1), 3 (18.8%) had OP associated with bone marrow transplantation, 3 (18.8%) had OP associated with collagen diseases (rheumatoid arthritis, in 2, and systemic lupus erythematosus, in 1), and http://dx.doi.org/10.1590/S1806-37132015000004544

Organizing pneumonia: chest HRCT findings

2 (12.5%) had OP associated with malignancy (lymphoma, in 1, and colon cancer, in 1). The causes of secondary OP vary widely across studies and include drugs, infections, solid or hematologic malignancies and their treatments (chemotherapy, radiation therapy, and bone marrow transplantation), and collagen diseases.(1,10-12) The diagnosis of OP is made by biopsy and histology. However, clinical and physical examination findings (including an investigation of possible causes), together with imaging changes, can suggest the diagnosis.(2) Histopathological examination reveals irregular filling of the alveoli, alveolar ducts, and respiratory bronchioles by granulation tissue plugs, which are known as Masson bodies.(3) There is also a process of intraalveolar fibrosis resulting from the organization of an inflammatory exudate. Unlike usual interstitial pneumonia, OP is not related to a progressive and irreversible fibrotic process.(17) After a diagnosis of OP is established, it is necessary to determine the cause, which can be relatively evident or require further investigation.(2) In our study, all cases of OP were histopathologically confirmed after transbronchial biopsy, in 17 (47.2%); CT-guided transthoracic biopsy, in 5 (13.9%); video-assisted thoracoscopic biopsy, in 8 (22.2%); and open lung biopsy, in 5 (13.9%). In 1 (2.8%), the diagnosis was confirmed by autopsy.

Although some authors have reported using surgical biopsies more frequently (in 88% of their patients),(12) transbronchial biopsy was used in most of the studies involving large samples of patients with OP (being used in 67-78% of the patients). (1,10) Although surgical biopsy (via thoracoscopy or open thoracotomy) remains the gold standard for the diagnosis of OP, transbronchial biopsy can be conclusive in most cases if the findings are appropriately related to the clinical and CT findings.(1) For evaluating OP, HRCT is the imaging method of choice. There are no differences between COP and secondary OP regarding HRCT findings. (1) However, Vasu et al.(12) showed that pleural effusion was more common in patients with secondary OP than in those with COP. The most common finding in patients with OP is that of consolidation and ground-glass opacities, which are usually bilateral and peripheral. (16) However, such opacities are nonspecific, being often mistaken for infectious pneumonia.(18,19) In our sample, the most common findings were http://dx.doi.org/10.1590/S1806-37132015000004544

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ground-glass opacities and consolidations, seen in 89% and 83%, respectively. Our findings are similar to those of larger studies.(1,20,21) A solitary focal opacity is an uncommon presentation of OP that is known as focal OP and accounts for 10-15% of all cases.(5) The diagnosis is usually made by biopsy of a nodule or mass that was removed because of a suspicion of bronchogenic carcinoma.(7) In the present study, only 1 patient (2.8%) had focal OP. In that patient, the HRCT finding was a nodule with the halo sign.

It is known that OP can also present as overlapping interstitial and alveolar opacities.

In addition, OP can overlap with other types of interstitial pneumonia, particularly idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia.(22) This pattern is characterized by a relative lack of consolidation and groundglass opacities, with a predominance of reticular opacities with architectural distortion.(23) In our sample, there were signs of architectural distortion in 14 patients (38.9%), a proportion that is higher than that reported in the literature (i.e., 10-18%).

(1,20) It should be noted that none of our patients had previously been treated for OP. Although the reversed halo sign was initially considered to be an OP-specific finding,(24) it was subsequently described in a number of other diseases.(25-27) Nevertheless, it is an important clue to the diagnosis of OP.(28,29) In our study, the reversed halo sign was seen in 6 patients (17.1%).

In a study by Kim et al., the reversed halo sign was found in 19% of the cases.(24) However, it was not found in other studies involving large samples of patients.(1,12,20,21) It is known that OP can present as centrilobular nodules of 3-5 mm and small (1- to 10-mm) nodular opacities that are typically ill-defined. The differential diagnosis with metastases is crucial, especially in patients with a history of cancer, given that there is an association between OP and cancer. (30) In our study, airspace nodules were seen in 4 patients (11.1%).

Another important aspect in the HRCT evaluation of OP is the distribution of opacities.

Subpleural/peribronchovascular distribution and a perilobular pattern can be found in approximately 60% of cases.(20,21,31) In the present study, peribronchovascular opacities were found in 19 patients (52.8%). However, a perilobular pattern was found in only 8 patients (22.2%). Bilateral J Bras Pneumol. 2015;41(3):231-237

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Faria IM, Zanetti G, Menna-Barreto M, Rodrigues RS, Araujo-Neto CA, Pereira-Silva JL, Escuissato DL, et al.

lung involvement predominated, being found in 33 (91.7%) of the 36 patients studied. Unilateral lung involvement was found in 3 patients, the right lung being affected in 2 (5.6%) and the left lung being affected in 1 (2.8%). With regard to the distribution of the HRCT findings, it was found to be random, peripheral, and central in 26 (72.2%), 9 (25%), and 1 (2.8%), respectively.

In the craniocaudal direction, the middle third of the lung was the most commonly affected area—in 33 (91.7%) of the 36 patients studied— followed by the lower third, in 28 (77.8%), and the upper third, in 21 (58.3%). Only one study involving a large sample of patients(1) showed the aforementioned patterns of distribution, having shown a predominance of lesions in the lower lung fields in 55% of cases.

Our study has some limitations. First, it was a retrospective study. Second, it was a crosssectional study, meaning that the progression and possible complications of OP were not evaluated. Third, the HRCT techniques varied according to the protocol used at each of the institutions involved in the study. Finally, the fact that the images were randomly collected from 8 institutions distributed in 6 Brazilian states made it difficult to collect clinical data to differentiate between COP and secondary OP. However, the aforementioned limitations did not negatively affect the analysis of the HRCT images. Despite its limitations, our study is one of the largest studies of HRCT scans of patients with histologically confirmed OP. In summary, the most common HRCT finding was that of ground-glass opacities and consolidation, followed by reticulation, bronchiectasis, interstitial nodules, interlobular septal thickening, perilobular pattern, reversed halo sign, airspace nodules, and halo sign. The lesions were predominantly bilateral, the middle and lower thirds of the lungs being the most commonly affected areas.

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Chest. 1995;108(1):271-7. http://dx.doi.org/10.1378/ chest.108.1.271 15. Henriet AC, Diot E, Marchand-Adam S, de Muret A, Favelle O, Crestani B, et al. Organising pneumonia can be the inaugural manifestation in connective tissue diseases, including Sjogren’s syndrome. Eur Respir Rev. 2010;19(116):161-3. http://dx.doi. org/10.1183/09059180.00002410 16. Epstein DM, Bennett MR. Bronchiolitis obliterans organizing pneumonia with migratory pulmonary infiltrates. AJR Am J Roentgenol. 1992;158(3):515-7. http://dx.doi. org/10.2214/ajr.158.3.1738986

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Chest. 1989;96(5):999-1004. http://dx.doi.org/10.1378/ chest.96.5.999 19. Drakopanagiotakis F, Polychronopoulos V, Judson MA. Organizing pneumonia. Am J Med Sci. 2008;335(1):34-9. http://dx.doi.org/10.1097/MAJ.0b013e31815d829d 20. Lee JW, Lee KS, Lee HY, Chung MP, Yi CA, Kim TS, et al. Cryptogenic organizing pneumonia: serial high-resolution CT findings in 22 patients. AJR Am J Roentgenol. 2010;195(4):916-22. http://dx.doi. org/10.2214/AJR.09.3940 21. Lee KS, Kullnig P, Hartman TE, M端ller NL. Cryptogenic organizing pneumonia: CT findings in 43 patients. AJR Am J Roentgenol. 1994;162(3):543-6. http://dx.doi. org/10.2214/ajr.162.3.8109493 22. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994;18(2):136-47. http://dx.doi.org/10.1097/00000478-199402000-00003 23. Oikonomou A, Hansell DM. Organizing pneumonia: the many morphological faces. Eur Radiol. 2002;12(6):148696. http://dx.doi.org/10.1007/s00330-001-1211-3 24. Kim SJ, Lee KS, Ryu YH, Yoon YC, Choe KO, Kim TS, et al.

Reversed halo sign on high-resolution CT of cryptogenic organizing pneumonia: diagnostic implications. AJR Am J Roentgenol. 2003;180(5):1251-4. http://dx.doi. org/10.2214/ajr.180.5.1801251

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Chest. 2011;140(3):789-91. http://dx.doi.org/10.1378/ chest.11-0055 26. Marchiori E, Zanetti G, Escuissato DL, Souza AS Jr, Meirelles GS, Fagundes J, et al. Reversed halo sign: high-resolution CT scan findings in 79 patients. Chest. 2012;141(5):1260-6. http://dx.doi.org/10.1378/chest.11-1050 27. Marchiori E, Zanetti G, Meirelles GS, Escuissato DL, Souza AS Jr, Hochhegger B. The reversed halo sign on highresolution CT in infectious and noninfectious pulmonary diseases. AJR Am J Roentgenol. 2011;197(1):W69-75. http://dx.doi.org/10.2214/AJR.10.5762 28. Marchiori E, Marom EM, Zanetti G, Hochhegger B, Irion KL, Godoy MC. Reversed halo sign in invasive fungal infections: criteria for differentiation from organizing pneumonia. Chest. 2012;142(6):1469-73. http://dx.doi. org/10.1378/chest.12-0114 29. Marchiori E, Meirelles GS, Zanetti G, Hochhegger B. Optimizing the utility of high-resolution computed tomography in diagnosing cryptogenic organizing pneumonia. Respir Med. 2011;105(2):322-3. http:// dx.doi.org/10.1016/j.rmed.2010.10.017 30. Orseck MJ, Player KC, Woollen CD, Kelley H, White PF. Bronchiolitis obliterans organizing pneumonia mimicking multiple pulmonary metastases. Am Surg. 2000;66(1):11-3.

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Original Article Risk factors for respiratory complications after adenotonsillectomy in children with obstructive sleep apnea* Fatores de risco para complicações respiratórias após adenotonsilectomia em crianças com apneia obstrutiva do sono

Renato Oliveira Martins1, Nuria Castello-Branco2, Jefferson Luis de Barros1, Silke Anna Theresa Weber3

Abstract Objective: To identify risk factors for respiratory complications after adenotonsillectomy in children ≤ 12 years of age with obstructive sleep apnea who were referred to the pediatric ICU (PICU). Methods: A cross-sectional historical cohort study analyzing 53 children after adenotonsillectomy who met predetermined criteria for PICU referral in a tertiary level teaching hospital. The Student’s t-test, Mann-Whitney test, and chi-square test were used to identify risk factors. Results: Of the 805 children undergoing adenotonsillectomy between January of 2006 and December of 2012 in the teaching hospital, 53 were referred to the PICU. Twenty-one children (2.6% of all those undergoing adenotonsillectomy and 39.6% of those who were referred to the PICU) had respiratory complications. Of those 21, 12 were male. The mean age was 5.3 ± 2.6 years. A high apneahypopnea index (AHI; p = 0.0269), a high oxygen desaturation index (ODI; p = 0.0082), a low SpO2 nadir (p = 0.0055), prolonged orotracheal intubation (p = 0.0011), and rhinitis (p = 0.0426) were found to be independent predictors of respiratory complications. Some of the complications observed were minor (SpO 2 90-80%), whereas others were major (SpO2 ≤ 80%, laryngospasm, bronchospasm, acute pulmonary edema, pneumonia, and apnea).

Conclusions: Among children up to 12 years of age with OSA, those who have a high AHI, a high ODI, a low SpO2 nadir, or rhinitis are more likely to develop respiratory complications after adenotonsillectomy than are those without such characteristics.

Keywords: Postoperative complications; Tonsillectomy; Sleep apnea, obstructive.

Introduction Obstructive sleep apnea (OSA) affects approximately 4% of the pediatric population(1) and is associated with significant medical problems, including cardiopulmonary abnormalities(2,3) and failure to thrive.(4) OSA is characterized by increased upper airway resistance leading to disordered sleep.

Adenotonsillectomy has become the most common approach in the treatment of pediatric OSA, increasing from 0% in 1978(5) to approximately 77% in 2005,(6) because it significantly improves

disordered sleep, physical and emotional symptoms,(7) and systemic inflammation secondary to OSA,(2) and because it can reverse cor pulmonale. (3) Adenotonsillectomy is not risk-free; there is the possibility of hemorrhage, dehydration, nausea, vomiting, pain,(8) and need for additional airway support postoperatively.(9-11) In children undergoing adenotonsillectomy for OSA, the rate of respiratory complications requiring medical intervention ranges from 21% to 36%.(9,10) OSA

1. Master’s Student in Fundamentals of Surgery. Faculdade de Medicina de Botucatu, Universidade Estadual Paulista – FMB-UNESP, São Paulo State University Botucatu School of Medicine – Botucatu, Brazil.

2. Postdoctoral Student in Sleep Medicine. Faculdade de Medicina da Universidade de São Paulo – FMUSP, University of São Paulo School of Medicine – São Paulo, Brazil.

3. Tenured Professor. Department of Ophthalmology, Otolaryngology and Head and Neck Surgery, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista – FMB-UNESP, São Paulo State University Botucatu School of Medicine – Botucatu, Brazil. *Study carried out in the Department of Ophthalmology, Otolaryngology and Head and Neck Surgery, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista – FMB-UNESP, São Paulo State University Botucatu School of Medicine – Botucatu, Brazil.

Correspondence to: Renato Oliveira Martins. Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Avenida Prof. Montenegro, s/n, Distrito de Rubião Júnior, CEP 18618-970, Botucatu, SP, Brasil.

Tel./Fax: 55 14 3811-6256 or 55 14 3811-6081. E-mail: renatoceres@yahoo.com.br Financial support: None.

Submitted: 5 September 2014. Accepted, after review: 3 February 2015.

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Risk factors for respiratory complications after adenotonsillectomy in children with obstructive sleep apnea

is commonly associated with risk factors for respiratory complications. It is important to identify those factors that can increase the risk of postoperative respiratory complications in children with OSA to ensure better quality of care and for safety reasons.

There is a consensus that children with severe OSA should be observed postoperatively.(1) However, there is disagreement over the safest place for clinical observation after surgery: an outpatient setting; a pediatric ward; or a pediatric ICU (PICU). Because of the paucity of evidence-based guidelines and studies for enabling better clinical practice, the objective of this study was to identify risk factors for possible respiratory complications after adenotonsillectomy in children ≤ 12 years of age with OSA who were referred to the PICU.

Methods This was a cross-sectional historical cohort study analyzing 53 children after adenotonsillectomy who met predetermined criteria for PICU referral in a tertiary level teaching hospital.

This study was approved by the Research Ethics Committee of the São Paulo State University Botucatu School of Medicine (Protocol no. CEP 4336-2012).

We included all male and female children 1 to 12 years of age, with adenotonsillar hypertrophy, admitted to the PICU after adenotonsillectomy, between January of 2006 and December of 2012.

We excluded children with cardiac, pulmonary, neuromuscular, or chromosomal abnormalities and children with craniofacial anomalies, as well as children concurrently undergoing other surgical procedures associated with adenotonsillectomy, such as myringotomy, insertion of ventilation tubes, and/or diagnostic laryngoscopy. Referral to the ICU was based on clinical and/or polysomnographic criteria, which included age < 3 years, obesity, underweight, asthma, and/or polysomnographic changes (SpO2 nadir ≤ 80%, AHI ≥ 10 events/h).

All patients were evaluated by a single researcher during the perioperative period.

Preoperative data were collected with a standardized history-taking questionnaire regarding age, gender, body mass index (BMI), presence of comorbidities—obesity (as defined on the basis of age-specific and gender-specific BMI percentile curves adopted by the World Health Organization [2007], with BMI percentiles ≥ 97 being a criterion of obesity), asthma, rhinitis, http://dx.doi.org/10.1590/S1806-37132015000004415

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and upper respiratory tract infection (URTI)— adenoid size (as determined by examination with a 2.4-mm-diameter rigid endoscope with a 0-degree lens, on the basis of the adenoid/ nasopharyngeal ratio), and tonsil size (as measured

by Brodsky’s scale) Cardiorespiratory monitoring to confirm the diagnosis of OSA was performed on an inpatient basis, through the Department of Otolaryngology, for up to 6 months before adenotonsillectomy.

The children underwent type I polysomnography (Alice®; Phillips Respironics, Murrysville, PA, USA), or type III polysomnography (Stardust II®; Phillips Respironics), or overnight oximetry to record SpO2 (PV 4000 LCD; Protec Equipamentos MédicoHospitalares, São Paulo, Brazil). The respiratory parameters analyzed were as follows: apneahypopnea index (AHI); hypopnea index (HI); oxygen desaturation index (ODI); and SpO2 nadir.

Data were recorded by the software of each device and were scored by a single rater. Oximetry was used to determine SpO2 nadir. Obstructive apnea was defined as a greater than 90% drop in nasal pressure excursions for at least 2 respiratory cycles, associated with thoracic and/or abdominal effort. Central apnea was defined as an absence of inspiratory effort throughout the event, with the event being ≥ 20 seconds in duration or lasting 2 respiratory cycles and being associated with an arousal or ≥ 3% oxygen desaturation. Hypopnea was characterized by a decrease of at least 50% in nasal pressure excursions, associated with ≥ 3% oxygen desaturation. The ODI was defined as the number of episodes of oxyhemoglobin desaturation ≥ 3% from baseline SpO2 per hour of sleep and ≥ 10 seconds in duration. SpO2 nadir was defined as the lowest SpO2 value, regardless of duration. OSA was classified as mild (AHI of 1 to 4.9 events/h), moderate (AHI of 5 to 9.9 events/h), or severe (AHI ≥ 10 events/h), and events were scored according to the recommended rules by the American Academy of Sleep Medicine (2007).

All surgical procedures were supervised, which allowed standardization of the surgical technique and the use of a standardized anesthetic protocol for children with OSA. Tonsillectomies and adenoidectomies were performed with the standard cold technique and a combination of intravenous (propofol [3mg/kg] and alfentanil [50mg/kg]) and inhalational (sevoflurane and/ or N2O/O2 50:50) anesthesia. After surgery, all children were referred, intubated, to the PICU, J Bras Pneumol. 2015;41(3):238-245

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where they remained intubated for up to 6 h and where they stayed for a minimum of 24 h, in accordance with the guidelines of the facility for children with severe apnea. The children were divided into two groups on the basis of absence of presence of respiratory complications after adenotonsillectomy.

Postoperative respiratory complications were divided into major complications (SpO2 ≤ 80%, laryngospasm, bronchospasm, apnea, pneumonia [confirmed by chest X-ray, leukocytosis with a left shift, and fever], and post-obstructive acute pulmonary edema [confirmed by chest X-ray or use of loop diuretics and reintubation]) and minor complications (SpO2between 90% and 80% requiring airway repositioning). In addition, we assessed duration of orotracheal intubation (OTI) after adenotonsillectomy as well as medical interventions (need for airway repositioning, use of positive pressure devices [continuous positive airway pressure or bilevel positive airway pressure], and reintubation).

Statistical analysis Normality of data was tested with the Kolmogorov-Smirnov test, which was applied to all continuous variables in each group.

The Student’s t-test, Mann-Whitney test, and chi-square test were used for between-group comparisons of the study variables. Multiple linear regression analysis was performed to determine which variables correlated most closely with an increased risk of respiratory complications after adenotonsillectomy.

All tests were performed with Statistica, version 6.0 (StatSoft Inc., Tulsa, OK, USA), and the level of significance was set at 5%.

Results Between January of 2006 and December of 2012, 805 adenotonsillectomies were performed in children with OSA in the teaching hospital, and 53 of those children were referred to the PICU. The reasons for referral to the PICU were age < 2 years (n = 2); obesity and/or asthma with an SpO2 nadir ≤ 80% (n = 10); an SpO2 nadir ≤ 75% (n = 4); mild OSA with an SpO2 nadir ≤ 70% (n = 1); moderate OSA associated with comorbidities (n = 5) or an SpO2 nadir ≤ 80% (n = 2); and severe OSA (n = 29). Respiratory parameters were recorded by type I polysomnography (n J Bras Pneumol. 2015;41(3):238-245

= 7), type III polysomnography (n = 30), and oximetry (n = 6).

Among the comorbidities assessed, rhinitis was the most common, occurring more frequently in the children with respiratory complications than in those without (Table 1). The children with respiratory complications had a higher AHI, a higher ODI, a lower SpO2 nadir, and a longer duration OTI than did those without complications (Table 2). After multiple linear regression analysis, the following independent variables were found to contribute to increasing the risk of respiratory complications after adenotonsillectomy: AHI; ODI; SpO2 nadir; rhinitis; and duration of OTI [p(R2) = 0.0099]; although, individually, no variable showed a close association with the clinical outcome (Table 3).

Of the 53 children studied, 21 (39.6%) had respiratory complications after adenotonsillectomy.

The children were divided into two groups on the basis of absence of presence of respiratory complications (Table 1). The group without complications consisted of 32 children, 16 of whom were male, and the mean age was 6.1 ± 3.1 years (range, 1.6-12 years). The group with complications consisted of 21 children, 12 of whom were male, and the mean age was 5.3 ± 2.6 years (range, 2.4-12 years).

Seven children had minor respiratory complications (SpO2 90-80%), and 14 children had major respiratory complications (SpO2 ≤ 80% [n = 2]; laryngospasm [n = 9]; bronchospasm [n = 5]; intraoperative bronchospasm [n = 2]; apnea [n = 1]; pneumonia [n = 1]; and acute pulmonary edema [n = 3]; Table 4). The group with respiratory complications remained in the PICU for ≥ 24 h, and the main medical interventions were antibiotic therapy (n = 1) for pneumonia, use of loop diuretics (n = 3) for acute pulmonary edema, continuous administration of nebulized bronchodilator or adrenaline (n = 12) for bronchospasm and laryngospasm, and reintubation (n = 3) for acute pulmonary edema and severe bronchospasm in the presence of URTI (Table 4). The postoperative mortality rate was zero, and the children with and without respiratory complications remained hospitalized for 3 ± 1 days and 5 ± 2 days, respectively.

The respiratory complications observed after adenotonsillectomy are described individually in Table 4. http://dx.doi.org/10.1590/S1806-37132015000004415

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Table 1 - Comparison of demographic data and comorbidities in children, by absence or presence of respiratory complications after adenotonsillectomy.a Variable Respiratory complications after p adenotonsillectomy Absence Presence (n = 32) (n = 21) Male/Female 16/16 12/9 0.6062* Age, years 6.2 ± 3.1 5.3 ± 2.6 0.2820** <3 4 3 0.4040*** 3-6 13 10 7-9 8 7 10-12 7 1 BMI, kg/m2 19.28 ± 5.27 18.76 ± 5.19 0.7257** < 3rd percentile 0 2 0.8489*** ≥ 3rd percentile and < 85th percentile 14 7 ≥ 85th percentile and < 97th percentile 5 2 ≥ 97th percentile 13 10 Comorbidity Obesity 13 10 0.4931* Asthma 4 6 0.1164* Rhinitisb 20 25 0.0426* Current URTI 0 2 0.0668* BMI: body mass index; and URTI: upper respiratory tract infection. aValues expressed as n of patients or as mean ± SD. b Variable selected for multiple linear regression analysis. *Chi-square test; **Student’s t-test; and ***Mann-Whitney test.

Table 2 - Comparison of polysomnographic data, duration of orotracheal intubation, and adenoid and tonsil size in children, by absence or presence of respiratory complications after adenotonsillectomy.

Variable Absence of complications Presence of complications p n of patients Mean ± SD n of patients Mean ± SD Polysomnographic variable AHI, events/ha 24 18.1 ± 11.2 13 28.6 ± 16.3 0.0269* HI, events/h 24 5.8 ± 6.0 13 10.5 ± 10.4 0.0882* ODI, episodes/ha 18 15.3 ± 9.4 12 29.8 ± 18.4 0.0082* SpO2 nadir, %a 28 76.8 ± 10.9 15 64.4 ± 16.9 0.0055* PO duration of OTI, ha 32 1.8 ± 2.0 21 5.0 ± 4.8 0.0011* Adenoid and tonsil size Adenoid, ANR 30 78 ± 17 17 87 ± 13 0.0705* Tonsils, Brodsky’s scale 1 0 − 0 − 0.3512** 2 4 − 2 − 3 18 − 10 − 4 10 − 9 − AIH: apnea-hypopnea index; HI: hypopnea index; ODI: oxygen desaturation index; PO: postoperative; OTI: orotracheal intubation; and ANR: adenoid/nasopharyngeal ratio. aVariables selected for multiple linear regression analysis. *Student’s t-test; and **Mann-Whitney test.

Discussion Of the 805 children undergoing adenotonsillectomy between January of 2006 and December of 2012 in the teaching hospital, 21 (2.6%) had postoperative respiratory complications.

This finding is similar to the results of other studies, http://dx.doi.org/10.1590/S1806-37132015000004415

in which the rate of respiratory complications ranged from 1.3% to 13.4%.(12-16) Analysis of the children at high risk for complications who were referred to the PICU (n = 53) revealed that the rate of respiratory complications was 39.6%, which is also consistent with the findings of other studies, in which rates ranged from J Bras Pneumol. 2015;41(3):238-245

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Table 3 - Multiple linear regression analysis considering respiratory complications after adenotonsillectomy as a dependent variable.a Independent Absence of Presence of Beta Partial Standard p R2 p (R2) variable complications complications regression error coefficient AHI 18.1 ± 11.2 28.6 ± 16.3 −0.0276 −0.0009 0.0073 0.8972 0.3722 < 0.0099 ODI 15.3 ± 9.4 29.8 ± 18.4 0.2730 0.0082 0.0075 0.2798 SpO2 nadir 76.8 ± 10.9 64.4 ± 16.9 −0.0077 −0.0003 0.0062 0.9650 Rhinitis 20 25 0.2679 0.3265 0.1843 0.0863 PO duration of 1.8 ± 2.0 5.0 ± 4.8 0.3781 0.0527 0.0267 0.0568 OTI, h AIH: apnea-hypopnea index; ODI: oxygen desaturation index; PO: postoperative; and OTI: orotracheal intubation. a Values expressed as mean ± SD or as n of patients.

25% to 60%. (11,17-21) It is of note that none of the children who had post-adenotonsillectomy follow-up in the pediatric ward had any major respiratory complications requiring transfer to the PICU. The postoperative referral of the 53 children to the PICU was motivated by the presence of OSA associated with one or more risk factors. According to the literature, children with OSA aged < 2 years (9,11,17,18) or < 3 years(21) and presenting with obesity,(9,12,15,22-24) underweight,(9,21) asthma,(11,14) polysomnographic changes (SpO2 nadir ≤ 80%(11) or < 72%,(9,15,19) AHI ≥ 24 events/h,(17) high HI and/ or high AHI),(15) CO2 pressure > 45 mmHg and SpO2 < 86%,(21) intraoperative laryngospasm,(17) or systemic comorbidities (neuromuscular abnormalities,(9,11,20) craniofacial anomalies,(9,11,20) cardiac abnormalities,(11,12,20,25) and chromosomal abnormalities)(11,12) have increased rates of respiratory complications after adenotonsillectomy.

However, after this study’s analyses of the results for postoperative respiratory complications, the local department of otolaryngology discontinued the routine practice of referring patients < 12 years of age with OSA and/or risk factors to the PICU after adenotonsillectomy. What is recommended is that a sleep study be performed to determine the severity of the respiratory disorder and a thorough clinical history be taken to identify risk factors. For patients with severe OSA associated with severe comorbidities (chromosomal, cardiac, and neuromuscular abnormalities, as well as craniofacial anomalies) and/or children < 2 years of age, the recommendation for postoperative observation in the PICU still applies.

The risk factors that could predict respiratory complications after adenotonsillectomy were polysomnographic parameters (high AHI [mean of 28.6 events/h]; high ODI [mean of 29.8 episodes/h]; J Bras Pneumol. 2015;41(3):238-245

and low SpO2 nadir [mean of 64.4%]), presence of rhinitis, and prolonged postoperative OTI (Table 2).

A higher AHI, a higher ODI, and a lower SpO2 nadir on the preoperative sleep study translate to a higher prevalence of respiratory complications in children. Our results were similar to those found in other studies that correlated polysomnographic findings with postoperative respiratory complications and medical interventions.

(10,11,15,17,26) Schroeder et al.(26) observed that 43% of the children with an AHI > 25 events/h required some intervention as a result of respiratory complications. Another study showed that a higher AHI (mean of 31.8 events/h), a higher HI (mean of 22.6 events/h), and a lower SpO2 nadir (mean of 71.7%) translate to a stronger correlation with respiratory complications, and that desaturation events were the ones most commonly requiring oxygen supplementation. (15) Therefore, it is clear that determining apnea severity via a sleep study (polysomnography) before surgery is important in predicting the risk of possible postoperative respiratory complications.

Among the comorbidities assessed, only rhinitis was found to be statistically significant in the group with respiratory complications. Because children with severe OSA have greater airway collapsibility(27,28) and are more susceptible to the respiratory-depressant effects of anesthetics and opioids,(29,30) it is possible that rhinitis associated with increased secretions and upper airway edema can contribute to greater resistance and, consequently, to an increased likelihood of perioperative respiratory complications.

Although several studies in the literature have demonstrated that age < 2 years(9,11,17,18) or < 3 years,(21) obesity,(9,12,15,22-24) and asthma(11,14) are related to a greater likelihood of respiratory http://dx.doi.org/10.1590/S1806-37132015000004415

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Asthma + rhinitis Asthma + rhinitis Obesity Obesity + rhinitis Rhinitis Obesity + rhinitis Obesity + rhinitis

Rhinitis Obesity + rhinitis Rhinitis Asthma + obesity + rhinitis Asthma + rhinitis

Asthma + rhinitis Asthma + obesity + rhinitis Obesity + rhinitis Obesity + rhinitis Rhinitis Obesity + rhinitis URTI+ rhinitis URTI + rhinitis Asthma + rhinitis

Comorbidity

BMI: body mass index; AHI: apnea-hypopnea index; HI: hypopnea index; ODI: oxygen desaturation index; M: male; APE: acute pulmonary edema; F: female; and URTI: upper respiratory tract infection.

Table 4 - Individual, descriptive data of children with major or minor respiratory complications after adenotonsillectomy.

Patient Gender Age BMI Postoperative complication Reintubation AHI HI ODI < SpO2 (years) percentile (%) (events/h) (events/h) (episodes/h) Major respiratory complication 1 M 7.0 85-97 APE Yes 8.8 5.3 18.2 80 2 M 3.6 ≥ 97 APE + laryngospasm Yes * * * * 3 M 3.3 ≥ 97 APE + laryngospasm No * * * * 4 F 7.1 ≥ 97 Laryngospasm No 17.8 11.7 25.6 82 5 F 4.7 85-97 Laryngospasm No 46.4 19 40.2 70 6 M 7.7 ≥ 97 Laryngospasm No * * * * 7 M 2.6 50-85 Laryngospasm + pneumonia No * * * 42 8 M 2.7 50-85 Laryngospasm + bronchospasm Yes * * * 72 9 F 2.4 50-85 Laryngospasm + intraoperative and No * * * * postoperative bronchospasm 10 F 3.3 50-85 Laryngospasm + bronchospasm No 18.7 7.2 16.6 55 11 F 4.1 ≥ 97 Intraoperative bronchospasm + SpO2 ≤ 80% No * * * * 12 M 3.2 50-85 Bronchospasm + apnea No 33.1 2 30.8 63 13 M 3.6 ≥ 97 Bronchospasm No 11.4 6.7 11.3 41 14 F 3.6 15-50 SpO2 ≤ 80% No * * * * Minor respiratory complication 1 M 8.0 ≤3 SpO2 90-80% No 18.9 5.8 0 70 2 M 3.7 50-85 SpO2 90-80% No 26.1 4.5 36.6 46 3 M 4.7 ≥ 97 SpO2 90-80% No 33.2 13.6 55.2 51 4 F 7.4 ≥ 97 SpO2 90-80% No 55.8 40.3 67.7 58 5 M 12.0 ≤3 SpO2 90-80% No 45.4 13.6 29.9 53 6 F 8.0 ≥ 97 SpO2 90-80% No 48.3 7.2 23.8 88 7 F 7.2 ≥ 97 SpO2 90-80% No 8 0 1.9 95

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Martins RO, Castello-Branco N, Barros JL, Weber SAT

complications after adenotonsillectomy, this study found no statistically significant differences among these variables in terms of the occurrence of respiratory events (Table 1). It may be that this lack of significance is due to the small sample size, to the fact that this was a group of children at increased risk for respiratory complications, and to the fact that the children were similar in terms of comorbidities.

Duration of OTI (Table 2) was statistically longer in patients with respiratory complications, corroborating Schroeder Jr. et al.,(26) who demonstrated that delaying extubation can increase the likelihood of respiratory complications in a group who is already at high risk. Therefore, children undergoing adenotonsillectomy for OSA associated with comorbidities who remained intubated after surgery had increased complication rates and, consequently, prolonged hospital stays.

This study was limited by its small sample size, surgeonsâ&#x20AC;&#x2122; varied preferences of where postoperative observation should occur, and a possible bias in selecting children for polysomnography. A prospective study with a larger sample size is needed to determine possible risk factors associated with an increased likelihood of respiratory complications after adenotonsillectomy.(17) The results of the present study indicate that, among children up to 12 years of age diagnosed with OSA, those who have a high AHI, a high ODI, and a low SpO2 nadir on preoperative polysomnography, as well as rhinitis, are more likely to develop respiratory complications after adenotonsillectomy than are those without such characteristics.

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2010;45(8):836-9. http://dx.doi.org/10.1002/ppul.21256 4. Freezer NJ, Bucens IK, Robertson CF. Obstructive sleep apnoea presenting as failure to thrive in infancy. J Paediatr Child Health. 1995;31(3):172-5. http://dx.doi. org/10.1111/j.1440-1754.1995.tb00779.x

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5. Rosenfeld RM, Green RP. Tonsillectomy and adenoidectomy: changing trends. Ann Otol Rhinol Laryngol. 1990;99(3 Pt 1):187-91.

6. Erickson BK, Larson DR, St Sauver JL, Meverden RA, Orvidas LJ. Changes in incidence and indications of tonsillectomy and adenotonsillectomy, 1970-2005.

Otolaryngol Head Neck Surg. 2009;140(6):894-901. http://dx.doi.org/10.1016/j.otohns.2009.01.044 7. Tran KD, Nguyen CD, Weedon J, Goldstein NA. Child behavior and quality of life in pediatric obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 2005;131(1):52-7. http://dx.doi.org/10.1001/archotol.131.1.52 8. Brigger MT, Brietzke SE. Outpatient tonsillectomy in children: a systematic review. Otolaryngol Head Neck Surg. 2006;135(1):1-7. http://dx.doi.org/10.1016/j. otohns.2006.02.036 9. Rosen GM, Muckle RP, Mahowald MW, Goding GS, Ullevig C. Postoperative respiratory compromise in children with obstructive sleep apnea syndrome: can it be anticipated?

Pediatrics. 1994;93(5):784-8.

10. McColley SA, April MM, Carroll JL, Naclerio RM, Loughlin GM. Respiratory compromise after adenotonsillectomy in children with obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 1992;118(9):940-3. http://dx.doi. org/10.1001/archotol.1992.01880090056017 11. Wilson K, Lakheeram I, Morielli A, Brouillette R, Brown K. Can assessment for obstructive sleep apnea help predict postadenotonsillectomy respiratory complications?

Anesthesiology. 2002;96(2):313-22. http://dx.doi. org/10.1097/00000542-200202000-00015 12. Tweedie DJ, Bajaj Y, Ifeacho SN, Jonas NE, Jephson CG, Cochrane LA, et al. Peri-operative complications after adenotonsillectomy in a UK pediatric tertiary referral centre. Int J Pediatr Otorhinolaryngol. 2012;76(6):80915. http://dx.doi.org/10.1016/j.ijporl.2012.02.048 13. Biavati MJ, Manning SC, Phillips DL. Predictive factors for respiratory complications after tonsillectomy and adenoidectomy in children. Arch Otolaryngol Head Neck Surg. 1997;123(5):517-21. http://dx.doi.org/10.1001/ archotol.1997.01900050067009 14. Kalra M, Buncher R, Amin RS. Asthma as a risk factor for respiratory complications after adenotonsillectomy in children with obstructive breathing during sleep. Ann Allergy Asthma Immunol. 2005;94(5):549-52. http:// dx.doi.org/10.1016/S1081-1206(10)61132-5 15. Jaryszak EM, Shah RK, Vanison CC, Lander L, Choi SS. Polysomnographic variables predictive of adverse respiratory events after pediatric adenotonsillectomy.

Arch Otolaryngol Head Neck Surg. 2011;137(1):15-8. http://dx.doi.org/10.1001/archoto.2010.226 16. Suen JS, Arnold JE, Brooks LJ. Adenotonsillectomy for treatment of obstructive sleep apnea in children. Arch Otolaryngol Head Neck Surg. 1995;121(5):525-30. http:// dx.doi.org/10.1001/archotol.1995.01890050023005 17. Hill CA, Litvak A, Canapari C, Cummings B, Collins C, Keamy DG, et al. A pilot study to identify pre- and perioperative risk factors for airway complications following adenotonsillectomy for treatment of severe pediatric OSA. Int J Pediatr Otorhinolaryngol. 2011;75(11):1385-90. http://dx.doi.org/10.1016/j.ijporl.2011.07.034 18. McCormick ME, Sheyn A, Haupert M, Thomas R, Folbe AJ. Predicting complications after adenotonsillectomy in children 3 years old and younger. Int J Pediatr Otorhinolaryngol. 2011;75(11):1391-4. http://dx.doi. org/10.1016/j.ijporl.2011.07.035

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19. Shine NP, Coates HL, Lannigan FJ, Duncan AW. Adenotonsillar surgery in morbidly obese children: routine elective admission of all patients to the intensive care unit is unnecessary. Anaesth Intensive Care. 2006;34(6):724-30.

20. Brown KA, Morin I, Hickey C, Manoukian JJ, Nixon GM, Brouillette RT. Urgent adenotonsillectomy: an analysis of risk factors associated with postoperative respiratory morbidity. Anesthesiology. 2003;99(3):586-95. http:// dx.doi.org/10.1097/00000542-200309000-00013 21. Ruboyianes JM, Cruz RM. Pediatric adenotonsillectomy for obstructive sleep apnea. Ear Nose Throat J. 1996;75(7):430-3.

22. Nafiu OO, Green GE, Walton S, Morris M, Reddy S, Tremper KK. Obesity and risk of peri-operative complications in children presenting for adenotonsillectomy. Int J Pediatr Otorhinolaryngol. 2009;73(1):89-95. http:// dx.doi.org/10.1016/j.ijporl.2008.09.027 23. Fung E, Cave D, Witmans M, Gan K, El-Hakim H. Postoperative respiratory complications and recovery in obese children following adenotonsillectomy for sleepdisordered breathing: a case-control study. Otolaryngol Head Neck Surg. 2010;142(6):898-905. http://dx.doi. org/10.1016/j.otohns.2010.02.012 24. Gleich SJ, Olson MD, Sprung J, Weingarten TN, Schroeder DR, Warner DO, et al. Perioperative outcomes of severely obese children undergoing tonsillectomy.

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Int J Pediatr Otorhinolaryngol. 2009;73(8):1095-9. http://dx.doi.org/10.1016/j.ijporl.2009.04.007 27. Gozal D, Burnside MM. Increased upper airway collapsibility in children with obstructive sleep apnea during wakefulness.

Am J Respir Crit Care Med. 2004;169(2):163-7. http:// dx.doi.org/10.1164/rccm.200304-590OC 28. Marcus CL, McColley SA, Carroll JL, Loughlin GM, Smith PL, Schwartz AR. Upper airway collapsibility in children with obstructive sleep apnea syndrome. J Appl Physiol (1985). 1994;77(2):918-24.

29. Brown KA, Laferrière A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia.

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Brief Communication Psychological criteria for contraindication in lung transplant candidates: a five-year study* Critérios psicológicos para contraindicação em candidatos a transplante pulmonar: um estudo de cinco anos

Elaine Marques Hojaij1, Bellkiss Wilma Romano1, André Nathan Costa2, Jose Eduardo Afonso Junior3, Priscila Cilene Leon Bueno de Camargo3, Rafael Medeiros Carraro3, Silvia Vidal Campos4, Marcos Naoyuki Samano5, Ricardo Henrique de Oliveira Braga Teixeira6

Abstract Lung transplantation presents a wide range of challenges for multidisciplinary teams that manage the care of the recipients. Transplant teams should perform a thorough evaluation of transplant candidates, in order to ensure the best possible post-transplant outcomes. That is especially true for the psychologist, because psychological issues can arise at any point during the perioperative period. The objective of our study was to evaluate the psychological causes of contraindication to waiting list inclusion in a referral program for lung transplantation.

We retrospectively analyzed data on psychological issues presented by lung transplant candidates, in order to understand these matters in our population and to reflect upon ways to improve the selection process.

Keywords: Lung transplantation; Interview, psychological; Psychological tests; Preoperative care.

Since lung transplantation evolved to be the standard of care for patients with advanced lung disease, more than 32,000 procedures have been performed worldwide.(1) At our facility, 220 patients have undergone lung transplantation since the year 2000. However, the shortage of suitable donor lungs requires transplant professionals to select patients for lung transplantation only if they are likely to derive a significant survival benefit from the procedure.(2,3) In fact, approximately 17% of all lung transplant recipients die within the first year after transplantation,(2) which raises special concern regarding the selection of lung transplant candidates, because physicians must ensure that organ recipients will adequately care for their new organ.

Because lung transplant candidates can show emotional imbalance due to the disabling and lifethreatening nature of their condition,(3) counseling such individuals presents a range of practice issues for psychologists. It is known that chronic lung disease is associated with an increased risk of depression and other mental disorders. Craven(4) studied 116 patients who were eligible for lung transplantation and found that nearly half had diagnosable psychiatric disorders such as major depressive disorder, anxiety disorder, and panic disorder, either in isolation or in combination.

In addition, as pointed out by Manzetti et al.,(5) the time spent on a lung transplant waiting list is a period marked by substantial anxiety, and patients on the list deal with numerous health-

1. Psychologist. Department of Psychology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

2. Attending Physician. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

3. Pulmonologist. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

4. Infectious Disease Specialist. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

5. Assistant Professor. Department of Thoracic Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.

6. Clinical Coordinator of the Lung Transplant Group. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. *Study carried out in the Departments of Psychology and Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Correspondence to: André Nathan Costa. Avenida Dr. Enéas de Carvalho Aguiar, 44, 2º Andar, Sala 9, Bloco 2, CEP 05403-900, São Paulo, SP, Brasil.

Tel: 55 11 3069-7202. E-mail: nathan.andre@gmail.com Financial support: None.

Submitted: 27 October 2014. Accepted, after review: 26 February 2015.

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Psychological criteria for contraindication in lung transplant candidates: a five-year study

related stressors such as loss of physical capacity, frequent hospitalization, and progressive oxygen dependency.(5) In a review of the literature, Barbour et al.(3) found that lung transplant candidates can present high levels of psychological distress at the time of evaluation. The authors also found that psychological comorbidities in such individuals, if left untreated, can have a significant negative effect on clinical outcomes after transplantation.(3) There is a general consensus that current or recent cigarette smoking is an absolute contraindication for lung transplantation, as are drug abuse, alcohol abuse, and severe psychiatric illness, and that adequate adherence to the prescribed medical regimen is critical to achieving a favorable prognosis.(6) Therefore, psychological assessment is an important step in the preoperative evaluation of transplant candidates, because it can identify behavioral patterns and emotional states that could affect the course of disease before and after transplantation.(7) The assessment of the patient level of understanding is another important aspect of the evaluation process, as is the determination of patient attitudes towards their disease, the determination of patient attitudes towards their upcoming transplantation, and the identification of a committed caregiver. The level of education, sociocultural competence, and cognitive functioning of lung transplant candidates should also be closely evaluated, because those are factors that could influence their adherence to post-transplant treatment.(3,7) Furthermore, in addition to the understanding of the transplant process, the patient level of motivation to undergo the procedure and to be involved in the process must also be taken into consideration.(3) At our facility, the medical and surgical staff, together with a psychologist, a nurse, a physiotherapist, a nutritionist, and a social worker, make a comprehensive pretransplant assessment of each lung transplant candidate.

All of the cases are then discussed in a weekly meeting of the multidisciplinary team, and this group collectively decides which patients will be placed on the lung transplant waiting list.

Our study, conducted by the Lung Transplant Group in the Pulmonology Department of the Heart Institute at the University of SĂŁo Paulo School of Medicine Hospital das ClĂ­nicas, in the city of SĂŁo Paulo, Brazil, was a retrospective analysis of the records of weekly multidisciplinary http://dx.doi.org/10.1590/S1806-37132015000004446

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team meetings held between May of 2009 and May of 2014, with a focus on assessing the psychological issues. Our objective was to evaluate the psychological causes of exclusion from the waiting list in a referral program for lung transplantation. The opinions expressed by the Heart Institute Department of Psychology were reviewed, and the issues considered to be potential causes of post-transplant complications were categorized according to the criteria for indication and contraindication established in international guidelines for the selection of lung transplant candidates.(8) We reviewed the data related to 345 cases presented at the weekly multidisciplinary team meetings. Patient ages ranged from 12 to 67 years, and 176 (51%) were female. Members of the Department of Psychology staff identified (relative or absolute) contraindications to transplant in 117 (33.91%) of the 345 patients (Table 1): chemical dependency within the last six months, in 4 patients; cognitive limitations associated with lack of adequate social support, in 3 patients; inadequate adherence to treatment, in 24 patients; the lack of a caregiver or absence of social support, in 43 patients; any psychological disorder that could compromise care (especially depression), in 34 patients; a lack of knowledge regarding the underlying disease and the transplant process, in 16 patients; uncertainty regarding the decision to undergo transplantation, in 11 patients; and absolute patient refusal to undergo transplantation, in 14 patients. It is of note that some of the patients had more than one complicating factor.

Of the 117 patients with psychological contraindications, 76 (64%) were referred for psychological follow-up and posterior reevaluation.

At the end of the psychological assessments, patients were informed of all observed complicating issues and received guidance on how best to address them. They were all instructed to seek psychological support at the referring hospital or at the health care facility nearest their place of residence. Of the 76 patients who were reassessed, 45 (59%) were subsequently placed on the lung transplant waiting list. At this writing, 17 of those patients had undergone transplantation and 21 were awaiting surgery. Seven of the 45 died while on the waiting list.

The present study paints an interesting picture of the psychological problems affecting patients J Bras Pneumol. 2015;41(3):246-249

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Hojaij EM, Romano BW, Costa AN, Afonso Junior JE, Camargo PCLB, Carraro RM, et al.

Table 1 - Contraindications to lung transplantation.

Contraindication Patient refusal to undergo transplantation, n (%) Chemical dependency within the last 6 months, n (%) Inadequate adherence to treatment, n (%) Any psychological disorder that could compromise care (especially depression), n (%) Cognitive limitations associated with inadequate social support, n (%) Lack of patient knowledge regarding the underlying disease and the transplant procedure, n (%) Lack of a caregiver or absence of social support, n (%) Uncertainty regarding the decision to undergo transplantation, n (%) Total, n (%)

evaluated for lung transplantation at a single center. Organ transplantation, especially lung transplantation, involves an arduous process, with difficult steps presenting many psychological challenges, and these difficulties persist throughout the life of the recipient.(9,10) Therefore, patients should be emotionally stable and capable of dealing with individual frustrations, and the preoperative psychological evaluation should be able to identify those who are not prepared for the surgery, preventing them from undergoing a potentially harmful and unsuccessful procedure.

However, because of their desire to gain acceptance from the transplant team, some patients might be guarded or could minimize their concerns.(3) The psychological evaluation should therefore be aimed at establishing empathy, providing patients the opportunity to share their concerns with a trained professional, and should be able to identify modifiable issues or absolute contraindications in this group of individuals.

For the transplant recipient, relief from the suffering associated with a chronic, incapacitating lung disease comes at a priceâ&#x20AC;&#x201D;the trials of adhering to a long-term treatment regimen(6)â&#x20AC;&#x201D;and psychological stability is essential to meeting that challenge. It is essential that patients recognize and consider these issues prior to transplantation, because comorbid psychological disorders, such as anxiety and depression, are associated with poor health practices throughout the transplant process and unfavorable post-transplant outcomes.

After transplantation, psychosocial concerns tend to revolve around readjustment to a new lifestyle, which should also be a matter of great concern to the health care team. Therefore, lung transplantation presents psychologists with many features for assessment and intervention.

Consequently, psychologists are fundamental members of the multidisciplinary team and are indispensable in the preoperative evaluation J Bras Pneumol. 2015;41(3):246-249

n = 345 14 (4.05) 4 (1.15) 24 (6.95) 34 (9.86) 3 (0.86) 16 (4.63) 43 (12.46) 11 (3.18) 117 (33.91)

of lung transplant candidates, because certain psychosocial factors can be used in order to identify patients who should not undergo the procedure. Concerns such as unhealthy lifestyle behaviors, nonadherence to treatment, and the lack of a reliable caregiver (all of which were observed in our study population) are significant risk factors for poor post-transplant outcomes and must be addressed before a patient can be placed on the transplant waiting list.(3) It is of note that having an inappropriate caregiver is a special concern at our facility. Our task is to identify such problems and avoid submitting high-risk patients to the surgical procedure, thus allowing us to ensure that the patients selected are those most likely to reap the full benefits of lung transplantation. We should attempt to help patients with psychological issues resolve those issues and eventually meet the criteria for inclusion on the waiting list.

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J Heart Lung Transplant. 2006;25(7):745–55 http:// dx.doi.org/10.1016/j.healun.2006.03.011.

9. Tavares, EM. A vida depois da vida: reabilitação psicológica e social na transplantação de órgãos. Análise Psicológica.

2004;22(4):765-77.

10. Biagi AU, Sugano CF. Transplante de órgãos. In: Romano BW, editor. Manual de Psicologia Clínica para Hospitais.

São Paulo: Casa do Psicólogo; 2008. p. 145-208.

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Continuing Education: Imaging Small interstitial nodules Pequenos nódulos intersticiais

Edson Marchiori1, Gláucia Zanetti2, Bruno Hochhegger3

Figure 1 - Small nodules evenly distributed throughout the lungs, no particular lung compartment being predominantly affected. Note that some of the nodules touch the pleural surface, whereas others are in contact with the fissures.

A 45-year-old male patient presented to our outpatient clinic with a three-week history of low-grade fever, mildly productive cough, headache, and asthenia. He had lost 5 kg in the last four months. The patient reported that he had a brother who had been diagnosed with pulmonary tuberculosis and had been receiving treatment for it for two months. He also reported that he habitually spent his weekends on a grange in a rural area. A HRCT scan of the chest showed small disseminated nodules (Figure 1).

Multiple, small interstitial nodules constituted the only abnormal HRCT finding in our patient.

Lung nodules appear as multiple round opacities that have soft tissue density and are smaller than 3 cm. Small nodules (or micronodules) are those of less than 1 cm in diameter. On the basis of their distribution throughout the lung parenchyma, they can be classified as perilymphatic, centrilobular, or random.

Perilymphatic nodules are small nodules located predominantly in the peribronchovascular interstitium, interlobular septa, and subpleural

regions (which contain the pulmonary lymphatic system). They are commonly found in cases of sarcoidosis, silicosis, and lymphangitic carcinomatosis. A centrilobular distribution is characterized by nodules that are located within a few millimeters of the pleural surface and fissures but do not touch them. Centrilobular nodules can be found in cases of hypersensitivity pneumonitis, silicosis, and infectious bronchiolitis, for example.

A random distribution is characterized by small nodules randomly distributed in the secondary lobule and uniformly disseminated throughout the lungs. This distribution pattern is consistent with nodular disease that is disseminated through the blood, including metastasis and miliary granulomatous disease, particularly tuberculosis and histoplasmosis.

In the case reported here, the nodules were evenly distributed throughout the lungs, displaying a random pattern of distribution. This distribution pattern is consistent with miliary tuberculosis, histoplasmosis, and hematogenous metastasis.

Metastatic nodules tend to predominate in the lower lung fields, whereas, in miliary tuberculosis, they tend to predominate in the upper lung fields. In addition, nodules commonly vary in size in cases of metastasis, whereas, in cases of miliary infection, they do not tend to. There are no CT criteria to aid in differentiating between miliary tuberculosis and histoplasmosis.

Our patient tested positive for HIV, his CD4 count was 140 cells/µL, and radial immunodiffusion was positive for histoplasmosis. In the case reported here, a final diagnosis of histoplasmosis was established on the basis of the clinical picture, the epidemiological history, serology results, and CT findings.

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

1. Full Professor Emeritus. Fluminense Federal University, Niterói; and Associate Professor of Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

2. Professor. Graduate Program in Radiology, Federal University of Rio de Janeiro, Rio de Janeiro; and Professor of Clinical Medicine, Petrópolis School of Medicine, Petrópolis, Brazil.

3. Radiologist. Santa Casa Hospital Complex in Porto Alegre; and Professor of Radiology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.

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Review Article Diagnosis of primary ciliary dyskinesia* Diagnóstico de discinesia ciliar primária

Mary Anne Kowal Olm1, Elia Garcia Caldini2, Thais Mauad3

Abstract Primary ciliary dyskinesia (PCD) is a genetic disorder of ciliary structure or function. It results in mucus accumulation and bacterial colonization of the respiratory tract which leads to chronic upper and lower airway infections, organ laterality defects, and fertility problems. We review the respiratory signs and symptoms of PCD, as well as the screening tests for and diagnostic investigation of the disease, together with details related to ciliary function, ciliary ultrastructure, and genetic studies. In addition, we describe the difficulties in diagnosing PCD by means of transmission electron microscopy, as well as describing patient follow-up procedures.

Keywords: Kartagener Syndrome; Cilia; Mucociliary clearance; Ciliary motility disorders; Diagnosis.

“Ciliary beating was one of the first characteristics—the Alpha—of animal life on Earth, and it will be the last—the Omega.”

– J. C. de Man, Dutch physician and historian

Introduction Primary ciliary dyskinesia (PCD) is a disease characterized by a change in ciliary beat frequency, ciliary beat pattern, or both and has a heterogeneous genetic basis, typically being an autosomal recessive disorder; the main consequence of ciliary dysfunction is a reduced efficiency of mucociliary clearance of the upper and lower airways, leading to chronic infections and inflammation.(1,2) Few countries have records of the prevalence, diagnosis, and prognosis of PCD, the data varying greatly across countries. The prevalence of PCD ranges from 1:2,200 to 1:40,000, PCD occurring most frequently in families with consanguineous marriages. Evidence suggests that the diagnosis of PCD is often delayed, which is mainly due to a failure to recognize the disease and the need for sophisticated technical resources for PCD screening.(1) In Europe, there are reports of more than 1,000 PCD patients at 223 centers in 26 countries.(1) In

the United States, there are reports of fewer than 1,000 patients with an established diagnosis of PCD.(3) In Brazil, most pulmonology clinics lack the resources required for the investigation of PCD; therefore, there are few reported cases,(4,5) which are not representative of the prevalence of PCD in the country. According to a European consensus statement, the diagnosis of PCD should be based on the presence of a phenotype consistent with the disease and confirmed by diagnostic tests performed at specialized centers. (6) Screening tests should precede the diagnostic investigation of PCD.(6) The objective of the present study was to review the literature on the diagnosis of PCD.

Ciliary biology Cilia are specialized hairlike structures covered by plasma membrane and extending from the cell surface. A cilium contains nine pairs of microtubules in a peripheral, radial distribution,

1. Postdoctoral Student. Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.

2. Associate Professor. Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.

3. Tenured Professor. Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil. *Study carried out in the Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.

Correspondence to: Mary Anne Kowal Olm. Avenida Dr. Arnaldo, 455, sala 1150, CEP 01246-903, São Paulo, SP, Brasil.

Tel. 55 11 5686-7301. E-mail: maryakolm@yahoo.com.br Financial support: None.

Submitted: 1 October 2014. Accepted, after review: 22 January 2015.

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with or without a central pair of microtubules, the microtubular patterns being designated 9+2 and 9+0, respectively. Cilia are classified as motile or nonmotile.(7,8) Motile cilia play a role in cell motility and extracellular fluid movement. Motile cilia with a 9+0 arrangement of microtubules are those in notochordal plate cells. During embryonic development (gastrulation), cells in the ventral node contain a single motile cilium per cell.

This specialized motile cilium has nine pairs of peripheral microtubules with dynein arms but no central pair of microtubules; its rotational motion contributes to the development of organ laterality during embryogenesis. In the absence of normal nodal ciliary function, organ placement is random. Motile cilia with a 9+2 arrangement of microtubules are those in ciliated airway epithelial cells, fallopian tube epithelial cells, ependymal cells, and sperm tails.

Nonmotile cilia play a role in the perception of extracellular physical and biochemical signals.

Nonmotile cilia with a 9+0 arrangement of microtubules are those in renal tubular epithelial cells (monocilia), bile duct epithelial cells, pancreatic duct epithelial cells, chondrocytes, and osteocytes, as well as the connecting cilia in retinal photoreceptor cells. Nonmotile cilia with a 9+2 arrangement of microtubules are those in the inner ear (i.e., kinocilia and stereocilia).

Normal ciliary ultrastructure in ciliated airway epithelial cells An axial view of a cilium (Figure 1) shows nine peripheral microtubule doublets. Each doublet consists of the A and B tubules. The uniform space between the microtubule doublets is maintained by nexin, which keeps the adjacent microtubules together. In addition, there are the outer and inner dynein arms throughout the A tubule, a central pair of isolated microtubules connected and surrounded by a discontinuous central sheath of protein, and radial spokes, which connect the central microtubules to the peripheral microtubules.

The outer and inner dynein arms have high, medium, and low molecular weight proteins.

The heavy protein chains have ATPase activity and, through ATP hydrolysis, the A tubule slides on the B tubule of each adjacent doublet. The microtubules on the opposite side mediate ciliary J Bras Pneumol. 2015;41(3):251-263

bending (a forward power stroke and a backward recovery stroke).(9) Motile ciliated airway epithelial cells are present in the nasal cavity, paranasal sinuses, middle ear, fallopian tube, cervix, vasa deferentia, and ependyma. In the airways, cilia can be found up to the 16th bronchial division. Ciliated respiratory epithelial cells are characterized by long cytoplasmic projections, with approximately 200 cilia per cell. Each cilium is 5-7 µm in length in the trachea and 2-3 µm in length in the seventh airway generation, being 0.25-0.33 µm in diameter.(10) The main function of ciliated airway epithelial cells is to mediate the propulsion of the mucus gel layer toward the head through coordinated movements. In the lungs of healthy individuals, mucus is propelled at a ciliary beat frequency of 12-15 Hz, in the form of waves, at a speed of 4-20 mm/min.(11)

Clinical picture The presence of general clinical indicators (for all age groups) and age-specific indicators should raise the clinical suspicion of PCD.(12) General indicators include situs abnormalities (dextrocardia and isomerism) and a personal or family history of ciliopathies. Age-specific indicators include prenatal indicators (situs abnormalities on ultrasound), neonatal indicators (rhinorrhea at birth, neonatal respiratory distress with no apparent cause in full-term infants, abnormal situs, complex congenital heart disease—especially with laterality disorders—and a family history of PCD), childhood indicators (chronic productive cough, atypical asthma unresponsive to treatment, idiopathic bronchiectasis, rhinosinusitis—the presence of nasal polyposis is rare—agenesis of one or more sinuses, severe otitis media with effusion, prolonged otorrhea after ventilation tube insertion, and having a family member diagnosed with PCD), and adulthood indicators (childhood data plus male infertility due to immotile sperm, ectopic pregnancy, and subfertility due to static cilia in the fallopian tube).(12) In addition to the aforementioned indicators, other authors consider the presence of pectus excavatum, which occurs in approximately 10% of patients with PCD and in 0.3% of the general population, and a high prevalence of scoliosis (5-10%).(13) With regard to ear, nose, and throat problems, approximately 85% of all children with PCD http://dx.doi.org/10.1590/S1806-37132015000004447

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A

253

B

Figure 1 - Schematic illustration and electron micrograph of a normal airway cilium. In A, schematic illustration of an axial section of a normal cilium in a ciliated airway epithelial cell, in which the peripheral microtubular doublets (comprising the A and B tubules) are numbered from 1 to 9; the central microtubules are designated C1 and C2. The A tubule contains the outer and inner dynein arms, which interact dynamically with the B tubule of the adjacent microtubule and produce the sliding of the peripheral microtubular doublets relative to one another. The illustration also shows nexin links, which connect the microtubular doublets (thus preventing structural disarray during their sliding motion), and radial spokes, which extend from the periphery to the center of the ciliary axis. In B, electron micrograph (original magnification, Ă&#x2014;50,000) showing the ultrastructural appearance of an axial section of a normal airway cilium. Source: Department of Pathology, University of SĂŁo Paulo School of Medicine, SĂŁo Paulo, Brazil, 2010.

present with severe otitis media with effusion, which usually improves by the age of 13 years.

Mucus accumulation in the Eustachian tube causes conductive hearing loss that varies with time. There is also an underdevelopment of the frontal and sphenoid sinuses in PCD patients, and nasal polyposis can occur in up to 18% of cases.(6) More than half of all PCD patients usually have problems in the paranasal sinuses, with frequent radiological investigations and local surgical procedures.(13)

Diagnosis According to a European consensus statement, diagnostic tests should be performed in the following groups: patients with situs inversus or heterotaxy; children with chronic productive cough, idiopathic bronchiectasis, or severe upper airway disease; children with cerebral ventriculomegaly; siblings of patients with PCD; infants with unexplained neonatal respiratory distress; males with immotile sperm; and females with recurrent ectopic pregnancy.(1) Patients should be referred to a specialized center(6) for clinical history taking and screening tests, as well as ciliary function tests (ciliary beat frequency and ciliary beat pattern),(2) ciliary ultrastructural analysis, immunofluorescence, http://dx.doi.org/10.1590/S1806-37132015000004447

and genetic analysis. In cases of idiopathic bronchiectasis, PCD is a diagnosis of exclusion, given that other causes of bronchiectasis should be ruled out before screening for PCD.(14) The diagnosis of PCD depends on appropriate training and resources. The consensus among American and British researchers is that the PCD phenotype and nasal NO measurements are important; ciliary motion has been studied in greater detail by European researchers,(15,16) as has ciliated cell culture. However, American centers for the diagnosis of PCD have reported difficulties in standardizing the interpretation of ciliary motion and electron microscopy. Therefore, at those centers, the diagnosis of PCD is based on the presence of a phenotype consistent with the disease and abnormal nasal NO values, associated with genetic testing to identify the mutations.(15) High-speed video imaging of the ciliary beat frequency and pattern contributes to the understanding of the effects of ciliary defects on mucus transport. It allows the visualization of the normal pattern of ciliary beating; that is, a forward power stroke followed by a slow, slightly sideways, backward recovery stroke. Changes in the normal pattern of ciliary beating can be associated with specific genetic defects.(16-18) Chart 1 shows the correlations among reported J Bras Pneumol. 2015;41(3):251-263

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ciliary ultrastructural defects, gene mutations, and ciliary beat patterns.(16) The most common genetic mutations include the DNAH5 gene mutation (in 15-28% of cases) and the DNAI1 gene mutation (in 2-10% of cases).(19) The study of ciliary beat frequency should be accompanied by ciliary beat patterns analysis, given that approximately 10% of individuals with normal ciliary beat frequency can present with an abnormal ciliary beat pattern.(20,21) Immunofluorescence assays of cilia collected by nasal brushing, performed with specific antibodies and based on established mutations, can aid in the genetic diagnosis of PCD.(22,23) Semen analysis is used in some centers in Brazil as an indirect indicator of PCD, given that sperm cells behave like modified cilia, with reduced motility. However, in patients with Kartagener syndrome, sperm flagella and respiratory cilia vary across individuals and might not be equal in the same patient; this suggests that ciliary

and flagellar axonemes(24,25) are controlled by common genes and different genes.(26) Therefore, patients with abnormal semen analysis results should be referred to tertiary care facilities for analysis of respiratory cilia, in order to establish a diagnosis.

Definitive diagnosis In order to establish a definitive diagnosis of PCD, certain phenotypic characteristics (at least three characteristics, typically five or more characteristics) should be present: neonatal respiratory distress in full-term infants; laterality defects; chronic, year-round nasal congestion; chronic, year-round productive cough; recurrent lower respiratory tract infections; bronchiectasis; chronic otitis media with effusion for more than 6 months; chronic pansinusitis; male infertility; and a history of ciliary dyskinesia in a close relative.(27)

Chart 1 - Ciliary ultrastructural defects, genetic mutations, and ciliary beat pattern in patients with primary ciliary dyskinesia.

Ultrastructural changes, genetic mutations, and associated Ciliary beat pattern chromosomes DNAI1 (9p21-p13); DNAI2 (17q25); DNAH5 DNAH5, DNAI1, DNAI2, ARMC4, and Outer dynein arm (5p15.2); DNAL1 (14q24.3); NME8/TXNDC3 CCDC103: residual, disorganized ciliary beat defects (7p14-p13); CCDC114 (19q13.32); and with uncoordinated neighboring cilia(6,16) ARMC4 (10p12.1-p11.23)(3,19,25) DNAAF1 (LRRC50): 16q24.1; DNAAF2 KTU/DNAAF2, LRRC50/DNAAF1, LRRC6, Proteins involved (KTU): 14q21.3; DNAAF3 (C19orf51): and ZMYND10: complete ciliary immotility; in the formation 19q13.42; CCDC103 (17q21.31); C21orf59 DYX1C1: complete ciliary immotility or of outer and inner (21q.22.1); DYX1C1 (15q21.3); LRRC6 reduced ciliary beat amplitude with a few dynein arms (8q24); HEATR2 (7p22.3); SPAG1 (8q22); static cilia(16) and ZMYND10 (3p21.31)(3,19,25) Inner dynein arm defects and CCDC39 (3q26.33) and CCDC40 (17q25.3) Stiff cilia with reduced ciliary beat (3,19,25) microtubular amplitude(16) disorganization CCDC164 (DRC1), 2p23.3: nexin link missing, axonemal disorganization in a Nexin links CCDC164: reduced ciliary beat amplitude(16) small proportion of cilia(23,25); CCDC65 (DRC2):12q13.12(23,25) HYDIN: reduced ciliary bending; some cilia HYDIN (16q22.2): mostly normal; RSPH9 Changes in the showing circular motion and others being (6p21.1), RSPH4 (6q22.1), and RSPH1 central pair of immotile; RSPH4A: stiff cilia; RSPH1: stiff (21q22.3): central pair defects in a small microtubules cilia and cilia showing circular motion(16); proportion of cilia(3,19,25) RSPH9: circular motion(6) DNAH11 (7p21): changes in outer dynein Reduced ciliary bending(16); stiff, Normal ultrastructure arm proteins(3,19,25) hyperkinetic, or static cilia(6,15) Reduced generation CCNO/MCIDAS (5q11)(60) Reduced number of motile cilia(60) of motile cilia Note: Nonmotile cilia: RPG (XP 21.1), associated with retinitis pigmentosa, and OFD1 (Xq22), associated with mental retardation.(3,25)

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According to BESTCILIA, a European Commission-funded consortium dedicated to improve PCD care and knowledge,(23) a diagnosis of PCD requires a) a clinical presentation consistent with the disease and b) confirmation by at least two of the following methods: unequivocally abnormal high-speed video microscopy finding; unequivocally abnormal transmission electron microscopy finding; unequivocally abnormal immunofluorescence microscopy finding; abnormally low nasal NO concentration/production; and demonstration of unequivocal biallelic disease-causing mutations by genotyping. In cases in which only high-speed video microscopy and nasal NO concentration/ production are abnormal, high-speed video microscopy should be repeated at least three times and show the same abnormal results each time.(23) Patients with typical clinical symptoms and only one abnormal diagnostic test are considered to have a possible diagnosis of PCD, exceptions being made on an individual basis.

At several centers worldwide, the use of nasal NO testing is recommended in order to confirm the diagnosis,(15) and the diagnostic tests should be repeated when the phenotype and low levels of nasal NO do not correlate with ciliary ultrastructure and beat frequency. Secondary defects should be excluded when the results of nasal NO testing are normal and accompanied by ciliary motility defects or ciliary ultrastructural defects.

A genetic test result is considered positive for PCD when there are two genes with trans mutations—in which the wild-type allele (A) and mutant allele (b) of one gene are located on one chromosome and the mutant allele (a) and wild-type allele (B) of another gene are located on the homologous chromosome—and no correcting mutations.(12)

Screening tests Screening tests are important in order to select which of the patients with signs and symptoms suggestive of PCD should undergo analysis of ciliary function and ultrastructure.

Nasal NO testing and the saccharin test are used as screening tests in 46% and 36%, respectively, of all centers in 26 European countries.(2)

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processes of nasal NO production and metabolism in PCD patients have yet to be fully elucidated.(29) The leading hypotheses to explain the reduced nasal NO levels in over 95% of patients with PCD are related to ciliated epithelial cells per se and anatomical obstructions. At the epithelial level, it has been suggested that there is reduced NO biosynthesis or increased NO metabolism caused by the accumulation of thick mucus or the presence of bacteria. At the anatomical level, it has been suggested that NO is sequestered in blocked nasal sinuses or, alternatively, nasal NO biosynthesis or NO storage capacity is limited because of agenesis of the paranasal sinuses.(29) Nasal NO levels are extremely low in PCD patients, for whom nasal NO measurement is strongly recommended.(30-32) In the airways, NO plays many roles—it mediates inflammation and stimulates ciliary motility, for example—and NO concentrations are much higher in the upper airways than in the lower airways (200-2,000 ppb vs. 4-160 ppb). Nasal NO production (nL/min) is calculated by multiplying nasal NO concentration by the sampling flow rate. Values of less than 100 nL/min indicate the possibility of PCD.(27) However, values of less than 77 nL/min have a sensitivity of 0.98 and a specificity of more than 0.999 for PCD (in patients over 5 years of age, with the use of palate closure maneuvers and nonmanual chemiluminescence analyzers). (32) Further studies are needed in order to define cut-off points for tidal volume measurements in uncooperative young children.(28,31) Of all PCD-associated gene mutations described to date, the RSPH1 gene mutation is an exception in that patients with that mutation can have normal nasal NO values.(15)

The saccharin test The saccharin test is a good test to assess nasal mucociliary transport, which is usually prolonged in individuals with PCD. It consists of placing a particle of saccharin of 1 mm in diameter on the floor of the nasal cavity, approximately 1 cm into the inferior turbinate. The patient sits quietly with the head bent forward and must not sniff, sneeze, cough, eat, or drink for the duration of the test. The time (in min) to tasting saccharin in the pharynx is measured. The result of the test is considered abnormal when the time to tasting saccharin in the pharynx is greater than 60 min. (14) However, a study conducted J Bras Pneumol. 2015;41(3):251-263

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in Brazil(33) and involving 238 children (in the 10-16 year age bracket) established a different cut-off point (of 30 min), showing that the test should not be performed during an acute viral infection or in the subsequent month. In patients with abnormal ciliary ultrastructure, the saccharin test has good sensitivity (95% of cases for values greater than 30 min and 75% of cases for values greater than 60 min). However, false positives can occur in 0.4-15% of cases in healthy adults. Nasal mucociliary transport can be slower in patients with septal deviation or rhinoscleroma. In a recent review,(6) the saccharin test was reported to be difficult to perform correctly and unreliable in children under 12 years of age. In addition, cases with extremely uncoordinated ciliary beating might be missed by the saccharin test.

Pulmonary radioaerosol mucociliary clearance testing Current clinical experience is insufficient to recommend the use of pulmonary radioaerosol mucociliary clearance tests in clinical practice.(2)

Genetics Genetic studies have identified mutations in several genes encoding ciliary structure and functional proteins; however, genetic tests are not readily available in clinical practice.(8) The finding of a PCD-associated gene mutation constitutes laboratory evidence for a definitive diagnosis of PCD.(27) Chart 1 presents the most important PCD-associated genes described to date. Mutations in genes such as RSPH1, RSPH4A, RSPH9, HYDIN, MCIDAS, and CCNO, which cause no laterality defects, allow clinical correlations to be established.(3,23)

Associated clinical conditions There is evidence that ciliary disorders are related to various developmental problems and clinical conditions, which are known as ciliopathies. A family history of ciliopathy should raise the suspicion of PCD in patients or their relatives with characteristics suggestive of PCD. (34) Nonsyndromic manifestations of ciliopathies typically involve the heart, kidney, liver, retina, and central nervous system, and are characterized by complex congenital heart disease, polycystic kidney disease, nephronophthisis, renal dysplasia, J Bras Pneumol. 2015;41(3):251-263

fibrocystic liver disease, retinitis pigmentosa, and hydrocephalus.

Ciliopathies constitute a group of diseases associated(12) with genetic mutations that result in changes in ciliary formation or function. Given that cilia are components of many cell types, ciliary dysfunction can manifest as a constellation of clinical features such as retinal degeneration, kidney disease, and cerebral abnormalities.

Molecular genetic studies conducted in recent years suggest a clear relationship between primary cilium development and function and various clinical conditions.(35) Syndromic manifestations of ciliopathies are found in Joubert syndrome, Meckel-Gruber syndrome, Senior-Loken syndrome, oral-facial-digital syndrome, Leber congenital amaurosis, BardetBiedl syndrome, AlstrĂśm syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Ellis-van Creveld syndrome, and Sensenbrenner syndrome.(12) Kartagener syndrome is a rare congenital malformation consisting of the triad of situs inversus, bronchiectasis, and sinusitis.(37) The association between immotile cilia and situs inversus was based on the hypothesis that, in the early stages of normal embryogenesis, the position of nodal and notochordal cilia and their ciliary beat orientation are predetermined, and that their ciliary beat frequency determines organ laterality through a cascade of molecular signaling.

When the aforementioned cilia are immotile, organ placement is random, resulting in many cases of situs inversus, which usually occurs in 50% of PCD patients,(36,37) some of whom are diagnosed with Kartagener syndrome.(38)

Standardization of electron microscopy analysis of ciliary ultrastructure Although several transmission electron microscopy facilities have been working on the standardization of diagnostic criteria to be used in ciliary ultrastructural analysis, no proposal has been universally accepted. The variety of PCD-associated defects and the rarity of the disease make it difficult to standardize the interpretation of electron microscopy.(39) There are multiple factors that limit the use of electron microscopy as a diagnostic test for PCD: secondary ciliary changes caused by infection or inflammation; difficulties in the fixation and processing of ciliated cells; the need for ultrathin sections; the technical complexity of http://dx.doi.org/10.1590/S1806-37132015000004447

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transmission electron microscopy; the need for an adequate number of interpretable images; and the fact that interpretation requires recognition of normal variability and nonspecific changes.(40) In addition, samples from children are usually less suitable for ciliary ultrastructural analysis than are those from adults (60% vs. 87%).(40,41)

Collection of ciliated cells For ciliated cell collection, nasal brushing has lower morbidity than does nasal biopsy, as well as being less costly and easier to perform. (14,42) Bronchoscopy brushes are used in order to collect ciliated cells from the inferior nasal turbinate, near the transverse septum. Some of the material is separated for ciliary beat frequency and ciliary beat pattern analysis, and the remainder is sent for electron microscopy analysis.(12,14) For ciliated cell collection, patients are required to be free of acute respiratory infection for 4-6 weeks in order to minimize the presence of changes caused by secondary dyskinesia.

Parameters for evaluating ciliary ultrastructure Ciliary orientation Ciliary disorientation is associated with PCD. In cases of ciliary disorientation, ciliary ultrastructure is normal and ciliary beat frequency is normal or near normal, but ciliary motion is inefficient because of ciliary beat disorientation; that is, it does not correctly propel the mucus.(42)

Microtubules The peripheral microtubules can show disorganization and inner dynein arm defects,(3) as well as transposition defects (the central pair being replaced by a peripheral microtubule).(43,44) Transposition defects(44,45) or translocation defects(3) are characterized by the absence of the central pair of microtubules in certain cross sections (9+0 arrangement), some sections showing the central pair replaced by an outer microtubule doublet (8+2 arrangement).(43,45) The absence of the central pair alone has been reported as a primary defect.(47)

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across centers.(17,39,43,46,48) Chart 2 summarizes the results of studies involving quantitative assessment of dynein arms.

With regard to dynein arm defects, absence of dynein arms can be found in more than 90% of cilia. (17) Isolated inner dynein arm defects constitute only a small fraction of confirmed PCD cases and require confirmation by repetition of the test with a healthy epithelium sample.(3) Partial absence of dynein as a primary defect is considered controversial and requires further studies for confirmation.(43) Figure 2 shows the major ultrastructural defects described to date.

Normal ciliary ultrastructure and PCD Extremely reduced nasal NO levels and abnormal ciliary function (ciliary beat frequency, ciliary beat pattern, or both) with normal ciliary ultrastructure require genetic testing for a mutation consistent with the disease (i.e., the DNAH11 gene mutation).(8,27) Patients with a clinical history consistent with PCD, low levels of exhaled nasal NO, and abnormal ciliary motility have been diagnosed with PCD, despite the recommendation that genetic testing be performed in order to confirm the diagnosis.(8,27) It has been reported that 3-30% of patients with PCD have uncertain or normal ciliary ultrastructure, the diagnosis of PCD in such patients not being based on ciliary ultrastructure alone.(44) Advances in the molecular genetics of PCD have allowed the identification of mutations in approximately 70% of patients.(15,25) Dynein arm defects are the most common defects in patients with PCD: outer dynein arm defects, in 30-43% of cases; outer and inner dynein arm defects, in 9-36%; inner dynein arm defects, in 11-30%; normal ultrastructure, in 25%; transposition, in 14%; central pair defects, in 9%; radial spoke defects, in 7%; and ciliary aplasia, in 6%.(34)

Rare defects In patients with PCD, ultrastructural changes include nexin link defects,(49) absence of the central pair of microtubules, and absence of the basal bodies and sheath (alternatively, the basal bodies and sheath are present but have a reduced number of cilia).(47,48) J Bras Pneumol. 2015;41(3):251-263

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Chart 2 - Quantitative assessment of dynein arms.

Outer dynein arm Author (number of arms per cilium) Normal: 8.7 ± 0.4 arms Jorissen et al.(43)

Chilvers et al.(17)

Carlén et al.(48) Plesec et al.(39) Shoemark et al.(46)

Inner dynein arm (number of arms per cilium) Normal: 3.0 ± 0.4 arms

Means of up to 2.7 arms for outer dynein arm defects Means of up to 1.1 inner dynein arms for outer and inner dynein arm defects Means of up to 2.2 outer dynein arms for outer and inner dynein arm defects Means of up to 0.7 outer dynein arms for outer and Means of up to 0.7 inner dynein arms for inner dynein arm defects outer and inner dynein arm defects Means of up to 1.7 outer dynein arms for outer Means of up to 2.3 inner dynein arms for dynein arm defects inner dynein arm defects Normal: 7.5-9.0 outer dynein arms per cilium Normal: 3.0-5.0 inner dynein arms Defective: Means of < 1.6 arms Defective: means of < 0.6 arms Defective: absent/truncated dynein arms Defective: absent/truncated dynein arms Normal: presence of 1 or more outer dynein arms Normal: presence of 1 or more inner dynein in each cilium arms in each cilium

A

B

C

D

Figure 2 - Electron micrographs of ciliary ultrastructural defects. In A, absence of outer dynein arms (magnification, ×65,000); in B, microtubular disorganization (magnification: ×30,000); in C, absence of the central pair of microtubules (9+0 arrangement), which is usually associated with the 8+2 transposition defect (magnification: ×65,000); in D, 8+2 transposition defect (magnification: ×65,000). Source: Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil, 2010.

Secondary ciliary dyskinesia Secondary or acquired ciliary dyskinesia can be caused by injury to ciliated airway epithelial cells by physical and chemical agents.

Respiratory infections and the inflammatory immune response to the infections can affect ciliary function, inducing secondary ciliary dyskinesia.

Secondary lesions include compound cilia (fused membranes or multiple axonemes within a single membrane), peripheral and central microtubular abnormalities, swelling of the membranes, shortened dynein arms, ciliary membrane blebs, and absence of the ciliary membrane.(50,51) In healthy individuals and in patients without ciliary dyskinesia, there are variations (of 4 ± 3%) in normality for secondary ciliary changes in healthy individuals, and the presence of up to 10% of altered cilia can be considered normal.(50,52) In cases of ciliary aplasia, bronchial mucosal biopsy is required in order to confirm the presence of a J Bras Pneumol. 2015;41(3):251-263

ciliary defect elsewhere in the airways. Patients with normal ciliary ultrastructure and abnormal ciliary function require ciliary orientation studies.(14)

Diagnosis confirmed by ciliated cell culture Ciliated cell cultures are performed only at specialized centers and are followed by transmission electron microscopy analysis, being recommended to differentiate between primary and secondary defects. Culture duration is approximately 6 weeks.

The success rate of ciliated cell cultures is 75%, cultures being conclusive in 85% of cases.(42,43) The absence of secondary defects after growth in culture media (ciliogenesis) contributes to the diagnosis of PCD.

Ciliary ultrastructure report and final results At internationally renowned PCD research centers, the diagnosis (report) of ciliary

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ultrastructural changes is based on the observation of 200-300 cilia,(46) a minimum of 100 cilia(44) being evaluated in cross sections (and approximately 30% of dynein arms being visualized). Abnormalities found in less than 10% of cilia are considered to be within the normal range.(50) PCD-related defects include absence of outer dynein arms, absence of outer and inner dynein arms, microtubular disorganization,(43) and changes in the central pair of microtubules (transposition defect).(44) The presence of inner dynein arm defects(3) or ciliary disorientation alone requires new samples in order to confirm the diagnosis. The ciliary ultrastructure report should be conclusive regarding the presence or absence of PCD-related defects. The results of all investigations should be expressed as a definitive diagnosis (Chart 3).

Radiology In patients with PCD, a HRCT scan of the chest (Figure 3) shows middle and lower lobe involvement—the middle and lower lobes being more affected than the upper lobes in PCD patients when compared with cystic fibrosis patients (in whom the upper lobes are more affected than the middle and lower lobes)—with subsegmental atelectasis, peribronchial thickening, mucus plugging, evidence of air trapping, groundglass opacities,(25) areas of consolidation, and well-defined bronchiectasis.(19) The presence of bronchiectasis is related to age. In a study of 72 patients, 98% of those over 18 years of age (in the 19-73 year age bracket) had signs and symptoms of bronchiectasis, as did 61% of those under 18 years of age.(53) Adult patients present with advanced lung disease.(54)

Pathophysiology of the disease in the airways and lung function Genetic defects in respiratory epithelial cilia cause a significant reduction in mucociliary transport, with retention of secretions, recurrent infections, and, consequently, bronchiectasis.

Impaired alveolar gas exchange can occur in the long term, causing respiratory failure, pulmonary hypertension, and right heart failure.(52) Loss of lung function occurs as a result of undertreatment or delayed diagnosis. There is a relationship between age and loss of lung function, FEV1 decreasing with age. A mean FEV1 drop of 0.8% per year—unrelated to ciliary http://dx.doi.org/10.1590/S1806-37132015000004447

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structural defects—has been reported.(53) However, in a recent longitudinal study of 74 patients, lung function varied widely over the course of 10 years, up to 34% of the patients having experienced a significant decline in lung function despite treatment; this shows that PCD poses a serious threat to lung function.(55,56)

Treatment Ciliary defects cannot be treated with the conventional pharmacological armamentarium, and there is no specific treatment for ciliary dysfunction. Therapy is aimed at improving mucociliary clearance, treating infections, and improving or stabilizing lung function, preventing chronic lung injury. The recommendations are based on expert opinion, being inferred from the available evidence for cystic fibrosis, although there are differences between the two diseases in terms of their pathophysiology.(6) Education and information are considered important tools for patients and their families.(14) Outpatient treatment is multidisciplinary, involving pulmonologists, otolaryngologists, nurses, physiotherapists, psychologists, and social workers.(19) Patients should be advised to avoid environmental allergens and smoking, and physical exercise can be a better bronchodilator than beta-agonists. Regular visits to referral centers are to take place every 2-3 months in children and every 6-12 months in adults, as needed.(14) In addition to basic immunization, patients should receive annual influenza vaccination and pneumococcal vaccination.

Respiratory monitoring The two pillars upon which respiratory treatment stands are antibiotic therapy and chest physiotherapy.

Chest physiotherapy should be performed twice a day for 20 min, increasing during exacerbations. (14) Sputum culture and serial spirometry should be performed in the follow-up of patients with PCD. Antibiotic therapy should be initiated at the first sign of any increase in respiratory symptoms or deterioration of lung function, lasting two weeks in general. Antibiotics should be given on the basis of culture sensitivity testing. Intravenous treatment should be used if symptoms do not respond to oral antibiotics. In adults, colonization with Pseudomonas aeruginosa is not rare and might J Bras Pneumol. 2015;41(3):251-263

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Chart 3 - Screening for primary ciliary dyskinesia.

Presence of a phenotype consistent with PCD (Check the items that are suggestive of PCD) Organ laterality defects: dextrocardia, situs inversus, isomerism Upper airway disease: otitis media, sinusitis Lower airway disease: recurrent pneumonia Idiopathic bronchiectasis Screening test used: The saccharin test (time to tasting saccharin: ____ minutes) Nasal NO testing (formal recommendation; method used and results obtained) Analysis of ciliary movement Ciliary waveform (Check) Static, reduced, circular, dyskinetic Ciliary beat frequency Patient:____ Hz. Control group (mean):_____ Hz. Definitive diagnosis Transmission electron microscopy analysis of ciliary ultrastructure Description of the predominant defect (A normal result does not rule out PCD) Genetic testing For patients with normal ultrastructure and abnormal phenotype, ciliary motion, and nasal NO values Immunofluorescence or gene mutation screening Ancillary tests Pulmonary function testing Semen analysis Chest HRCT bronchiectasis score HRCT sinus score Sputum culture ENT examination Quality of life assessment Referral to fertility clinics PCD: primary ciliary dyskinesia; ENT: ear, nose, and throat. Source: Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil, 2014.

The use of recombinant human DNase, which reduces the viscoelasticity of respiratory mucus, shows conflicting results and requires further investigation before it can be recommended for PCD patients. Hypertonic saline can be effective in improving mucociliary clearance; however, to date, there have been no controlled clinical trials to support its use.(6,23)

Auditory monitoring Figure 3 - Axial HRCT scan of the chest of a 30-year-old patient with primary ciliary dyskinesia (absence of outer and inner dynein arms) and advanced lung disease.

Note significant involvement of the lung bases, with bronchial wall thickening, the signet ring sign, areas of consolidation, and attenuation differences. Source: Department of Clinical Pulmonology, Heart Institute, University of São Paulo School of Medicine - Hospital das Clínicas, São Paulo, Brazil, 2014.

At otolaryngology clinics, patients should be monitored for hearing loss, which requires specific procedures.(13) The results of studies on the treatment of otitis media with effusion are contradictory regarding the use of ventilation tubes, larger samples being required in order to draw conclusions.(57) Endoscopic sinus surgery appears to improve local symptoms.(13)

Other referrals require more aggressive intravenous therapy and long-term use of inhaled antibiotics.(2,3,6,23)

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require psychosocial support in order to cope with the stigmata attached to the disease, including infertility and possible school problems.(14) Surgical resection for localized bronchiectasis can be beneficial in some cases.(58) Although lung transplantation is a possibility, only a few cases have been reported in the literature.(59)

Prognosis To date, there have been no large-scale, longterm studies for a more detailed prognosis of PCD. The high genetic variability of the disease determines differences in progression among patients. Pulmonary impairment is more severe in patients diagnosed in adulthood than in those diagnosed in adolescence. A minority of patients might progress to severe lung disease with respiratory failure requiring lung transplantation.(25)

Final considerations The diagnostic report of PCD should include the results of all investigations that led to the diagnosis of the disease, including phenotyping, screening tests, analysis of ciliary function (ciliary beat frequency, ciliary waveform, or both), qualitative and quantitative assessment of ciliary ultrastructure, immunofluorescence, and gene mutation screening. Ciliated cell cultures can aid in the diagnosis of PCD. Normal ciliary ultrastructure does not rule out PCD. The results of all investigations should be expressed as a definitive diagnosis.

Acknowledgments We would like to thank Dr. Samia Rached for the CT image.

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Review Article PET/CT imaging in lung cancer: indications and findings* PET/TC em câncer de pulmão: indicações e achados

Bruno Hochhegger1, Giordano Rafael Tronco Alves2, Klaus Loureiro Irion3, Carlos Cezar Fritscher4, Leandro Genehr Fritscher5, Natália Henz Concatto6, Edson Marchiori7

Abstract The use of PET/CT imaging in the work-up and management of patients with lung cancer has greatly increased in recent decades. The ability to combine functional and anatomical information has equipped PET/CT to look into various aspects of lung cancer, allowing more precise disease staging and providing useful data during the characterization of indeterminate pulmonary nodules. In addition, the accuracy of PET/CT has been shown to be greater than is that of conventional modalities in some scenarios, making PET/CT a valuable noninvasive method for the investigation of lung cancer. However, the interpretation of PET/CT findings presents numerous pitfalls and potential confounders. Therefore, it is imperative for pulmonologists and radiologists to familiarize themselves with the most relevant indications for and limitations of PET/CT, seeking to protect their patients from unnecessary radiation exposure and inappropriate treatment. This review article aimed to summarize the basic principles, indications, cancer staging considerations, and future applications related to the use of PET/ CT in lung cancer.

Keywords: Carcinoma, non-small-cell lung; Small cell lung carcinoma; Positron-emission tomography; Tomography, X-ray computed; Neoplasm staging.

Introduction The incidence of lung cancer has rapidly increased since the beginning of the 20th century and currently represents the main cause of cancer-related mortality worldwide. The most recent data indicate that, in Brazil as a whole, lung cancer was responsible for 22,424 deaths in 2011, affecting men and women in similar proportions (approximate male/female ratio, 1.6:1.0).(1) Lung cancer also constitutes the second most common type of cancer (in men and women) in Europe and the United States, creating a remarkable burden not only for the health care system but also for society and the economy.(2) Smoking is, independently, the most important risk factor for lung cancer development, the likelihood ratio between smokers and non-smokers having been estimated at 10:1.(3) Non-small cell lung cancer (NSCLC), which is the predominant

histology (seen in 85-90% of all cases of lung cancer), encompasses three subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The remaining 10-15% of cases are small cell lung cancer (SCLC).(4) The assessment of patients with suspected lung cancer has routinely included morphological imaging evaluation, with either chest X-rays or CT of the thorax. In addition—although not diagnostic in character—18F-fluorodeoxyglucose positron emission tomography (FDG-PET), bone scintigraphy, and (occasionally) somatostatin receptor scintigraphy have been increasingly incorporated into daily practice in recent decades, providing physicians with useful and complementary information on the functional characteristics of lesions.(2) More recently, the emergence of combined PET/CT imaging has

1. Postdoctoral Fellow in Radiology. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

2. Master’s Student. Graduate Program in Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

3. Consultant Radiologist. Radiology Department, Royal Liverpool and Broadgreen University Hospital, Liverpool, United Kingdom.

4. Professor. Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.

5. Pulmonologist. São Lucas Hospital, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil.

6. Medical Student. University of Caxias do Sul, Caxias do Sul, Brazil.

7. Professor of Radiology. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. *Study carried out under the auspices of the Graduate Program in Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Correspondence to: Giordano Alves. Rua Professor Rodolpho Paulo Rocco, 255, CEP 21941-913, Rio de Janeiro, RJ, Brasil.

Tel. 55 51 9850-2544. E-mail: grtalves@gmail.com Financial support: None.

Submitted: 2 November 2014. Accepted, after review: 27 February 2015.

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greatly aided the investigation of lung cancer by allowing even better delineation of areas with increased tracer uptake. This modality has helped radiologists avoid the technical difficulties that arose from the independent combination of PET and CT examinations, which resulted in substantial artifacts. In addition, PET/CT has been shown to be an accurate tool for the work-up of solitary pulmonary nodules (SPNs) and for lung cancer stagingâ&#x20AC;&#x201D;by improving the detection of metastatic disease, guiding therapy, and allowing clinical outcomes to be predicted.(2,3) Currently, PET/CT is considered a reliable imaging modality that is particularly suitable for the evaluation of cancer patients, including those with lung cancer. Therefore, this study sought to summarize the indications for, findings from, and overall impact of PET/CT on the diagnosis, staging and follow-up of patients with NSCLC and other types of lung cancer.

Indications for PET/CT Images acquired by PET/CT can be quite useful in the evaluation of suspected or pathologically proven lung cancer cases, in several ways. The most common indications for PET/CT are as follows(5,6): for the morphological and functional characterization of pulmonary nodules or masses; for tumor-node-metastasis (TNM) staging of the mediastinum and screening for metastases that might not be detected by CT alone; for radiotherapy planning; and for restaging lung cancer patients following treatment. In addition, PET/CT can offer insights into the histology of a lesion under investigation. Previous studies evaluating the preoperative maximum standardized uptake value (SUVmax) have shown that bronchioloalveolar carcinoma and other well-differentiated tumors are less FDG-avid than are squamous cell carcinomas.(7) Such additional characterizations can also facilitate the differentiation of synchronous primary tumors from metastatic disease, as well as providing prognostic information beyond what is gathered with CT-based imaging.

NSCLC In up to 90% of all cases of lung cancer, the histological analysis identifies the tumor as NSCLC.(4) In the majority of cases, symptoms will depend heavily on the stage and histological http://dx.doi.org/10.1590/S1806-37132015000004479

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subtype of the tumor. An SPN can be the initial presentation of peripherally located lesions, whereas lobar atelectasis, obstructive pneumonia, or an abnormally enlarged mediastinal lymph node can indicate the presence of central tumors.

Staging In patients with newly diagnosed NSCLC, the initial disease staging is a crucial step in selecting the most appropriate therapy and determining the prognosis.(2) The TNM staging system, which is kept up-to-date by the American Joint Committee on Cancer and the International Union Against Cancer, is presently the standard tool for staging lung cancer patients. This system is based on a combination of three basic aspects: the location and extent of the primary tumor (T); the presence or absence of changes in intrapulmonary, hilar, or mediastinal lymph nodes (N); and the presence or absence of other pulmonary nodules, pleural effusion, or extrathoracic (distant) metastases (M). The combination of the T, N, and M scores is then used to place a given lesion in one of four disease stages (I-IV), stratifying individuals by prognosis and therapeutic prospects.(8-10) An appropriate differentiation between patients with potentially curable disease and those who will be receiving palliative therapies is therefore of utmost importance. In light of this, PET/CT has increasingly supplanted CT as the imaging modality of choice for NSCLC staging, because previous reports have demonstrated that integrated PET/CT is more accurate in characterizing TNM status than is CT alone, PET alone, or visually correlated PET and CT.(2,8,10) For instance, in the newly adopted 7th edition of the TNM classification for lung cancer, NSCLC metastatic disease is subdivided into M1a, which comprises cases with pleural nodules or malignant pleuropericardial effusion and contralateral pulmonary nodules; and M1b, which comprises those with other distant metastases. Particularly in M1a disease, PET/CT may figure as a useful tool for the detection of either pleural or pericardial metastases, given that previous studies involving PET imaging have reported a methodological inability to outline such lesions precisely.(11)

T staging The T staging describes the location, size, and extent of the primary tumor, as well as J Bras Pneumol. 2015;41(3):264-274

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the presence or absence of satellite nodules. In general, the extent of a primary lesion can be properly evaluated with thoracic CT. Occasionally, as in cases in which the lesions show superior sulcus involvement, thoracic wall invasion, or close proximity to the heart and large vessels, magnetic resonance imaging (MRI) of the chest can provide useful complementary information.(8,12) Given its excellent anatomical resolution, CT remains an important modality for T stage assessment, although its ability to evaluate soft tissue invasion or to distinguish primary lesions from post-obstructive atelectasis is fairly limited.

Comparatively, PET imaging provides pertinent data on the metabolic behavior of a lesion, although it is unable to detect microscopic tumor deposits and low-activity nodules (such as adenomas, carcinoid tumors and bronchioloalveolar carcinomas) or to detail important anatomical findings in NSCLC. Nevertheless, PET/CT significantly improves T staging, due to its precise CT correlation with the degree of FDG uptake (Figure 1). Previous studies have demonstrated that integrated PET/ CT provides crucial information on mediastinal infiltration and chest wall invasion, as well as allowing the differentiation between tumor and post-obstructive atelectasis, which can present challenges when the T staging of NSCLC is performed with CT alone.(3,13) Pleural effusion is a relatively common finding in patients with NSCLC, and determining its etiology is decisive for the proper planning of

treatment. In cases in which CT and thoracentesis would lack specificity and sensitivity, respectively, PET/CT can allow a more detailed characterization of pleural effusions. Similarly, in cases of suspicious pleural effusions, MRI studies have also been found to be unable to discriminate benign from malignant causes with desirable accuracy.(3,12) Finally, although it has been hypothesized that SUVmax would correlate with overall survival in patients with NSCLC, it has yet to be proven to be an independent predictor of survival.(3)

N staging The presence of nodal involvement in lung cancer is of great importance, especially in patients with mediastinal disease but no obvious extrathoracic disease, for whom the N stage will have therapeutic and prognostic implications.(8) Patients staged as N0 or N1 (with no metastatic lymph nodes or metastases in only intrapulmonary/hilar nodes) are generally treated with local intervention, whereas patients with N2 disease (with ipsilateral mediastinal lymph node metastases) might benefit from a combination of local and systemic therapies. Patients with N3 disease (with contralateral mediastinal lymph node metastases) are considered incurable and will eventually receive palliative care.(3,14) In daily practice, CT continues to be the most widely used technique for N staging in patients with NSCLC. However, the accuracy of CT imaging for this purpose appears to be

Figure 1 - Thoracic PET/CT scans (left) and a PET scan (right), which were performed for the staging of a 57-year-old female patient diagnosed with non-small cell lung cancer. By combining anatomical details with functional data, PET/CT allows more reliable detection of mediastinal and ipsilateral metastatic disease.

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limited, because it is based on morphological characteristics only. In this context, mediastinal and hilar lymph nodes with a shortest axis diameter greater than 10 mm are habitually described as enlarged. Nevertheless, the distinction between benign and malignant causes of lymph node enlargement is often challenging, making it difficult to determine whether the detected node presents metastatic disease or the enlargement is inflammatory (reactive) in nature. In addition, upon histological examination, even smaller lymph nodes can reveal lung cancer stage progression.(15) Functional scans obtained with FDG-PET not only complement those obtained with conventional modalities but can have greater sensitivity for N staging, given that alterations in tissue metabolism usually precede anatomical changes. However, the poor spatial resolution of PET and the nonspecific tracing of FDG result in inaccuracies, particularly in areas of normal physiological uptake.

It has been suggested that recent technical advances in MRI techniques, such as magnetization transfer imaging, diffusion weighted imaging, and dynamic enhanced imaging, will improve the overall diagnostic accuracy in mediastinal staging in lung cancer. Further investigation is warranted in order to determine whether chest MRI can figure as an alternative or even surpass PET/CT in its ability to detect nodal involvement.

However, previous investigations have pointed out critical advantages of PET/CT over CT and MRI, given the ability of PET/CT to identify neoplastic lymph nodes smaller than 10 mm in diameter.(3,9) Despite producing promising results, PET/ CT imaging has been shown to have a relatively low positive predictive value (PPV). Especially in virtue of that, the method has not yet proven to be a reliable replacement for CT or MRI imaging as a routine procedure; nor can positive PET/CT findings, such as those shown in Figure 2, eliminate the need for invasive procedures (mediastinoscopy sampling, followed by histological analysis). It is worth noting that PPVs always depend on population characteristics; for example, endemic granulomatous diseases and occupational-related lung disorders can lower the PPV of PET/CT. However, in most patients without findings indicative of malignancy, PET/CT can safely obviate sometimes harmful interventions. Nevertheless, PET/CT can occasionally yield false-negative http://dx.doi.org/10.1590/S1806-37132015000004479

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results in cases of low-growth lesions (either primary or metastatic). Some authors refer to this exceptional situation as â&#x20AC;&#x153;minimal N2â&#x20AC;?, taking into account the better prognosis of such cases in comparison with that of other N2 tumors. In addition, the proximity of various mediastinal structures can occasionally diminish tracer uptake in centrally located malignant nodes.(8) However, it should be borne in mind that PET/CT could be crucial in evaluating nodal sites that are typically inaccessible to mediastinoscopy, such as the aortopulmonary window, anterior mediastinum, and posterior subcarinal nodes. In such cases, it might be advisable to conduct further evaluations by following PET/CT with mediastinotomy, transbronchial biopsy, or endoscopic ultrasoundguided fine needle aspiration.

In summary, PET/CT appears to represent the best noninvasive modality for the detection of nodal metastasis. However, mediastinoscopy is still the gold-standard method and should be performed whenever there is uncertainty regarding the status of any one lymph node in patients with NSCLC.

M staging Identification of distant metastases has major implications for management and prognosis of NSCLC, because metastatic disease is present at the time of diagnosis in nearly half of all cases.

In addition, among patients who have received radical and supposedly curative therapy, up to 20% are likely to experience recurrence due to undetected foci of metastasis at M staging.

Metastatic disease in NSCLC patients demonstrates preferences for (in descending order) the brain, bone, liver, and adrenals.(14) The conventional M staging protocol has long included CT scans of the chest and upper abdomen (liver and adrenal gland screening).

When IIIA or IIIB disease occurs, bone scintigraphy and brain imaging (with either CT or MRI) are typically also performed in order to investigate lesions of the bone and central nervous system (CNS), respectively.(3) However, PET/CT imaging has recently shown great utility in the M staging of patients with NSCLC (Figure 3), particularly in those with clinical manifestations of the disease.

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the two modalities yield similar results and have similar limitations.(12) Adrenal masses are present as an initial finding in up to 20% of all patients diagnosed with NSCLC. (8) However, approximately two thirds of such masses are found to be adenomas rather than metastases. Abdominal CT assesses adrenal lesions

Figure 2 - PET/CT axial scan of a 55-year-old male patient, showing two slightly enlarged supraclavicular lymph nodes, which were suspected of malignancy given their hypermetabolic character and location.

Subsequent specimen analyses confirmed the presence of metastatic disease.

A

based on their morphological characteristics and attenuation values, which can lead to debatable conclusions in many situations. The increasing use of MRI of the adrenal glands, especially with the recently developed fat-saturation, chemical shift, and dynamic gadolinium-enhanced techniques, has increased the accuracy of the modality in making the distinction between benign and malignant lesions. For the assessment of adrenal masses, PET/CT has also demonstrated high sensitivity and specificity, which could help avoid unnecessary interventions. Nevertheless, false-negative results are possible due to a partial volume effect in very small (< 1 cm) lesions, as well as to hemorrhage, necrosis, or micrometastases, in which FDG uptake can be decreased. Similarly, benign adrenal adenomas can occasionally display high levels of FDG uptake, producing false-positive results. In light of this, histological confirmation is generally recommended when decisions are to be based solely on adrenal lesions.(8) The most widely adopted imaging tool for diagnosing metastatic bone involvement in patients B

C

Figure 3 - PET/CT assessment allowing the diagnosis of bone metastases (A) and adrenal metastases (B) in a 79-year-old male patient with non-small cell lung cancer. Although such lesions were suggested by PET alone (C), their precise location and delineation could not be determined without the addition of CT.

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with NSCLC is technetium-99m scintigraphy.

It is noteworthy, though, that this method is typically nonspecific, because any hypermetabolic change—such as trauma, arthritis, and degenerative disorders—can cause the method to yield falsepositive results. In addition, because of their minimal tissue reaction, lytic and slow-growing metastases can be missed on scintigraphy. For such metastases, PET/CT demonstrates similar sensitivity but greater specificity than does scintigraphy. However, two main limitations of PET/CT regarding metastatic bone disease must be recognized: its routine acquisition protocol includes only the region from head to pelvis; and it can yield false-negative results in the presence of osteoblastic formations, because bone matrix proliferation tends to reduce the glycolytic activity necessary for contrast uptake.

Another possible mechanism includes the release of antitumor cytokines, which could contribute to inhibiting FDG uptake.(3) Among all of the potential metastatic sites in NSCLC, the liver is the least challenging, from an imaging standpoint, mainly because it is rarely the only site affected. For decades, the standard investigation for liver metastases comprised ultrasonography and CT, although FDG-PET is more accurate than is CT in detecting liver metastases, primarily due to its better specificity. The PET/ CT combination has improved the specificity in detecting liver metastases, although there has been very little gain in sensitivity.(4,6) Therefore, the use of PET/CT for the detection of liver metastases is recommended only in the presence of atypical presentations.

Due to the high glucose uptake rate in normal CNS cells, previous experiences with PET/CT for the investigation of brain lesions indicated that the method had very limited specificity. The use of different tracers, such as 11C-methionine, has been suggested in order to offset this limitation, although additional studies are needed in order to validate the use of such tracers as alternatives to FDG. In contrast, MRI studies of the brain have already achieved greater accuracy than PET/CT, remarkably with the development of novel technical improvements, and are currently the state-of-art noninvasive modality for CNS assessment.

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and small supraclavicular lymph nodes). The benefit of combining conventional CT with PET imaging has been estimated to increase the odds of identifying metastases at those uncommon sites by 5-29%. (12) Nevertheless, the chance of false-positive results in PET studies must be kept in mind, and histological confirmation should therefore routinely be obtained in surgical candidates who were diagnosed with a single atypical lesion.

In summary, the authors understand that the use of PET/CT can significantly contribute to the staging of NSCLC cases, providing crucial information that can have a major impact on the management of several aspects of the disease. In selected cases, the use of PET/CT in the preoperative phase can reduce the number of patients required to undergo thoracentesis and other futile interventions.(16) It should be borne in mind that, although histology continues to provide the most important information regarding the diagnosis of lung cancer, PET/ CT not only can avoid unnecessary procedures but also exhibits great utility when used prior to endobronchial ultrasound, endoscopic ultrasound, or mediastinoscopy.

Radiotherapy and chemotherapy planning It is currently estimated that approximately 75% of all NSCLC patients could benefit from radiotherapy at some point during their treatment. (17-19) For example, in NSCLC patients who are staged as having I-II disease and are not candidates for surgery (because of cardiopulmonary comorbidities or other reasons), radiotherapy is considered the treatment of choice for increasing overall survival rates.(19) The higher diagnostic accuracy provided by PET/CT has had a major impact on the treatment of lung cancer patients undergoing radiotherapy.

That accuracy has improved radiotherapy for lung cancer mainly because it allows the limits of the tumor(s) to be defined with precision, thus preventing mistargeting and the unnecessary irradiation of adjacent structures (Figure 4). For instance, recent studies have demonstrated that the use of PET/CT in the planning of radiotherapy was consistently able to reduce radiation doses for esophageal and pulmonary lesions.(19,20) In addition, the higher sensitivity of FDG-PET (in comparison with CT) in detecting abnormal J Bras Pneumol. 2015;41(3):264-274

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mediastinal lymph nodes has allowed PET/CT to be used in performing target volume delineation using anatomical biological contouring, with even better results.(3) In contrast to its usefulness in radiotherapy, PET/CT has thus far proven to be unreliable in the restaging of patients after neoadjuvant chemotherapy. The proper identification of residual N2 disease following neoadjuvant therapy allows the selection of patients who will most likely benefit from surgery. The mean survival for patients restaged as having N0 disease after neoadjuvant therapy and subsequent resection for N2 NSCLC is 28-30 months, whereas the mean survival for those with residual N2 disease is 9-15 months.

Similarly, in patients with persistent N2 disease, the five-year survival rate ranges from 0% to 19%, compared with 36% to 43% for those in whom the mediastinal involvement is downstaged after neoadjuvant therapy. However, the results of several studies have indicated the need for pathological confirmation of PET/CT findings after neoadjuvant therapy.(17,21,22)

Cost-effectiveness of PET/CT in NSCLC staging The relative superiority of PET/CT over conventional modalities for oncological staging has been reported with increasing frequency. However, whether this method should be widely applied in daily practice remains under debate because of its extremely high cost.(14) In many situations, findings that appear to be pathological on PET/CT A

will require further (invasive) investigation, which will also increase health care system expenditures.

The current costs of PET/CT notwithstanding, some authors believe—based on its potential to inform the decision-making process—that it will increase the life expectancy of and provide other benefits to patients with NSCLC, as well as that it might, in the near future, cut health system expenditures by precluding the need for (invasive or noninvasive) diagnostic procedures.(23,24)

Limitations of PET/CT in NSCLC staging Although PET/CT has proven to be a particularly promising modality in NSCLC staging, several pitfalls must be taken into account when interpreting PET/CT findings.

When the physiological or anatomical registration is imprecise, which most commonly occurs in areas close to the diaphragm or the heart, there can be misregistration artifacts—resulting in misalignment between the CT and PET scans during acquisition. Such discrepancies can allow microlesions to go unnoticed, producing falsenegative results.(7) As a general rule, SUVmax values ≥ 2.5 are considered indicative of malignant processes, whereas tumors showing an SUVmax < 2.5 are more likely to be benign. However, many conditions that increase metabolic activity can lead to increased FDG uptake on PET/CT imaging (Figure 5), thus producing numerous challenging situations. Such conditions include infections (such as tuberculosis and aspergillosis), B

Figure 4 - PET/CT images of a 60-year-old male patient diagnosed with non-small cell lung cancer and undergoing radiotherapy. Although a large mass in the right upper lobe was detected on chest CT imaging (A), the differentiation between the tumor and normal surrounding structures would not have been feasible without the aid of PET/CT (B).

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inflammation (iatrogenic or caused by rheumatoid arthritis or amyloidosis), and even pulmonary infarction. In addition, the physiological uptake of FDG that is typically present in the brain, heart, gastrointestinal tract, genitourinary tract, and striated muscles can occasionally give the impression of increased FDG uptake on PET/ CT imaging, leading to false-positive results.(14) Another cause of false-negative FDG uptake is inherent to the technological limitations of PET/ CT and to the properties of tumor cells. Lesions that measure less than two to three times the spatial resolution of the scanner will usually appear less active due to the partial volume effect. Furthermore, lesions containing few cells, or cells with low metabolic rates, such as highly differentiated tumors, can also create pitfalls in PET/CT interpretation.(8)

SCLC Because of its high metastatic potential, SCLC is considered the most aggressive form of lung cancer. It is estimated that SCLC accounts for approximately 10-15% of all lung cancer cases. The overall prognosis is remarkably severe. Although SCLC is usually chemosensitive in the early stages, most patients with SCLC will experience recurrences that ultimately lead to death. The association with active smoking is as evident as in NSCLC, and nearly all SCLC patients (over 95%) are current or former smokers.(3) Traditionally, SCLC has been divided into two stagesâ&#x20AC;&#x201D;limited disease and extensive diseaseâ&#x20AC;&#x201D;in accordance with the criteria established by the Veterans Administration Lung Group.(25) Limited disease comprises lesions that are confined to one hemithorax, to the mediastinum, and to the supraclavicular lymph nodes. All other presentations, including those with malignant pleural effusion, are categorized as extensive disease. The fact that almost 70% of patients with SCLC are classified as having extensive disease at diagnosis illustrates the significant morbidity of this form of cancer.(13) The poor prognosis of SCLC notwithstanding, tumor staging is quite important in patients with SCLC, because it can increase survival and improve quality of life. Available therapies in SCLC treatment include radiotherapy and chemotherapy regimens, although patients with extensive disease are typically treated with chemotherapy regimens alone. Within this context, the accurate http://dx.doi.org/10.1590/S1806-37132015000004479

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staging of SCLC can also have implications for the periodicity of follow-up evaluations, as well as for the determination of toxicity profiles and the prognostic assessment.(25) The usefulness of PET imaging in SCLC disease staging has been validated, PET findings having been shown to lead to therapeutic modifications in 10-33% of cases.(13) In view of this, the use of PET/CT might allow an even better assessment of SCLC. Patients could benefit from correct PET/CT-based upstaging from limited disease to extensive disease, which would reduce ineffective approaches and prevent unnecessary patient suffering. In addition, on the basis of PET/CT findings, patients with indeterminate M stage could be correctly downstaged from extensive disease to limited disease (or very limited disease) and, in some cases, could be offered potentially curative treatments. Furthermore, the targeted volume during radiotherapy could be more precisely outlined by PET/CT, and that volume could be adapted for additional metastatic sites.(13) Nevertheless, because of high neural glucose consumption, PET/CT has limited diagnostic value in the evaluation of brain metastases. Therefore, in cases of suspected CNS involvement, methionine-PET and MRI are preferable to PET/CT.(3) Moreover, PET/CT might be ineffective in detecting the occurrence of micrometastases, which underscores the recommendation for the use of PET/CT mainly in the early stages of SCLC, when it has the potential to inform decisions regarding the planning and modification of local treatments.

The capacity of PET imaging to assess treatment response has proven to be useful in SCLC, in which most tumors will undergo functional changes before undergoing anatomical changes. There is evidence that PET can detect

Figure 5 - PET/CT scan of the chest, revealing numerous areas of high 18F-fluorodeoxyglucose uptake in a 72-year-old male patient with osteoarthritis. In this case, the greater uptake arose from the abnormal inflammatory status, which led to higher glucose consumption.

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early-stage disease, as well as residual disease in scar tissue or otherwise unsuspicious structures.

In addition, it has been demonstrated that there is a positive relationship between SUVmax values and overall survival rates in SCLC.(3) In view of the fact that the natural history of SCLC indicates an unfavorable prognosis, the prediction/early detection of a response to treatment is crucial and should be always encouraged.(25)

SPNs Many patients with early stage lung cancer will present with an SPN, defined as a single spherical or oval lesion that is less than 3 cm in diameter and is completely surrounded by pulmonary parenchyma without accompanying atelectasis or lymph node enlargement.(2) A very important step in investigating the etiology of an SPN is to determine whether it is benign or malignant in nature. However, the critical dilemma regarding the assessment of SPNs is that they are common, affecting between 0.1% and 0.2% of adults, and it is not always possible to rule out malignancy with conventional CT imaging. For lesions that are greater than 8 mm in diameter, evaluation with PET/CT might be advisable in patients who are at low or moderate risk for malignancy (5-20% and 20-80% of all patients with an SPN, respectively), depending on their radiological characteristics.

In addition, PET/CT could benefit patients at high risk for SPN malignancy, by evaluating the local extent of the mass and detecting distant metastases.(26) Although CT remains an excellent modality for SPN evaluation, given its extremely high sensitivity, its specificity tends to be limited.

The recent introduction of PET/CT imaging into clinical practice has had a positive impact on diagnostic specificity in patients presenting with SPNs, because it provides functional and anatomical data.(27) However, there are a number of pitfalls to be considered during the assessment of SPNs with PET. In patients with inflammatory conditions or infectionsâ&#x20AC;&#x201D;such as bacterial or fungal infections; granulomatous diseases (tuberculosis, sarcoidosis, histoplasmosis, etc.), and pyogenic abscessesâ&#x20AC;&#x201D;there is a greater likelihood of higher metabolic activity due to increased granulocyte or macrophage activity,(27-29) and such comorbidities have become a cause for great concern in some regions of Brazil. Patient body size, patient blood glucose concentration, and the timing of PET acquisition can also hinder the interpretation of J Bras Pneumol. 2015;41(3):264-274

the results. Therefore, PET results for patients with uncontrolled diabetes or very poor clinical status can be especially difficult to interpret. In addition, PET can yield false-negative results due to the relatively limited spatial resolution of PET cameras, which is currently up to approximately 7-8 mm. Consequently, the metabolic activity level of smaller masses must be relatively high in order to become evident on PET imaging, and lesions < 1 cm in diameter or demonstrating low metabolic activity can occasionally be missed by PET scans.(2)

Newer directions in tracers: beyond FDG Because PET/CT is now an established modality in the management of lung cancer, novel radiopharmaceuticals have been widely investigated, in various aspects of tumor biology, in order to broaden the applications for and accuracy of this imaging method. Improvements include the increasingly widespread use of 18F-fluorothymidine, which is considered to be even more sensitive than is standard 18F-FDG for evaluating early treatment responses. Other tracers have been found to provide information regarding various conditions and processes, including hypoxia (18F-fluoromisonidazole and 64Cu-ATSM), angiogenesis (RGD peptides), amino acid metabolism (11C-methionine), and choline metabolism (11C-choline and 18F-fluorocholine).

An additional matter of interest is the noninvasive analysis (with PET imaging) of epidermal growth factor receptor (EGFR) and EGFR tyrosine kinase overexpression in tumors. Albeit quite infrequently, the suspicion of such tumors can occasionally be raised by the presence of isolated pleural effusion or miliary metastases. (14,30) It has been demonstrated that PET has the potential for in vivo, a priori determination of EGFRtargeted drug efficacy. The newly developed tracers described above might provide better insight into tumor behavior and therapy-related toxicity, thereby facilitating the formulation of individualized treatment strategies. However, the incipient results will require further corroboration before being applicable to daily practice.(22)

Final considerations The use of PET/CT scans has become a reliable tool that can complement and sometimes take http://dx.doi.org/10.1590/S1806-37132015000004479

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the place of conventional imaging modalities in the radiological assessment of lung cancer. The most widely employed radiotracer, 18F-FDG, provides critical information about the biological aggressiveness of a tumor and the corresponding prognosis. Particular attention is advised when using PET/CT in the investigation of diabetic patients, as well as in regions where there is high prevalence of infectious and inflammatory conditions. For NSCLC and SCLC, PET/CT has revolutionized staging and the planning of treatment. Nevertheless, radiologists and pulmonologists should become familiar with the potential pitfalls that they might encounter in their interpretation of PET/CT findings.

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2010;27(8):e47-53. http://dx.doi.org/10.1016/j. rmr.2009.12.003 12. Sahiner I, Vural GU. Positron emission tomography/ computerized tomography in lung cancer. Quant Imaging Med Surg. 2014;4(3):195-206. http://dx.doi.org/10.3978/j. issn.2223-4292.2014.03.05 13. Hellwig D, Baum RP, Kirsch C. FDG-PET, PET/CT and conventional nuclear medicine procedures in the evaluation of lung cancer: a systematic review. Nuklearmedizin.

2009;48(2):59-69. http://dx.doi.org/10.3413/nukmed-0217 14. Rankin S. PET/CT for staging and monitoring non small cell lung cancer. Cancer Imaging. 2008;8 Spec No A:S27-31.

15. Nomori H, Ohba Y, Yoshimoto K, Shibata H, Shiraishi K, Mori T. Positron emission tomography in lung cancer.

Gen Thorac Cardiovasc Surg. 2009;57(4):184-91. http:// dx.doi.org/10.1007/s11748-008-0371-3 16. Taus Á, Aguiló R, Curull V, Suárez-Piñera M, RodríguezFuster A, Rodríguez de Dios N, et al. Impact of 18F-FDG PET/CT in the treatment of patients with non-small cell lung cancer. Arch Bronconeumol. 2014;50(3):99-104. http://dx.doi.org/10.1016/j.arbres.2013.09.017 17. Broderick SR, Patterson GA. Performance of integrated positron emission tomography/computed tomography for mediastinal nodal staging in non-small cell lung carcinoma. Thorac Surg Clin. 2013;23(2):193-8. http:// dx.doi.org/10.1016/j.thorsurg.2013.01.014 18. Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG, et al. Non-small-cell lung cancer. Lancet.

2011;378(9804):1727-40. http://dx.doi.org/10.1016/ S0140-6736(10)62101-0 19. De Ruysscher D, Nestle U, Jeraj R, Macmanus M. PET scans in radiotherapy planning of lung cancer. Lung Cancer. 2012;75(2):141-5. http://dx.doi.org/10.1016/j. lungcan.2011.07.018 20. Zheng Y, Sun X, Wang J, Zhang L, DI X, Xu Y. FDG-PET/ CT imaging for tumor staging and definition of tumor volumes in radiation treatment planning in non-small cell lung cancer. Oncol Lett. 2014;7(4):1015-20. http:// dx.doi.org/10.3892/ol.2014.1874 21. Skoura E, Datseris IE, Platis I, Oikonomopoulos G, Syrigos KN. Role of positron emission tomography in the early prediction of response to chemotherapy in patients with non--small-cell lung cancer. Clin Lung Cancer. 2012;13(3):181-7. http://dx.doi.org/10.1016/j. cllc.2011.05.004 22. Behzadi A, Ung Y, Lowe V, Deschamps C. The role of positron emission tomography in the management of non-small cell lung cancer. Can J Surg. 2009;52(3):235-42.

23. Langer A. A systematic review of PET and PET/CT in oncology: a way to personalize cancer treatment in a cost-effective manner? BMC Health Serv Res. 2010;10:283. http://dx.doi.org/10.1186/1472-6963-10-283 24. Cao JQ, Rodrigues GB, Louie AV, Zaric GS. Systematic review of the cost-effectiveness of positron-emission tomography in staging of non--small-cell lung cancer and management of solitary pulmonary nodules. Clin Lung Cancer. 2012;13(3):161-70. http://dx.doi.org/10.1016/j. cllc.2011.09.002 25. Joyce EA, Kavanagh J, Sheehy N, Beddy P, O’Keeffe SA. Imaging features of extrapulmonary small cell carcinoma.

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http://dx.doi.org/10.1590/S1806-37132015000004479

Case Series Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations* Uso de sirolimo no tratamento de linfangioleiomiomatose: resposta favorável em pacientes com diferentes manifestações extrapulmonares

Carolina Salim Gonçalves Freitas1, Bruno Guedes Baldi2, Mariana Sponholz Araújo1, Glaucia Itamaro Heiden1, Ronaldo Adib Kairalla3, Carlos Roberto Ribeiro Carvalho4

Abstract Objective: Lymphangioleiomyomatosis (LAM) is a rare disease that is currently considered a low-grade neoplasm with metastatic potential and variable progression. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have recently become a treatment option for LAM patients, especially those with extrapulmonary manifestations. The objective of the present study was to describe a case series of four patients with LAM in Brazil who showed significant improvement, particularly in their extrapulmonary manifestations, after treatment with sirolimus (at 1-4 mg/day). Methods: We describe four cases of LAM patients with different extrapulmonary manifestations who were treated with sirolimus. Results: After treatment with sirolimus for 12 months, one patient presented resolution of severe chylothorax; one had a significant reduction in renal angiomyolipoma volume; and one showed significant regression of retroperitoneal lymphangioleiomyomas and abdominal lymph node enlargement. After treatment with sirolimus for 6 months, the remaining patient had a significant reduction in the volume of a massive retroperitoneal lymphangioleiomyoma. Conclusions: Our findings confirm that mTOR inhibitors are beneficial for patients with LAM, especially those with extrapulmonary manifestations, such as renal angiomyolipoma, lymphangioleiomyomas, and chylous effusions. However, certain aspects, such as the optimal dose, duration of treatment, and long-term adverse effects, have yet to be sufficiently clarified for mTOR inhibitors to be incorporated into LAM management protocols.

Keywords: Neoplasms; Lymphangioleiomyomatosis/therapy; TOR serine-threonine kinases; Sirolimus.

Introduction Lymphangioleiomyomatosis (LAM) is a rare disease of unknown etiology. It primarily affects women of childbearing age, and the prevalence of LAM is approximately 1/1,000,000 population.

It can occur in isolation or in association with tuberous sclerosis complex (TSC).(1-3) The disease is characterized by proliferation of atypical cells

(LAM cells) with characteristics of low-grade neoplasm and metastatic potential, leading to vascular and bronchial obstruction and cyst formation.(4-8) Major clinical manifestations of LAM include progressive dyspnea on exertion, dry cough, recurrent spontaneous pneumothorax, chylothorax,

1. Collaborating Physician. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

2. Attending Physician. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

3. Associate Professor. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

4. Full Professor. Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil. *Study carried out in the Department of Pulmonology, Instituto do Coração – InCor, Heart Institute – University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

Correspondence to: Carolina Salim Gonçalves Freitas. Divisão de Pneumologia, Instituto do Coração – InCor – Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Enéas de Carvalho Aguiar, 44, 8o andar, bloco 2, CEP 05403-900, São Paulo, SP, Brasil.

Tel. 55 11 2661-5191. Fax: 55 11 2661-5695. E-mail: carolinasalim@gmail.com Financial support: None.

Submitted: 13 January 2015. Accepted, after review: 8 April 2015.

http://dx.doi.org/10.1590/S1806-37132015000004553

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and hemoptysis.(1,3,9) Renal angiomyolipomas and lymphangioleiomyomas can occur. A CT scan of the chest typically shows the presence of diffuse, well-defined, thin-walled lung cysts. Although pulmonary function test results can be normal, variable and progressive lung function decline can occur over time. Reduced DLCO is the most common change, and spirometry most commonly reveals airflow obstruction and air trapping; bronchodilator test results can be positive in up to 25% of cases.(10-12) A definitive diagnosis of LAM is based on the following(3,6): • typical chest HRCT findings, i.e., diffuse, well-defined lung cysts, in association with renal angiomyolipoma, pleural effusion/ chylous ascites, lymphangioleiomyoma/ lymph node involvement, or a definite or probable diagnosis of TSC • presence of lung cysts consistent with LAM on chest HRCT scans and pathological findings of LAM in a lung tissue sample preferably obtained by surgical biopsy Determination of serum levels of VEGF-D, which is a marker of lymphangiogenesis, has been increasingly used in order to aid in the diagnosis of LAM and to evaluate disease progression. Chest CT findings consistent with LAM associated with elevated VEGF-D levels are currently considered to be sufficient for the diagnosis of LAM.(13,14) The progression of LAM is highly variable, ranging from asymptomatic patients to patients with progressive respiratory failure requiring lung transplantation. Survival has been shown to be better in recent studies than in previous studies; a recent study conducted in Brazil showed a five-year survival of 90%.(15) Various drugs have been used in an attempt to control LAM. Matrix metalloproteinase inhibitors, such as doxycycline, and hormonal blockade have yielded controversial results and are not recommended for the treatment of LAM.(16-19) Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, are promising in the treatment of LAM, particularly in improving extrapulmonary manifestations and stabilizing or even improving lung function.(20,21) The objective of the present study was to describe a case series of patients with LAM in Brazil treated with sirolimus, which had positive effects, particularly on extrapulmonary manifestations.

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Case series Of a total of 10 patients with LAM treated with sirolimus at our center during the study period, we describe four cases of patients in whom the drug was primarily used because of extrapulmonary involvement.

Case 1 A 48-year-old smoker (with a smoking history of 15 pack-years) was admitted with a two-year history of dyspnea, which had worsened one week prior. She reported no other diseases. The patient reported that she had undergone oophorectomy nine years prior because of a benign tumor and right nephrectomy six months prior because of renal angiomyolipoma. She had no relevant exposure history. Physical examination revealed that the patient had lost weight, breath sounds being absent in the right hemithorax and her SpO2 being 92% on room air. A chest X-ray showed a large right pleural effusion (Figure 1). The patient underwent thoracentesis, and a diagnosis of chylothorax was established. A pulmonary function test performed after chest tube drainage showed an FVC of 3.12 L (100% of predicted), an FEV1 of 1.95 L (75% of predicted), an FEV1/FVC ratio of 0.62, a TLC of 5.27 L (92% of predicted), and a DLCO of 15.41 mL/min/ mmHg (65% of predicted; Table 1). A chest CT scan showed diffuse, well-defined lung cysts.

Her dyspnea worsened, and she presented with difficult-to-manage chylothorax, with a high output from the chest tube despite treatment with total parenteral nutrition. A decision was made to treat her with sirolimus (at 1 mg/day).

Resolution of the chylothorax and functional stability were observed after 12 months of treatment (Figure 1 and Table 1).

Case 2 A 25-year-old patient diagnosed with LAM and TSC presented with a two-year history of recurrent pneumothorax and pleurodesis. She reported no smoking and had no relevant exposure history. Because of the neurological impairment associated with TSC, the patient had frequent convulsive seizures and a cognitive deficit. She also had large bilateral renal angiomyolipomas and had previously undergone a right partial nephrectomy because of hemorrhage. She had http://dx.doi.org/10.1590/S1806-37132015000004553

Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

A

277

B

Figure 1 - Chest X-rays taken before treatment with sirolimus (in A) and after 12 months of treatment with the drug (in B), showing resolution of chylothorax.

Table 1 - Pulmonary function test results before and after treatment with sirolimus.a Case FVC FEV1 DLCO pre-treatment post-treatment pre-treatment post-treatment pre-treatment post-treatment 1 3.12 (100) 3.22 (103) 1.95 (75) 2.0 (77) 15.41 (65)b 17.54 (74)b 3 2.36 (61) 3.53 (91) 1.49 (46) 2.02 (62) 4 3.96 (90) 3.92 (89) 3.37 (89) 3.4 (90) 20.12 (98)b 20.4 (99)b Values expressed as L (% of predicted), except where otherwise indicated. bValues expressed as mL/min/mmHg (% of predicted). a

been using goserelin and doxycycline since 2010, and the renal tumor had progressively increased in the last two years. A decision was made to treat her with sirolimus, initially at 6 mg/day and subsequently at 2 mg/day because of nausea and vomiting. After 12 months of treatment, there was a significant reduction in the size of the angiomyolipoma (from approximately 20 cm, with confluent masses, to approximately 3 cm; Figure 2). Because of her cognitive deficit, the patient did not undergo pulmonary function testing.

enlargement. A diagnosis of LAM was established, and initial pulmonary function test results were as follows: FVC, 2.36 L (61% of predicted); FEV1, 1.49 L (46% of predicted); and FEV1/FVC, 0.63.

The patient was started on sirolimus (at 2 mg/ day) and after 12 months of treatment with the drug showed significant regression of the retroperitoneal and abdominal masses (Figure 3), as well as improved lung function (Table 1).

Case 3

A 37-year-old nonsmoker presented with diffuse abdominal pain. The patient had no respiratory symptoms, relevant exposure history, or associated diseases. During the investigation, a large, heterogeneous retroperitoneal mass of approximately 18 cm in size was identified. A biopsy was performed, and the mass was diagnosed as a lymphangioleiomyoma. A chest CT scan showed diffuse cysts in the lung parenchyma, whereas pulmonary function test results, including DLCO, were normal (Table 1). The patient was started

A 26-year-old nonsmoker with a three-year history of dyspnea on exertion presented with acute worsening of dyspnea. Although a large chylothorax was identified in 2011, it was not investigated at the time. One year later, the patient was admitted for investigation. Chest and abdominal CT scans showed diffuse cysts in the lung parenchyma, as well as large retroperitoneal lymphangioleiomyomas and abdominal lymph node http://dx.doi.org/10.1590/S1806-37132015000004553

Case 4

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A

B

Figure 2 - Abdominal CT scans taken before treatment with sirolimus (in A) and after 12 months of treatment with the drug (in B), showing a reduction in bilateral renal angiomyolipoma volume.

A

B

Figure 3 - Abdominal CT scans taken before treatment with sirolimus (in A) and after 12 months of treatment with the drug (in B), showing a significant reduction in retroperitoneal lymphangioleiomyoma volume (white arrow).

A

B

Figure 4 - Abdominal CT scans taken before treatment with sirolimus (in A) and after 6 months of treatment with the drug (in B), showing resolution of an abdominal lymphangioleiomyoma (white arrow).

on sirolimus (at 2 mg/day) because of the size of the mass, which was symptomatic and posed a risk of hemorrhage. After 6 months of treatment with the drug, there was a significant reduction in lymphangioleiomyoma volume (Figure 4).

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Discussion In the four cases of patients with LAM described above, the use of sirolimus (at 1-6 mg/day) had positive effects, particularly on http://dx.doi.org/10.1590/S1806-37132015000004553

Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

extrapulmonary manifestations, including a reduction in renal angiomyolipoma volume, abdominal mass volume, and retroperitoneal mass volume, as well as resolution of chylothorax.

On the basis of the various mechanisms involved in the pathophysiology of LAM, several drugs have been used in an attempt to control the disease.

Although doxycycline blocks metalloproteinases, it is currently not recommended, because a recent randomized study showed that it had no effect on lung function.(16,17) Hormonal blockade with the use of progesterone and gonadotropin-releasing hormone analogs has yielded controversial results and is currently not recommended.(18,19) Mutations in the TSC1 and TSC2 genes, which can be found in patients with LAM, are associated with deregulation and hyperactivation of the mTOR pathway, which controls protein synthesis and cell growth. Inhibitors of mTOR inhibit T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation, binding to the FKBP-12 protein to form an immunosuppressive complex. This complex binds to mTOR, an important regulatory kinase, inhibiting its activity and ultimately blocking cell proliferation.

Recent evidence has shown that mTOR inhibitors are promising options for patients with LAM and can be used in cases of large renal angiomyolipomas and lymphangioleiomyomas, as well as in the control of chylothorax and chylous ascites; in addition, mTOR inhibitors have beneficial effects on lung function, particularly in patients with a rapid decline in respiratory capacity and mild to moderate airflow limitation,(20,22) as observed in our case series.

Although the use of sirolimus in patients with LAM is promising, certain issues have yet to be clarified, including the need for determining serum levels of the drug (as is done in kidney or lung transplant recipients, for example), treatment duration, and long-term treatment safety. Recent studies have shown that it is possible to use sirolimus at lower doses in order to reduce adverse effects without compromising treatment efficacy. (23) Doses of 1-2 mg/day are habitually used; however, in cases of large renal angiomyolipomas, higher initial doses can be used.

A study by Yao et al. showed that the favorable effects of sirolimus on lung function remained after long-term treatment (approximately three and a half years) and that although adverse effects http://dx.doi.org/10.1590/S1806-37132015000004553

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are common, including hypercholesterolemia, increased respiratory tract infections, diarrhea, and stomatitis, as well as acne and other skin disorders, they are usually mild and do not result in treatment discontinuation.(24) However, the risk of recurrence after treatment discontinuation has yet to be determined.

Inhibitors of mTOR have become an important treatment option for selected cases of patients with LAM, especially those with significant extrapulmonary manifestations, such as renal angiomyolipomas, lymphangioleiomyomas, and chylous effusions. However, certain issues (such as the optimal dose and duration of treatment) have yet to be investigated in prospective studies for mTOR inhibitors to be permanently incorporated into LAM management protocols.

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Am J Respir Crit Care Med. 2012;186(4):341-8. http:// dx.doi.org/10.1164/rccm.201203-0372OC 13. Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest. 2009;135(5):1293-300. http:// dx.doi.org/10.1378/chest.08-1160 14. Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases.

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Case Report Formation of multiple pulmonary nodules during treatment with leflunomide* Formação de múltiplos nódulos pulmonares durante tratamento com leflunomida

Gilberto Toshikawa Yoshikawa1, George Alberto da Silva Dias1, Satomi Fujihara1, Luigi Ferreira e Silva2, Lorena de Britto Pereira Cruz3, Hellen Thais Fuzii4, Roberta Vilela Lopes Koyama1

Abstract Pulmonary involvement is one of the extra-articular manifestations of rheumatoid arthritis and can be due to the disease itself or secondary to the medications used in order to treat it. We report the case of a 60-year-old woman who had been diagnosed with rheumatoid arthritis and developed multiple pulmonary nodules during treatment with leflunomide.

Keywords: Arthritis, rheumatoid; Immunosuppressive agents; Rheumatoid nodule; Lung.

Introduction Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology that is characterized by symmetric polyarthritis and can lead to joint deformity and destruction.(1,2) When RA involves other organs besides the joints, there is an increase in morbidity and severity, and life expectancy can be reduced by 5 to 10 years.(1) Pulmonary involvement in RA was first described by Ellman and Ball,(3) who reported diffuse pulmonary fibrosis in three patients with RA. Since then, the association between pulmonary involvement and RA has been described by several authors. The risk factors for pulmonary involvement include middle age, male gender, severe erosive arthritis, high titers of rheumatoid factor, subcutaneous nodules, smoking, genetic predisposition (HLA-DRB1), and other extraarticular manifestations of RA.(4,5) Pulmonary involvement is a severe complication of RA and can manifest as upper airway disease, interstitial lung disease, pleural effusion, bronchiolitis obliterans, fibrosing alveolitis, pulmonary rheumatoid nodules, bronchiectasis,

Caplan syndrome, pulmonary hemorrhage, organizing pneumonia, vasculitis, and pulmonary infections.(6-9)

Case report A 60-year-old White female librarian, who had been born and raised in the city of Belém, Brazil, presented with an approximately 10-year-history of RA, as defined on the basis of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. At the time of diagnosis, she was started on methotrexate, the dose of which was progressively increased to 15 mg/week. Subsequently, methotrexate was discontinued because of gastrointestinal intolerance, and, at that time, it was decided to start the patient on leflunomide (20 mg/day) and deflazacort (12 mg/day). During the treatment period, the patient had joint improvement and, on her own initiative, reduced her leflunomide dose from 20 mg/day to 20 mg/every other day.

A chest X-ray performed 8 years previously to screen the patient for fractures after chest trauma

1. Senior Assistant Professor. Federal University of Pará, Belém, Brazil.

2. Medical Student. Federal University of Pará, Belém, Brazil.

3. Junior Assistant Professor. Federal University of Pará, Belém, Brazil.

4. Adjunct Professor II. Federal University of Pará, Belém, Brazil. *Study carried out at the Federal University of Pará, Belém, Brazil.

Correspondence to: Gilberto Yoshikawa. Avenida Senador Lemos, 443, Edifício Village Executive, sala 908/909, CEP 66050-000, Belém, PA, Brasil.

Tel. 55 91 3241-7905. E-mail: gyoshikawa@uol.com.br Financial support: None.

Submitted: 8 May 2014. Accepted, after review: 24 November 2014.

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had shown a pulmonary nodule in the right lung base. A chest X-ray performed before the patient was started on leflunomide had been normal. On that basis, the patient sought a pulmonologist, who requested further investigation. The results of the ancillary tests were as follows: blood workup, no changes; ESR, 65 mm/h; levels of transaminase and nitrogenous compounds, normal; antinuclear factor, negative; PCR, 6.2 mg/L; serology for viral hepatitis, negative; rheumatoid factor, positive (443 IU/mL); perinuclear and cytoplasmic antineutrophil cytoplasmic antibody (p-ANCA and c-ANCA), negative on several occasions; bronchoscopy results, normal; BAL microscopy, negative for bacteria; BAL cultures, negative; and BAL cytology, low cellularity and autolytic pattern. A CT scan of the chest showed multiple cavitary pulmonary nodules predominantly in the left lung base (Figure 1). A biopsy of a peripheral nodule revealed an acute suppurative inflammatory process with necrosis. At the time, it was decided that the patient should undergo clinical and radiological follow-up.

After a five-month follow-up of the pulmonary nodules, the patient developed dyspnea on exertion accompanied by dry cough, but no fever. Another bronchoscopy revealed laryngitis and a nodule on the right vocal fold. The tracheobronchial tree was endoscopically normal; BAL was negative for AFB, BAL microscopy revealed gram-negative bacilli (Klebsiella pneumoniae and Pseudomonas fluorescens were isolated by using an automated culture system), BAL cultures for mycobacteria and fungi were negative, and BAL cytology revealed no neoplastic cells. At that time, the patient was started on antibiotic therapy with clindamycin

Figure 1 - CT scan of the chest showing cavitary nodular opacities.

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and fluconazole. After bronchoscopy showed negative BAL fluid cultures, prednisone (40 mg/ day) was commenced in an attempt to stabilize her condition. However, despite the therapeutic approach used, another CT scan of the chest revealed increased pulmonary nodules (Figure 2). At that point, the patient was referred to the city of S達o Paulo, Brazil, for evaluation.

A lung biopsy (Figure 3) by video-assisted thoracoscopy showed a chronic inflammatory lesion, with an exudative center, adjacent to the lung parenchyma (disrupted by lymphocytic vasculitis), as well as a central cavitation filled with fibrinoleukocytic exudate and a lymphocytic infiltrate surrounded by granulation tissue. The results of AFB and fungal testing were negative, as was the result of neoplastic cell testing. In view of this result, which ruled out neoplastic and infectious disease, it was decided to discontinue leflunomide. Systemic corticosteroid therapy was continued, and azathioprine (1 mg/kg/day) was commenced. Six months after leflunomide was discontinued, the pulmonary nodules disappeared.

At this writing, the patient was free of disease activity, was taking abatacept (500 mg/month), and had been off systemic corticosteroid therapy for over a year.

Discussion Pulmonary rheumatoid nodules are extraarticular manifestations of RA.(2,4) The prevalence of these nodules is variable: they are detected on chest X-ray in only 1% of RA patients, whereas they

Figure 2 - CT scan of the chest showing a nodular opacity adjacent to the pleural surface, located in the right lower lobe.

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Formation of multiple pulmonary nodules during treatment with leflunomide

A

283

B

Figure 3 - Lung biopsy. In A, fibrin and collagen deposition (red arrow) surrounded by cell debris (dark arrow), with an area of necrosis. In B, inflammatory infiltrate with multinucleated cells (dark arrow) and central necrosis.

are identified on chest HRCT in up to 20-22% and are detected by open lung biopsy in 32%.(7,10-12) Pulmonary rheumatoid nodules can be single or multiple and range from a few millimeters to 7 cm in diameter. They are mostly asymptomatic or produce few symptoms, although they can cause cough and bloodstained sputum, and tend to involve both lungs. They occur at the periphery of the lung, just beneath the pleura, and can cavitate in approximately one third of cases, causing hemoptysis, bronchopleural fistula, spontaneous pneumothorax, secondary infection, and abscess.(4,10,13) The appearance of pulmonary nodules in RA patients is a diagnostic problem, and the possibilities of malignancy and tuberculosis should be ruled out.(10,13) Nodules due to lung cancer are characteristically greater than 10 mm in diameter and have irregular borders. Metastases can also appear as multiple nodules in the lungs; however, no primary cancer was found in the case reported here.(11,12,14) Other diagnostic possibilities include mycobacterial and fungal infections, which can manifest as nodules; however, the absence of systemic symptoms is rare.(11) A relevant aspect in the case reported here is that the pulmonary nodules were likely related to the use of leflunomide, since there are several arguments in favor of this hypothesis: the patient in question had a long-term history of RA and had shown no signs of pulmonary involvement prior to treatment with leflunomide; pulmonary http://dx.doi.org/10.1590/S1806-37132015000004247

rheumatoid nodules can appear during treatment with leflunomide; and there have been reports of peripheral and/or pulmonary rheumatoid nodules in patients undergoing treatment with leflunomide.(8,15,16)

References 1. Zhu H, Deng FY, Mo XB, Qiu YH, Lei SF. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update. Pharmacogenomics. 2014;15(4):551-66. http:// dx.doi.org/10.2217/pgs.14.25 2. Atzeni F, Boiardi L, Sall矛 S, Benucci M, Sarzi-Puttini P. Lung involvement and drug-induced lung disease in patients with rheumatoid arthritis. Expert Rev Clin Immunol. 2013;9(7):649-57. http://dx.doi.org/10.158 6/1744666X.2013.811173 3. Ellman P, Ball RE. Rheumatoid disease with joint and pulmonary manifestations. Br Med J. 1948;2(4583):81620. http://dx.doi.org/10.1136/bmj.2.4583.816 4. Chanin K, Vallejo-Manzur F, Sternbach GL, Fromm R, Varon J. Pulmonary manifestations of rheumatoid arthritis. Hosp Physician. 2001;37(7):23-8.

5. van Ede A, den Broeder A, Wagenaar M, van Riel P, Creemers MC. Etanercept-related extensive pulmonary nodulosis in a patient with rheumatoid arthritis. J Rheumatol. 2007;34(7):1590-2.

6. Karadag F, Polatli M, Senturk T, Kacar F, Sen S, Cildag O. Cavitary necrobiotic nodule imitating malignant lung disease in a patient without articular manifestations of rheumatoid arthritis. J Clin Rheumatol. 2003;9(4):246-52. http://dx.doi.org/10.1097/01.rhu.0000081260.50171.bf 7. Dawson JK, Graham DR, Lynch MP. Lung disease in patients with rheumatoid arthritis. CPD Rheumatol.

2002;3(2):38-42.

8. Gauhar UA, Gaffo AL, Alarc贸n GS. Pulmonary manifestations of rheumatoid arthritis. Semin Respir

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Crit Care Med. 2007;28(4):430-40. http://dx.doi. org/10.1055/s-2007-985664 9. Rosa DJ, Paula EA, Bonfante HLM, Bonfante HL, Areal CE, Baião GS, et al. Accelerated nodulosis in rheumatoid arthritis during Leflunomide therapy [Article in Portuguese].

Rev Bras Reumatol. 2007;47(3):228-31. http://dx.doi. org/10.1590/S0482-50042007000300015 10. Burke GW, Carrington CB, Grinnan R. Pulmonary nodules and rheumatoid factor in the absence of arthritis.

Chest. 1977;72(4):538-40. http://dx.doi.org/10.1378/ chest.72.4.538 11. Espinoza-Poblano E, Betancourt-Hernández L, CanizalesCobos M, Careaga-Reyna G, Esparza-Pantoja J. Nódulos pulmonares necrobióticos en ausencia de artritis reumatoide. Reporte de un caso. Neumol Cir Torax.

2000;59(4):109-11.

12. Case records of the Massachusetts General Hospital.

Weekly clinicopathological exercises. Case 10-2001. A

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53-year-old woman with arthritis and pulmonary nodules.

N Engl J Med. 2001;344(13):997-1004. http://dx.doi. org/10.1056/NEJM200103293441308 13. Kairalla RA. Manifestações pulmonares das doenças do tecido conectivo (DTC). In: Zamboni M, Pereira CAC, editors. Pneumologia - Diagnóstico e Tratamento. vol.1.

São Paulo: Editora Atheneu; 2006. p. 235-44.

14. Alušík Š, Fanta J, Eis V, Mandys V, Pavlicek J. Formation of rheumatoid pulmonary nodules during the leflunomide treatment. Case Rep Clin Pract Rev. 2006;7(2):139-42.

15. Yachoui R, Ward C, Kreidy M. A rheumatoid nodule in an unusual location: mediastinal lymph node. BMJ Case Rep. 2013;2013. pii: bcr2013009516.

16. Rozin A, Yigla M, Guralnik L, Keidar Z, Vlodavsky E, Rozenbaum M, et al. Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy. Clin Rheumatol. 2006;25(3):384-8. http://dx.doi.org/10.1007/ s10067-005-0024-1

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Images in Pulmonary Medicine Intracavitary pulmonary aspergilloma: endoscopic aspects Aspergiloma pulmonar intracavitário: aspectos endoscópicos

Evelise Lima1, André Louis Lobo Nagy1, Rodrigo Abensur Athanazio2 A

B

C

D

Figure 1 - In A, CT scan of the chest showing an intracavitary mass suggestive of fungus ball. In B, right upper lobe orifice showing destruction of the architecture of the apical segment. In C and D, a whitish intracavitary mass with areas of necrosis and an endoscopic appearance suggestive of fungal infection.

A 49-year-old female patient presented with a diagnosis of parathyroid carcinoma that had been made in 2007. She underwent surgical treatment and chemotherapy.

Five years later, the patient developed cough and fever. A CT scan of the chest revealed a thin-walled cavitary lesion in the right upper lobe. Bronchoscopy with transbronchial biopsy confirmed the diagnosis of pulmonary metastasis. After radioablation therapy, the patient developed cavitary sequelae that were followed up radiologically.

A follow-up CT scan of the chest obtained in 2013 revealed an increase in the size of the cavitary lesion, thickening of its walls, and an intracavitary image suggestive of fungus ball.

The patient underwent a second bronchoscopy, which showed structural change in the apical

segment of the right upper lobe, with a large cavity containing an extensive, whitish, exophytic, irregular mass.

Biopsies and bronchoalveolar lavage were performed that confirmed the diagnosis of infection with Aspergillus fumigatus.

The patient was started on oral antifungal treatment and began outpatient follow-up treatment.

Aspergillosis is a multifaceted disease whose clinical manifestations (allergic, saprophytic, and invasive forms) are determined by the host immune response.

Invasive pulmonary aspergillosis has emerged as an infectious disease of high morbidity and mortality in immunocompromised patients and should be treated early. Voriconazole is recommended as the treatment of choice.

In some cases, there can be extensive destruction of the parenchymal architecture, allowing communication with the central airway and enabling endoscopic intracavitary visualization.

However, this is an extremely rare finding. In the literature, case reports are limited to patients with endobronchial aspergilloma. Endoscopically, whitish necrotic masses suggest fungal infection.

However, the diagnosis should be confirmed via histopathological documentation and positive culture.

Recommended reading 1. Schweer KE, Bangard C, Hekmat K, Cornely OA. Chronic pulmonary aspergillosis. Mycoses. 2014;57(5):257-70. http://dx.doi.org/10.1111/myc.12152 2. Patterson KC, Strek ME. Diagnosis and treatment of pulmonary aspergillosis syndromes. Chest.

2014;146(5):1358-68. http://dx.doi.org/10.1378/ chest.14-0917 3. Ma JE, Yun EY, Kim YE, Lee GD, Cho YJ, Jeong YY, et al. Endobronchial aspergilloma: report of 10 cases and literature review. Yonsei Med J. 2011;52(5):787-92. http://dx.doi.org/10.3349/ymj.2011.52.5.787

1. Attending Physician. Department of Respiratory Endoscopy, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

2. Attending Physician. Department of Pulmonology, Heart Institute, University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.

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Letter to the Editor Reversed halo sign in acute schistosomiasis Sinal do halo invertido em esquistossomose aguda

Arthur Soares Souza Jr.1, Antonio Soares Souza2, Luciana Soares-Souza3, Gláucia Zanetti4, Edson Marchiori5

To the Editor: A 35-year-old rural worker presented with a 15-day history of progressive dyspnea, which, for the last 5 days, had been accompanied by dry cough, myalgia, asthenia, and fever. The patient also mentioned that he had swum in natural waters within the last 20 days. Physical examination showed mild painful hepatomegaly and splenomegaly. Chest X-rays showed bilateral reticulonodular infiltrates. An HRCT scan revealed patchy areas of ground-glass attenuation, irregular interlobular septal thickening, intralobular interstitial thickening, and small confluent nodules. Nodular reversed halos (focal, rounded areas of ground-glass opacity surrounded by more or less complete rings of consolidation) were also observed in the lower lobes of the lungs (Figure 1).

Blood tests showed leukocytosis with eosinophilia. Bronchoalveolar lavage findings were negative. The patient underwent open lung biopsy. Histological examination of the biopsy sample demonstrated areas of parenchymal granulomatous inflammation, with clusters of epithelioid histiocytes, giant cells, and some eosinophils. In addition, those areas were surrounded by chronic inflammatory cell infiltrate and numerous schistosome ova (Figure 2). The final diagnosis was acute schistosomiasis.

The patient was treated with thiabendazole and oxamniquine, showing improvement of the clinical and imaging findings over the following days. Another HRCT scan, obtained four months after treatment, showed no abnormalities.

Schistosomiasis is a major helminthic infection in tropical and subtropical regions; it has affected

an estimated 200 million people, resulting in considerable morbidity and occasional mortality.(1-3) In such regions, native populations and travelers are at risk of infection with Schistosoma spp.(2) The infection is acquired through direct contact with contaminated freshwater.(2) The spread of infection requires an intermediate host—freshwater snails specific to each Schistosoma species—whose geographic distribution limits the distribution of the parasite.(3) Humans are colonized by three major species of the parasite(1): S. mansoni, common in Africa, the Middle East, and South America; S. haematobium, common in Africa and the Middle East; and S. japonicum, common in Japan and China.

Schistosomiasis progresses through three phases, as defined by the migration of the helminth: allergic (cercarial) dermatitis, which occurs during the penetration of cercariae into the skin; acute schistosomiasis, which occurs during the oviposition phase; and chronic schistosomiasis, caused by the formation of granulomas and fibrosis around the helminth eggs retained in the pulmonary vasculature, which can result in arteriolitis obliterans, pulmonary hypertension, and cor pulmonale.(1) Although the clinical presentation of acute schistosomiasis varies widely, most individuals are asymptomatic.

Symptoms and signs can include fever, chills, weakness, weight loss, headache, nausea, vomiting, diarrhea, hepatomegaly, and splenomegaly. The disease is usually self-limited, but severe cases can result in death.(2,3) Marked eosinophilia can be present.(1-3)

1. Professor, Graduate Program in Health Sciences, Faculdade de Medicina de São José do Rio Preto – FAMERP, São José do Rio Preto School of Medicine – São José do Rio Preto, Brazil 2. Adjunct Professor, Faculdade de Medicina de São José do Rio Preto – FAMERP, São José do Rio Preto School of Medicine – São José do Rio Preto, Brazil 3. Physician, Ultra X, São José do Rio Preto, Brazil 4. Professor, Graduate Program in Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; and Professor of Clinical Medicine, Petrópolis School of Medicine, Petrópolis, Brazil 5. Full Professor Emeritus, Fluminense Federal University, Niterói, Brazil; and Associate Professor, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Reversed halo sign in acute schistosomiasis

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Figure 1 - HRCT scans showing patchy areas of ground-glass attenuation, small nodules, and nodular reversed halo signs in both lower lobes of the lungs.

The diagnosis of schistosomiasis is based on clinical findings, the identification of exposure to contaminated water in endemic areas, the documentation of eggs in stool samples, or serological positivity for Schistosoma sp.(4) Early diagnosis and treatment of the disease are important to prevent severe late complications, such as pulmonary hypertension, cor pulmonale, and pulmonary arteriovenous fistulas.(1) The most common CT finding in patients with acute pulmonary schistosomiasis is that of small (2- to 15-mm) pulmonary nodules. Larger nodules are typically surrounded by halo signs. A pattern of bilateral diffuse ground-glass opacity with ill-defined nodules has also been reported.

Significant lymphadenopathy and pleural effusion are very rare findings.(1-3) Although organizing pneumonia is considered to be the most frequent cause of the reversed halo sign, morphological aspects of the halo, particularly the presence of small nodules in the wall or inside the reversed halo, strongly suggest a diagnosis of active granulomatous disease, especially pulmonary tuberculosis or pulmonary sarcoidosis. Histopathological analysis has revealed the presence of granulomas within the ring portion of or within the reversed halo sign. http://dx.doi.org/10.1590/S1806-37132015000004444

Figure 2 - Histological sections: in A, areas of granulomatous inflammation and inflammatory infiltration of the alveolar septa (H&E staining; magnification, Ă&#x2014;40); in B, schistosome ova (arrows) inside a granuloma. (H&E staining; magnification, Ă&#x2014;100).

In the present case, the reversed halo sign was observed in a patient with acute schistosomiasis.

In conclusion, schistosomiasis should be considered in the differential diagnosis of nodular reversed halo sign, particularly in patients with an epidemiological history suggestive of the disease. In the case presented here, the analysis of histological sections demonstrated that the nodules were related to the presence of granulomas.

(4-6)

References 1. Bastos Ade L, Brito IL. Acute pulmonary schistosomiasis: HRCT findings and clinical presentation. J Bras Pneumol. 2011;37(6):823-5. http://dx.doi.org/10.1590/ S1806-37132011000600018 2. Soares Souza A Jr, Marchiori E, Maluf Cury P, Gasparetto EL, Escuissato DL. Acute pulmonary schistosomiasis: correlation between the high-resolution CT and pathological findings [Article in Portuguese]. Rev Port Pneumol. 2007;13(5):741-4.

3. Nguyen LQ, Estrella J, Jett EA, Grunvald EL, Nicholson L, Levin DL. Acute schistosomiasis in nonimmune travelers: chest CT findings in 10 patients. AJR Am J Roentgenol. 2006;186(5):1300-3. http://dx.doi. org/10.2214/AJR.05.0213

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Souza Jr AS, Souza AS, Soares-Souza L, Zanetti G, Marchiori E

4. Marchiori E, Zanetti G, Hochhegger B, Irion KL. Re: Reversed halo sign: nodular wall as criteria for differentiation between cryptogenic organizing pneumonia and active granulomatous diseases. Clin Radiol. 2010;65(9):770-1. http://dx.doi.org/10.1016/j.crad.2010.02.015 5. Marchiori E, Zanetti G, Irion KL, Nobre LF, Hochhegger B, Manรงano AD, et al. Reversed halo sign in active pulmonary

tuberculosis: criteria for differential diagnosis from cryptogenic organizing pneumonia. AJR Am J Roentgenol.

2011;197(6):1324-7. http://dx.doi.org/10.2214/AJR.11.6543 6. Marchiori E, Zanetti G, Hochhegger B, Irion KL, Carvalho AC, Godoy MC. Reversed halo sign on computed tomography: state-of-the-art review. Lung. 2012;190(4):389-94. http://dx.doi.org/10.1007/s00408-012-9392-x

Submitted: 30 October 2014. Accepted, after review: 9 December 2014.

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Letter to the Editor Pulmonary large-cell neuroendocrine carcinoma presenting as multiple cutaneous metastases Carcinoma neuroendócrino de grandes células do pulmão diagnosticado a partir de múltiplas metástases cutâneas

Tiago Mestre1, Ana Maria Rodrigues2, Jorge Cardoso3

To the Editor: Here, we describe the case of a 66-year-old, male nonsmoker with a history of type 2 diabetes mellitus, hypertension, and dyslipidemia. The patient was referred to our hospital after the emergence of four painful erythematous nodules on his face, scalp, and trunk, over a three-week period (Figure 1). Determination of tumor markers showed elevated levels of procalcitonin (30.83 ng/ mL; reference value, < 0.5 ng/mL), carbohydrate antigen 19-9 (2,700 U/mL; reference value, < 37 U/ mL), and lactate dehydrogenase (850 U/L; reference range, 313-618 U/L). The histopathological examination of two nodules revealed strands and nests of large pleomorphic cells with vesicular nuclei and prominent nucleoli. Tumor cells were found to be immunohistochemically positive for chromogranin A, synaptophysin, and CD56 (Figure 2), as well as for cytokeratin 7, whereas they were immunohistochemically negative for CD20. A CT scan of the chest revealed a 4-cm mass in the left lower lobe (Figure 1). The results of a transbronchial biopsy (via bronchoscopy) confirmed the diagnostic hypothesis of largecell neuroendocrine carcinoma (LCNEC) of the lung. The patient died three months after the diagnosis.

Cutaneous metastases are a sign of poor prognosis. They are the first sign of an internal malignancy in only 0.8% of cases. The neoplasms that most often present as cutaneous metastasis are breast cancer in women and lung carcinoma in men. Cutaneous metastases can have a multitude of presentations, the abdomen, chest, scalp, and face being the sites that are most often affected.(1) Only 0.3% of all lung cancers are LCNECs, which rarely present as cutaneous metastasis. The typical LCNEC patient is a male smoker in the

seventh decade of life.(2) This type of carcinoma has an aggressive course and is rapidly metastatic.

However, LCNEC rarely presents as endocrine syndromes, cutaneous metastases, or involvement of the surrounding structures. It can occur in the lungs, breasts, uterine cervix, gallbladder, urinary bladder, and ovaries, as well as (rarely) in the colon.(3,4) There have been only four reported cases of LCNEC presenting as cutaneous metastasis, and the primary origin of the neoplasia (lung, bladder, and rectum, respectively) was identified in three of those cases.(3-5) The case in which the origin could not be identified was the only one in which multiple cutaneous metastases occurred. To our knowledge, ours is the first report of multiple cutaneous metastases as the presenting sign of LCNEC of the lung. When there is no extracutaneous involvement, excision of cutaneous metastases of LCNEC should be considered because it could increase survival.

If there are internal metastases, chemotherapy should be considered the first-line treatment, albeit having been shown to elicit a weak response.

Survival after cutaneous metastasis ranges from two to five months.(6) It is important to distinguish cutaneous metastases of LCNEC from Merkel cell carcinoma, a rare lesion seen mainly in areas of the skin that have been exposed to the sun.(3) In the latter, the cells are usually smaller and are cytokeratin 20-positive.(3) The case presented here helps clarify the biological behavior and the immunohistochemical profile of LCNEC of the lung. Our findings also underscore the importance of early recognition of cutaneous metastases to the accurate diagnosis and prompt, appropriate treatment of neoplasia.

1. Resident in Dermatology, Department of Dermatology, Curry Cabral Hospital, Centro Hospitalar de Lisboa Central, Lisbon, Portugal 2. Senior Consultant, Department of Dermatology, Curry Cabral Hospital, Centro Hospitalar de Lisboa Central, Lisbon, Portugal 3. Head, Department of Dermatology, Curry Cabral Hospital, Centro Hospitalar de Lisboa Central, Central Lisbon Hospital Center – Lisbon, Portugal

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Figure 1 - Eruptive painful erythematous nodules on the face and scalp (photographs on the left). CT scans (on the right) revealed a 4-cm mass in the left lower lobe.

Note the left adrenal gland metastasis (arrow).

H&E

Chromogranin

Synaptophysin

CD56

Figure 2 - On the upper left, histopathological staining showing sheets of pleomorphic tumor cells with a trabecular growth pattern in the dermis (H&E; magnification, Ă&#x2014;100). Immunohistochemical staining for CD56 showed positivity for tumor cells in a cytoplasmic pattern (lower right). Tumor cells were focally positive for chromogranin (lower left) and synaptophysin (upper right).

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Pulmonary large-cell neuroendocrine carcinoma presenting as multiple cutaneous metastases

References 1. Ardavanis A, Orphanos G, Ioannidis G, Rigatos G. Skin metastases from primary lung cancer. Report of three cases and a brief review. In Vivo. 2006;20(5):671-3.

2. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors.

Cancer. 2008;113(1):5-21. http://dx.doi.org/10.1002/ cncr.23542 3. Shin MK, Choi CM, Oh YJ, Kim NI. CK20 Positive Largecell Neuroendocrine Carcinoma Presenting with Skin Metastases. Ann Dermatol. 2011;23 Suppl 1:S20-4. http://dx.doi.org/10.5021/ad.2011.23.S1.S20

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4. Yuan C, Keating B, Farricielli LA, Z Kuixing. Large-cell neuroendocrine carcinoma (LCNEC) without pulmonary symptoms diagnosed in a cutaneous metastasis. Am J Case Rep. 2014;15:97-102. http://dx.doi.org/10.12659/ AJCR.890094 5. Lee WJ, Kim CH, Chang SE, Lee MW, Choi JH, Moon KC, et al. Cutaneous metastasis from large-cell neuroendocrine carcinoma of the urinary bladder expressing CK20 and TTF-1. Am J Dermatopathol. 2009;31(2):166-9. http:// dx.doi.org/10.1097/DAD.0b013e31818eba4c 6. Beachkofsky TM, Wisco OJ, Osswald SS, Osswald MB, Hodson DS. Pulmonary cutaneous metastasis: a case report and review of common cutaneous metastases.

Cutis. 2009;84(6):315-22.

Submitted: 16 November 2014. Accepted, after review: 1 December 2014.

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Letter to the Editor Nontuberculous mycobacteria in respiratory specimens: clinical significance at a tertiary care hospital in the north of Portugal Micobactérias não tuberculosas em espécimes respiratórios: significado clínico em um hospital terciário no norte de Portugal

Hans Dabó1, Vanessa Santos1, Anabela Marinho2, Angélica Ramos3, Teresa Carvalho3, Manuela Ribeiro3, Adelina Amorim2

To the Editor: Nontuberculous mycobacteria (NTM) are ubiquitous in the human environment, and more than 150 NTM species have been described to date.(1) When inhaled by susceptible individuals, such as those with chronic lung disease, NTM can lead to chronic, progressive, and sometimes fatal respiratory symptoms. Over the last three decades, the incidence of NTM laboratory isolation and related lung disease has been increasing, surpassing that of tuberculosis in some areas.(1,2) However, the isolation of NTM from respiratory specimens might be due to contamination of specimens or colonization of patients that is transient, not necessarily indicating disease.(1) Here, we report the incidence of NTM isolation in the Pulmonology Department of the São João Hospital Center, a tertiary care university hospital located in Porto, the second most populous city in Portugal. It is the largest hospital in the northern region and one of the three largest in the country. We retrospectively analyzed patients who were seronegative for HIV and for whom NTM had been isolated in at least one respiratory specimen between January of 2008 and December of 2012. The samples were decontaminated with the N-acetyl-L-cysteine-sodium hydroxide method and inoculated into Middlebrook 7H9 broth medium (BBL Mycobacteria Growth Indicator Tube [MGIT]; Becton Dickinson, Franklin Lakes, NJ, USA), in accordance with the manufacturer instructions. Positive cultures, incubated and monitored in an automated culture system (BACTEC MGIT 960; Becton Dickinson), were examined by smear microscopy with Kinyoun staining for AFB. In the presence of AFB, we used

a molecular assay for common mycobacteria and additional species (GenoType Mycobacterium CM/ AS; Hain Lifescience GmbH, Nehren, Germany), in accordance with the manufacturer instructions, to determine the species of the isolates. Demographic, clinical, radiological, and microbiological data were collected. The clinical relevance of the isolation in the respiratory sample was defined in accordance with the current American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria.(3) Two hundred and two patients were included in this study. Of those, 118 (58%) were male. The mean age was 64 years (range, 23-89 years). The main risk factors identified were the underlying structural lung disease, such as COPD, in 73 patients (36%), bronchiectasis, in 62 (31%), and tuberculosis sequelae, in 40 (20%); and nonpulmonary conditions, such as diabetes mellitus, in 18 patients (9%), gastroesophageal reflux disease, in 16 (8%), and receiving immunosuppression therapy, in 12 (6%). Data on environmental exposure were not available. A total of 407 isolates were obtained, and the species were identified in 378 (93%). Of the 407 isolates, 237 (58%) were identified as being within the Mycobacterium avium complex (MAC) group and 141 (35%) were identified as belonging to one of 11 other Mycobacterium species, the remaining 29 (7%) being identified as mycobacteria but not down to the species level (Table 1). These isolates were obtained from sputum samples in 192 (95%) of the patients, bronchial lavage fluid samples in 13 (6%), BAL fluid samples in 7 (4%), a lung biopsy sample in 1 (0.5%), and a gastric aspirate sample in 1

1. Intern in the Department of Pulmonology, São João Hospital Center, EPE, Porto, Portugal.

2. Attending Physician. Department of Pulmonology, São João Hospital Center, EPE, Porto, Portugal.

3. Attending Physician. Department of Clinical Pathology, São João Hospital Center, EPE, Porto, Portugal.

J Bras Pneumol. 2015;41(3):292-294

http://dx.doi.org/10.1590/S1806-37132015000000005

Nontuberculous mycobacteria in respiratory specimens: clinical significance at a tertiary care hospital in the north of Portugal

Table 1 - Nontuberculous mycobacteria isolated from respiratory specimens collected from 202 patients.

NTM species Number of isolates MAC 237 M. gordonae 43 M. peregrinum 33 M. chelonae 26 M. kansasii 13 M. abscessus 12 M. scrofulaceum 8 M. xenopi 2 M. malmoense 1 M. mucogenicum 1 M. lentiflavum 1 M. fortuitum 1 M. spp.

29 TOTAL 407 NTM: Nontuberculous mycobacteria; and MAC: Mycobacterium avium complex.

(0.5%). The number of isolates increased each year, from 52 in 2008 to 58 in 2009, 74 in 2010, 86 in 2011, and 137 in 2012. Of the 202 patients, 36 (18%) were submitted to treatment for NTM-related lung disease, and 32 (89%) of those met the current ATS/IDSA criteria for the diagnosis. Among the 36 patients treated, the mean age was 62 years (range, 32-89 years) and 22 (61%) were male. The most common lung disease was COPD, seen in 12 (33%) of the 36 patients, followed by bronchiectasis, in 9 (25%), and tuberculosis sequelae, in 8 (22%). There were 31 patients (86.1%) presenting with cough, 29 (80.6%) presenting with sputum production, and 23 (63.9%) presenting with dyspnea. The main radiological findings were bronchiectasis, nodules, and micronodules. Among the 36 patients treated, the NTM identified were MAC in 34 (94%), M. kansasii in 1 (3%), and M. xenopi in 1 (3%). All patients were treated according to the ATS/IDSA statement recommendations.(3) The 34 patients with MAC lung disease were treated with rifampin, ethambutol, and a macrolide (clarithromycin or azithromycin). The patient with M. kansasii infection was treated with rifampin, isoniazid, and ethambutol. The patient with M. xenopi infection was treated with rifampin, ethambutol, and clarithromycin. After the completion of treatment, relapse occurred in 5 (13.9%) of the 34 patients with MAC infection, and 4 of those 5 had met the ATS/IDSA criteria. In three of those cases, the decision was made to submit the patients to http://dx.doi.org/10.1590/S1806-37132015000000005

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retreatment—1 was cured, 1 died from lung cancer while still under treatment, and 1 is still under treatment at this writing—and in another case, the decision was not to treat, because the patient had been diagnosed with advanced cancer. There was no relapse in either of the patients treated for infection with M. kansasii and M. xenopi, respectively. In 2 (5.6%) of the 36 patients, there was reinfection with other species (M. abscessus and M. scrofulaceum, respectively) after the completion of treatment, and both of those patients are still under treatment at this writing.

In Portugal, epidemiological studies are scarce.

In 2008, Marinho et al.(4) reported on 102 non-HIVinfected patients with NTM isolated from the respiratory system at our hospital over a 7-year period (from 1997 to 2004). In that study, the majority of the patients were male, the median age was 63 years, and most had an underlying lung disease, mainly tuberculosis sequelae or bronchiectasis. The authors reported that 16 (15.7%) of the patients were treated for lung disease, and that 14 (88%) of those patients met the ATS criteria in use at the time.(4) In the present study, we identified nearly twice as many such patients over a period of only 4 years. The demographic profile of our sample was similar to that of the sample evaluated by Marinho et al.(4) In our study, the most common lung diseases were COPD and bronchiectasis. Although the criteria used in order to define lung disease differed between the two studies, the proportion of patients treated and of those that met the respective ATS criteria were quite similar. In our study, the NTM most frequently isolated were MAC, which also had the greatest clinical relevance. Other studies conducted in Portugal have also reported MAC as the most frequently isolated NTM.(4-6) In a recent global epidemiological study,(5) the most frequently isolated NTM were M. avium, M. gordonae, M. xenopi, and M. fortuitum. In another hospital-based study,(7) 16% of the patients with NTM isolated from respiratory specimens met the current ATS/ IDSA criteria.

The rapid increase in the incidence of NTM infection worldwide in recent years is probably due to the combination of growing awareness; improved culturing and molecular techniques for the detection of NTM; an aging population; and the increased prevalence of chronic lung disease and of diseases that result in immunosuppression. (1,2) In addition, some J Bras Pneumol. 2015;41(3):292-294

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Dab贸 H, Santos V, Marinho A, Ramos A, Carvalho T, Ribeiro M, Amorim A

authors have suggested that the decline in the incidence of tuberculosis has decreased the crossprotective mycobacterial immunity associated with M. tuberculosis infection, which has somehow promoted an increase in the incidence of NTM infection.(2) Our study has some limitations. Because our data were collected only from patients seen in a pulmonology department, they might not be representative of the general population. What our results clearly indicate is that NTM is an emerging health problem at our hospital and possibly in the northern region of Portugal.

Although a hospital-based study to confirm these results and larger-scale studies to evaluate the magnitude of the problem in the region would be advisable, clinicians need to be aware of the possibility of NTM infection, which can have devastating consequences for patients if not diagnosed and treated properly.

References 1. Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014;6(3):210-20. http://dx.doi.org/10.3978/j.issn.2072-1439.2013.12.24

2. Kendall BA, Winthrop KL. Update on the epidemiology of pulmonary nontuberculous mycobacterial infections.

Semin Respir Crit Care Med. 2013;34(1):87-94. http:// dx.doi.org/10.1055/s-0033-1333567 3. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416. http://dx.doi. org/10.1164/rccm.200604-571ST 4. Marinho A, Fernandes G, Carvalho T, Pinheiro D, Gomes I. Nontuberculous mycobacteria in non-AIDS patients.

Rev Port Pneumol. 2008;14(3):323-37. http://dx.doi. org/10.1016/S0873-2159(15)30241-5 5. Hoefsloot W, van Ingen J, Andrejak C, Angeby K, Bauriaud R, Bemer P, et al. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study.

Eur Respir J. 2013;42(6):1604-13. http://dx.doi. org/10.1183/09031936.00149212 6. Amorim A, Macedo R, Lopes A, Rodrigues I, Pereira E. Non-tuberculous mycobacteria in HIV-negative patients with pulmonary disease in Lisbon, Portugal.

Scand J Infect Dis. 2010;42(8):626-8. http://dx.doi. org/10.3109/00365541003754485 7. Panagiotou M, Papaioannou AI, Kostikas K, Paraskeua M, Velentza E, Kanellopoulou M, et al. The epidemiology of pulmonary nontuberculous mycobacteria: data from a general hospital in Athens, Greece, 2007-2013. Pulm Med. 2014;2014:894976. http://dx.doi.org/10.1155/2014/894976

Submitted: 9 January 2015. Accepted, after review: 26 April 2015.

J Bras Pneumol. 2015;41(3):292-294

http://dx.doi.org/10.1590/S1806-37132015000000005

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SOCIEDADE SERGIPANA DE PNEUMOLOGIA E TISIOLOGIA

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CEP: Telefone: E-mail:

Margarida Célia Lima Costa Neves Nélia Claudia Araújo Av. Oceânica, 551 - Ed. Barra Center - sala 112 - Barra 40.160-010 - Salvador – BA (71)3264-2427 spba@terra.com.br | www.pneumobahia.com.br Cilea Aparecida Victória Martins Karina Tavares Oliveira Rua Eurico de Aguiar, 130, Sala 514 –Ed. Blue Chip Praia do Campo 29.055-280 - Vitória – ES (27)3345-0564 Fax: (27)3345-1948 cilea38@hotmail.com

Presidente: Ayrdes Benedita Duarte dos Anjos Pivetta Secretário: Paulo Cesar da Silva Neves Endereço: Av. Érico Preza, 1275 Res. Alphaville

Rua das Mangabas 1440 - Jardim Itália CEP: 78060-758- Cuiabá – MT Telefone: (65)99779367 E-mail: dpivetta@terra.com.br

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

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

Presidente: Cromwell Barbosa de Carvalho Melo Secretária: Tatiana Santos Malheiros Nunes Endereço: Avenida Jose dos Santos e Silva, 1903

Nucleo de Cirurgia Torácica CEP: 64001-300- Teresina – PI Telefone: (86)32215068 E-mail: cromwellmelo.cirurgiatoracica@gmail.com Presidente: José Barreto Neto Secretário: Almiro Oliva Sobrinho Endereço: Av. Gonçalo Prado Rollemberg, 211, Sala 206

Bairro São José CEP: 49010-410 - Aracaju - SE Telefone: (79)3213-7352 E-mail: j.barreto@uol.com.br

Eventos 2015 NACIONAIS XIX Congresso da Sociedade Brasileira de Cirurgia Torácica

8º Congresso do Centro-Oeste de Pneumologia e Tisiologia Data: 26 e 27 de junho 2015 Local: Associação Médica de Brasília Informações: sbdt@ambr.org.br | Telefone: 61-32458001

Data: 27 a 29 de maio de 2015 Local: Fábrica de Negócios, Fortaleza -Ceará Organização: Ikone Eventos Informações: 85-3261-1111

X Curso Nacional de Doenças Intersticiais | 7th International Wasog Conference on Diffuse Parenchymal Lung Diseases Data: 04 a 06 de junho de 2015 Local: Centro de Convenções Rebouças, São Paulo/SP Informações: 0800616218 ou eventos@sbpt.org.br

Pneumo in Rio XV Congresso de Pneumologia e Tisiologia do Estado do Rio de Janeiro Data: 18 a 20 de junho de 2015 | Local: PENEDO -RJ Informações: 21 2548-5141 Método Eventos www.metodoeventosrio.com.br/pneumo2015 pneumo2015@metodorio.com.br

XVIII Congresso Mineiro de Pneumologia e Cirurgia de Tórax Data: 25 a 27 de junho de 2015 Local: Belo Horizonte -MG Informações: Sociedade Mineira de Pneumologia e Cirurgia Torácica smpct@smpct.org.br | www.smpct.org.br

VII Congresso Gaúcho de Pneumologia e Tisiologia e XVIII Encontro dos Pneumologistas, Cirurgiões Torácicos e Pneumopediatras do RS Data: 02 a 04 de julho de 2015 Local: Hotel Plaza e Centro de Eventos São Rafael – Porto Alegre -RS Informações: www.sptrs.org.br | sptrs@sptrs.org.br | (51)3384-2889 XVI Congresso Norte-Nordeste de Pneumologia e Tisiologia IX Fórum Norte-Nordeste Data: 09 a 11 de julho de 2015 | Local: Salvador-BA Informações: www.pneumobahia.com.br | sbpa@terra.com.br

INTERNACIONAIS ATS 2015 Data: 15-20 de Maio de 2015 | Local: Denver/CO-USA Informações: www.thoracic.org ERS 2015 Data: 26-30 de Setembro de 2015 | Local: Amsterdã, Holanda Informações: www.ersnet.org CHEST 2015 Data: 24 a 29 de outubro de 2015 | Local: Montreal/Canadá Informações: www.chestnet.org