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E V I D E N C E F O R H E A L T H C A R E

Descriptive study:• WOMAC and SF-36: instruments

for evaluating the health-related quality of life of elderly people with total hip arthroplasty

Cross-cultural adaptation study:• Cross-cultural adaptation

of the Social and Emotional Questionnaire on Dementia for the Brazilian population

Descriptive criticalappraisal study:• Hierarchy of evidence referring

to the central nervous system in a high-impact radiation oncology journal:a 10-year assessment

Retrospectiveobservational study:• Neuroprotective body

hypothermia among newborns with hypoxic ischemic encephalopathy:three-year experience in a tertiary university hospital

São Paulo Medical Journal/Evidence for H

ealth Care, 2015 July 2; 133(4):283-384

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Sao Paulo Med J. 2015; 133(4):i-ii i

INDEX

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APOIO

Editorial283 Non-communicable diseases in Brazil: a � ood of data is coming!

Paulo Andrade Lotufo

286 Lifestyles and chronic non-transmissible diseases of the Brazilian population according to the National Health Survey: balance of the main resultsDeborah Carvalho Malta, Célia Landmann Szwarcwald

Original article290 WOMAC and SF-36: instruments for evaluating the health-related quality of life of elderly people with total hip

arthroplasty. A descriptive studyMariana Kátia Rampazo-Lacativa, Ariene Angelini dos Santos, Arlete Maria Valente Coimbra, Maria José D’Elboux

298 Relationship between the Brazilian version of the Montreal-Toulouse language assessment battery and education, age and reading and writing characteristics. A cross-sectional study Karina Carlesso Pagliarin, Gigiane Gindri, Karin Zazo Ortiz, Maria Alice Mattos Pimenta Parente, Yves Joanette,Jean-Luc Nespoulous, Rochele Paz Fonseca

307 Hierarchy of evidence referring to the central nervous system in a high-impact radiation oncology journal: a 10-year assessment. Descriptive critical appraisal studyFabio Ynoe Moraes, Lorine Arias Bonifacio, Gustavo Nader Marta, Samir Abdallah Hanna, Álvaro Nagib Atallah,Vinícius Ynoe Moraes, João Luis Fernandes Silva, Heloísa Andrade Carvalho

314 Neuroprotective body hypothermia among newborns with hypoxic ischemic encephalopathy: three-year experience in a tertiary university hospital. A retrospective observational studyMauricio Magalhães, Francisco Paulo Martins Rodrigues, Maria Renata Tollio Chopard, Victoria Catarina de Albuquerque Melo, Amanda Melhado, Inez Oliveira, Clery Bernardi Gallacci, Paulo Roberto Pachi, Tabajara Barbosa Lima Neto

320 Retrospective cohort of trisomy 18 (Edwards syndrome) in southern BrazilDaniela Denardin, Fabíola Elizabete Savaris, André Campos da Cunha, Rosilene da Silveira Betat, Jorge Alberto Bianchi Telles, Luciano Vieira Targa, Aline Weiss, Paulo Ricardo Gazzola Zen, Rafael Fabiano Machado Rosa

326 Frequency of nutritional disorders and their risk factors among children attending 13 nurseries in São Paulo, Brazil.A cross-sectional studyTulio Konstantyner, José Augusto Aguiar Carrazedo Taddei, � ais Cláudia Roma Oliveira Konstantyner,Laura Cunha Rodrigues

336 Greater expression of the human leukocyte antigen-G (HLA-G) and interleukin-17 (IL-17) in cervical intraepithelial neoplasia: analytical cross-sectional study Lidyane Neves Miranda, Fernanda Priscila Santos Reginaldo, Daliana Maria Berenice Oliveira Souza, Christiane Pienna Soares, Tarsia Giabardo Alves Silva, Keyla Borges Ferreira Rocha, Carlos André Nunes Jatobá, Eduardo Antonio Donadi,Joanlise Marco Leon Andrade, Ana Katherine Silveira Gonçalves, Janaína Cristiana Oliveira Crispim

343 Semiquantitative fecal calprotectin test in postinfectious and non-postinfectious irritable bowel syndrome:cross-sectional studyLiliana-Elisabeta David, Teodora Surdea-Blaga, Dan-Lucian Dumitrascu

350 Development of psychiatric risk evaluation checklist and routine for nurses in a general hospital: ethnographic qualitative study Ana Luiza Lourenço Simões Camargo, Alfredo Maluf Neto, Fátima Tahira Colman, Vanessa de Albuquerque Citero

Short communication358 Cross-cultural adaptation of the Social and Emotional Questionnaire on Dementia for the Brazilian population

Tatiana Belfort, Jessica Bramham, José Pedro Simões Neto, Maria Fernanda Barroso de Sousa, Raquel Luiza dos Santos,Marcela Moreira Lima Nogueira, Bianca Torres, Rachel Dias Lopes da Rosa, Marcia Cristina Nascimento Dourado

367 Main reasons for medical consultations in family healthcare units in the city of Recife, Brazil: a cross-sectional study Rinailda de Cascia Santos Torres, Karine Sobral Marques, Kamila de Nazaré Ribas Leal, Pedro Augusto Sampaio Rocha-Filho

Case report371 Nimesulide-induced fatal acute liver failure in an elderly woman with metastatic biliary adenocarcinoma. A case report

Sara Santos Bernardes, André Souza-Nogueira, Estefânia Gastaldello Moreira, Marina Okuyama Kishima, Alda Fiorina Maria Losi Guembarovski, Tercilio Luiz Turini, Conceição Aparecida Turini

377 Microcephaly-chorioretinopathy syndrome, autosomal recessive form. A case reportRafael Fabiano Machado Rosa, Flávia Enk, Korine Camargo, Giovanni Marco Travi, André Freitas,Rosana Cardoso Manique Rosa, Carla Graziadio, Vinicius Freitas de Mattos, Paulo Ricardo Gazzola Zen

Letter to the editor381 Possible implication of vagal nerve stimulation for treating refractory psoriasis

Nima Derakhshan, Mahboubeh Kazemi

Cochrane highlights383 Antiviral treatment for Bell’s palsy (idiopathic facial paralysis)

Ildiko Gagyor, Vishnu B. Madhok, Fergus Daly, Dhruvashree Somasundara, Michael Sullivan, Fiona Gammie, Frank SullivanComments: Osvaldo Massaiti Takayanagui

384 In� uenza vaccines for preventing cardiovascular diseaseChristine Clar, Zainab Oseni, Nadine Flowers, Maryam Keshtkar-Jahromi, Karen ReesComments: Juvencio José Duailibe Furtado

I Instructions for authors (www.scielo.br/spmj)

ii Sao Paulo Med J. 2015; 133(4):i-ii

ORGANIZATION

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Sao Paulo Med J. 2015; 133(4):283-5 283

EDITORIALDOI: 10.1590/1516-3180.2015.13340806

Non-communicable diseases in Brazil: a �ood of data is coming!Doenças não-transmissíveis: uma inundação de dados está chegando!Paulo Andrade LotufoI

Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

FIRST DATA-GENERATION PERIODOver the last two or three decades, academic researchers within health sciences frequently com-plained about the “drought” of information concerning chronic diseases in Brazil. �is comment, by quali�ed physicians and scientists, was made much more frequently than would be justi-�ed by the reality of epidemiological production relating to non-communicable diseases, albeit restricted to mortality data and surveys. Even though both mortality data and surveys present relatively limited scope for reaching conclusions, the data produced were enough to understand some aspects of the epidemiological pro�le of chronic diseases in Brazil.

�e mortality data was su�ciently accurate to show that a decline in cardiovascular diseases was occurring in Brazil, in contrast with other countries with the same level of eco-nomic development.1 In addition, survey data made it possible to ascertain the following points: (1) premature heart disease rates in Brazil were higher than in a�uent countries;2 (2) cancer mortality among Japanese descendants in São Paulo showed di�erences accord-ing to the generation of migration, compared with individuals living in Japan;3 (3) Brazil had the highest death rate due to stroke in the Western world;4 (4) the burden of cardiovascular diseases was inversely associated with formal education levels among Brazilian municipali-ties;5 (5) the decline in the risk of death due to heart disease was not taking place uniformly, such that the pace was slower among people living in the poorest neighborhoods, compared with the wealthiest ones in São Paulo;6 and (6) the impact of the smoking habit on all causes of death in Brazil.7

Likewise, surveys addressing diabetes have been extremely useful for planning diabetes control programs over the whole country, among adults, pregnant women and the indigenous population.8-10 Every year since 2006, VIGITEL (Surveillance System of Risk and Protective Factors for Chronic Non-Communicable Diseases through Telephone Interviews), which is a telephone-based behavioral survey conducted among the 27 state capitals of Brazil, has been providing data on dietary habits, obesity, alcohol intake, physical activity and smoking habit.11 However, the most important e�ort by the Ministry of Health and the academic community has been the National Health Survey (“Pesquisa Nacional de Saúde”).12 �e concept, design and pre-liminary results of this survey are presented in this issue of the Journal.

SECOND DATA-GENERATION PERIODSince the beginning of this century, the academic and government sectors have been making joint e�orts to provide better information through new studies: longitudinal studies, hospital registry studies and randomized trials. �e stage of maturation of these studies is not uni-form, but they are leading to increased levels of publication, at a fast rate. Table 1 summarizes some observational studies addressing non-communicable diseases that were designed and funded in Brazil.13-20

Indeed, these new studies with much more data will open up a new window with impacts on National Health System policies, professional activity, the industry and science on the bench. Over the next issues of the Journal, each of these studies will be presented in greater detail.

IMD, DrPH. Full Professor, Department of Internal Medicine, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.

EDITORIAL | Lotufo PA

284 Sao Paulo Med J. 2015; 133(4):283-5

Concluding, the drought of epidemiological information has come to an end in Brazil. Now, we will need to prepare ourselves so that we do not drown in the �ood of data that is coming.

REFERENCES1. Lolio CA, Souza JMP, Laurenti R. Decline in cardiovascular disease

mortality in the city of São Paulo, Brazil, 1970 to 1983. Rev Saude

Publica. 1986;20(6):454-64.

2. Lotufo PA. Mortalidade precoce por doenças do coração no Brasil.

Comparação com outros países [Premature mortality from heart diseases

in Brazil. An international comparison]. Arq Bras Cardiol. 1998;70(5):321-5.

3. Tsugane S, Gotlieb SL, Laurenti R, Souza JM, Watanabe S. Mortality

and cause of death among �rst-generation Japanese in São Paulo,

Brazil. Int J Epidemiol. 1989;18(3):647-51.

4. Lotufo PA. Stroke in Brazil: a neglected disease. Sao Paulo Med J.

2005;123(1):3-4.

5. Ishitani LH, Franco GC, Perpétuo IHO, França E. Desigualdade

social e mortalidade precoce por doenças cardiovasculares no

Brasil [Socioeconomic inequalities and premature mortality due to

cardiovascular diseases in Brazil]. Rev Saude Publica. 2006;40(4):684-91.

6. Lotufo PA, Fernandes TG, Bando DH, Alencar AP, Benseñor IM. Income

and heart disease mortality trends in Sao Paulo, Brazil, 1996 to 2010.

Int J Cardiol. 2013;167(6):2820-3.

7. Corrêa PC, Barreto SM, Passos VM. Smoking-attributable mortality and

years of potential life lost in 16 Brazilian capitals, 2003: a prevalence-

based study. BMC Public Health. 2009;9:206.

8. Malerbi DA, Franco LJ. Multicenter study of the prevalence of

diabetes mellitus and impaired glucose tolerance in the urban

Brazilian population aged 30-69 yr. The Brazilian Cooperative

Group on the Study of Diabetes Prevalence. Diabetes Care.

1992;15(11):1509-16.

9. Reichelt AJ, Spichler ER, Branchtein L, et al. Fasting plasma glucose

is a useful test for the detection of gestational diabetes. Brazilian

Study of Gestational Diabetes (EBDG) Working Group. Diabetes Care.

1998;21(8):1246-9.

10. Dal Fabbro AL, Franco LJ, da Silva AS, et al. High prevalence of type

2 diabetes mellitus in Xavante Indians from Mato Grosso, Brazil. Ethn

Dis. 2014;24(1):35-40.

11. Moura EC, Malta DC, Morais Neto OL, Monteiro CA. Prevalence and

social distribution of risk factors for chronic noncommunicable

diseases in Brazil [Prevalencia y distribución social de los factores

de riesgo de enfermedades crónicas no transmisibles en Brasil]. Rev

Panam Salud Publica. 2009;26(1):17-22.

12. Malta DC, Szwarcwald CL. Lifestyles and chronic non-transmissible

diseases of the Brazilian population according to the National Health

Survey: balance of the main results. Sao Paulo Med J. 2015;133(4):286-9.

Acronym Name Design PlaceNumber of

participantsPopulation

Age (years)

Aim Year Evaluation

ELSA-Brasil13

Brazilian Longitudinal Study of Adult Health

cohortBelo Horizonte, Porto Alegre, Rio de Janeiro,

Salvador, São Paulo, Vitória15,105 civil servants 35-74

cardiovascular diabetes and all chronic diseases

since 2008

2008-10; 2012-14

SABE14

Survey on Health and Wellbeing of the

Elderly

3 birth cohorts

São Paulo 1,080 elderly > 60 disabilitiessince 2001

only baseline

SPAH15São Paulo aging and

health studycross-

sectionalSão Paulo 2,072 elderly > 65 cognition 2000

only baseline

Bambuí16Bambuí Health and

Aging Studycohort Bambuí 1,606 elderly > 60

adverse-health outcomes

1997only

baseline

ERICO17

Strategy of Registry of Acute Coronary

Syndrome

survival cohort

São Paulo, community hospital

964�rst-ever

myocardial infarction

> 30morbidity and

mortality2009-

12yearly

EMMA18

Study of Stroke Mortality and

Morbidity

survival cohort

São Paulo, community hospital

665�rst-ever

stroke> 30

morbidity and mortality

2006-10

yearly

Pró-Saúde19

Pro Saude Study cohort Rio de Janeiro 4,030 civil servants > 20adverse-health

outcomes1999-2001

20042007

ERICA20

Study of Cardiovascular Risk in

Adolescents

cross-sectional

276 Brazilian towns 85,000 adolescents 12 to 17metabolic syndrome

2011only

baseline

Table 1. Observational studies in Brazil addressing the epidemiology of chronic diseases

Non-communicable diseases in Brazil: a �ood of data is coming! | EDITORIAL

Sao Paulo Med J. 2015; 133(4):283-5 285

13. Schmidt MI, Duncan BB, Mill JG, et al. Cohort Pro�le: Longitudinal

Study of Adult Health (ELSA-Brasil). Int J Epidemiol. 2015;44(1):68-75.

14. Andrade FC, Guevara PE, Lebrão ML, Duarte YA. Correlates of the

incidence of disability and mortality among older adult Brazilians

with and without diabetes mellitus and stroke. BMC Public Health.

2012;12:361.

15. Scazufca M, Menezes PR, Araya R, et al. Risk factors across the life course

and dementia in a Brazilian population: results from the Sao Paulo

Ageing & Health Study (SPAH). Int J Epidemiol. 2008;37(4):879-90.

16. Lima-Costa MF, Firmo JO, Uchôa E. Estudo de coorte de idosos de

Bambuí: metodologia e per�l de saúde dos participantes [The

Bambuí Cohort Study of Aging: methodology and health pro�le

of participants at baseline]. Cad Saude Publica. 2011;27(Supl.

3):s327-s335.

17. Santos IS, Goulart AC, Brandão RM, et al. One-year Mortality after an

Acute Coronary Event and its Clinical Predictors: The ERICO Study. Arq

Bras Cardiol. 2015;105(1):53-64.

18. Goulart AC, Fernandes TG, Santos IS, et al. Predictors of long-term

survival among �rst-ever ischemic and hemorrhagic stroke in a

Brazilian stroke cohort. BMC Neurol. 2013;13:51.

19. Guimarães JM, Werneck GL, Faerstein E, Lopes CS, Chor D. Early

socioeconomic position and self-rated health among civil servants

in Brazil: a cross-sectional analysis from the Pró-Saúde cohort study.

BMJ Open. 2014;4(11):e005321.

20. Vasconcellos MT, Silva PL, Szklo M, et al. Sampling design for the

Study of Cardiovascular Risks in Adolescents (ERICA). Cad Saude

Publica. 2015;31(5):921-30.

286 Sao Paulo Med J. 2015; 133(4):286-9

EDITORIAL DOI: 10.1590/1516-3180.2015.13340308

Lifestyles and chronic non-transmissible diseases of the Brazilian population according to the National Health Survey: balance of the main resultsEstilos de vida e doenças crônicas não transmissíveis da população brasileira segundo a Pesquisa Nacional de Saúde: um balanço dos principais resultadosDeborah Carvalho MaltaI, Célia Landmann SzwarcwaldII

Ministério da Saúde, Brasília, Brazil

�e National Health Survey (Pesquisa Nacional de Saúde, PNS) involved a partnership between the Ministry of Health and the Brazilian Institute for Geography and Statistics (Instituto Brasileiro de Geogra�a e Estatística, IBGE) and forms the most extensive health survey ever con-ducted in Brazil.1 Preparation of the PNS began in 2009, with participation from researchers and representatives of the technical sectors of the Ministry of Health, in a wide-ranging consultation process. Over subsequent years, the survey was prepared and managed, including implementation of measures such as ensuring resources from the Ministry of Health, creation of the partnership with the IBGE to conduct the PNS, de�nition of the scope of the research, sampling, reviewing the literature, de�nition of questionnaires and purchasing of equipment, among other activities.1-4

In 2012, tests were applied to the questionnaire and a pilot study was conducted. In 2013, the study was approved by the National Research Ethics Committee (CONEP). In July 2013, training for �eld personnel was conducted. In August 2013, the �eldwork started, with a duration of six months. �e PNS involved more than 1000 IBGE technicians, who gathered data in 1600 Brazilian municipalities. �e �rst results were released in December 2014, and these related to lifestyle, self-perceived health, and chronic diseases. �is led to production of the �rst thematic edition of the “Revista Epidemiologia e Serviços de Saúde” (volume 24, number 2, Brasília, June 2015); and an article currently underway will seek to make a synthesis of these �rst analyses in the �rst thematic edition of that journal on the PNS.2-4

�e PNS is a household-based cross-sectional study, with sampling strati�ed into three clus-ter stages. Census tracts formed the primary sampling units; households were the second-stage units, and the adults in these households (18 years of age and over) were the third-stage units. Information on 64,348 households was gathered, and 60,202 people living in these households were drawn and then interviewed. �e sample size took into consideration the level of precision desired for the estimates of some indicators at di�erent levels of group subdivision and popu-lation groups. Sampling weights were de�ned. �e interviews were conducted using personal digital assistance (PDA) devices, which are handheld computers containing so�ware appropri-ate for critically assessing the variables.1-3

�e PNS questionnaire on lifestyles encompassed questions on the following two topics: dietary pattern and physical activity and tobacco and alcoholic drink consumption. �e ques-tionnaire on chronic diseases included topics such as hypertension, diabetes, cardiovascular diseases, respiratory diseases, mental diseases, depression, chronic kidney disease and cancer, among others. Anthropometric data and arterial blood pressure measurements were also gath-ered from all the adults selected. Biochemical tests were performed on a subsample.4

In relation to lifestyles among the Brazilian population, the markers of a healthy diet5 were regular consumption of beans (�ve or more times a week), which was reported by 71.9% (95% con�dence interval, 95% CI: 71.2-72.6); consumption of fruit and vegetables �ve times a day, reported by 37.3% (95% CI: 36.4-38.1); and consumption of �sh once a week, reported by 54.6%

IMD, PhD. Director, Department of Non-transmissible Disease and Disorder Surveillance, Department of Health Surveillance, Ministry of Health, Brasília, Federal District; and Professor and Researcher, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.IIPhD. Professor and Researcher, Institute of Health Communication and Scienti�c and Technological Information, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.

Lifestyles and chronic non-transmissible diseases of the Brazilian population according to the National Health Survey: balance of the main results | EDITORIAL

Sao Paulo Med J. 2015; 133(4):286-9 287

(95% CI: 53.7-55.5). �e distribution of the dietary markers was in�uenced by the age, sex, educational level, race/skin color and place of residence of the interviewees (Table 1).6

Investigation of the prevalence of non-healthy food mark-ers consumed �ve or more times a week showed that there was excessive consumption of fats (37.2%; 95% CI: 36.4%-38.0%), so� drinks (23.4%; 95% CI: 22.7%-24.1%) and whole milk (60.6%; 95% CI: 59.8-61.4) and excessive regular consumption of sweets (21.7%; 95% CI: 21.0-22.3). �ese factors were seen more frequently among men, young adults and people with lower educational levels.7 According to the PNS, there was a high consumption of salt among 14.2% (95% CI: 13.6%-14.7%) of the adults, with greater prevalence among men (16.1%; 95% CI: 15.3-16.9), individuals aged 18-29 years (17.7%; 95% CI: 16.2-19.2), individuals with completed higher education (17.3%; 95% CI: 15.6-19.0) and people living in urban areas (14.8%; 95% CI: 13.6-14.7).8

Practicing physical activity during free time was observed among 22.5% of the adults (95% CI: 21.8%-23.1%), and this per-centage was higher among men and people living in urban areas; 31.9% (95% CI: 31.0-32.7) were active in moving around, while 46.0% (95% CI: 45.2-46.8) were insu�ciently active; the propor-tion of adults who watched television for three or more hours per day was 28.9% (95% CI: 28.2-29.6).6,9

�e prevalence of current use of tobacco was 15.0% (95% CI: 14.4%-15.5%), and most of this was smoked (14.7%; 95% CI: 14.2%-15.2%). Over the 12-month period preceding the inter-view, 51% (95% CI: 49.3%-52.9%) of the current smokers had tried to stop smoking. �e prevalence of former smokers was 17.5% (95% CI: 16.9%-18.0%), i.e. 19.2% (95% CI: 18.3%-20.1%)

among men and 11.2% (95% CI: 10.6%-11.8%) among women. �e prevalence of exposure to tobacco smoke at home was 10.7% (95% CI: 10.2%-11.3%) and in closed work locations it was 13.5% (95% CI: 12.6%-14.4%). It should be noted that the prevalence of tobacco use in 2008 had been 18%, and, therefore, a 20% reduc-tion took place over the subsequent �ve years.10

The prevalence of abusive alcohol consumption was 13.7% (95% CI: 13.1%-14.2%), and this was greater among men (21.6%; 95% CI: 20.7-22.5%) than among women (6.6%; 95% CI: 6.1-7.1%). Higher prevalence was observed among young adults, i.e. 18 to 29 years of age (18,8%; 95% CI: 17.5-20.0%), individuals with black skin color (16.6%; 95% CI: 14.9-18.4%), occasional smokers (35.2%; 95% CI: 30.4-40.0%), individuals who assessed their own health as good or very good (15.6%; 95% CI: 14.9-16.3%) and individuals without any reported morbidity.11

Regarding chronic non-transmissible diseases (CNTDs), 36.9% reported having at least one. It has been estimated that more than 53 million Brazilians have prior diagnoses of some form of CNTD. �e most prevalent CNTD was self-reported arterial hypertension (21.4%), followed by chronic spinal prob-lems (18.5%), depression (7.6%), arthritis (6.4%), diabetes (6.2%), asthma (4.4%), heart disease (4.2%), cancer (1.8%), stroke (1.5%), kidney failure (1.4%) and lung disease (1.8%) (Table 2).12

�e prevalence of reported hypertension was greater among women (24.2%; 95% CI: 23.4-24.9), individuals over the age of 75 years (55.0%; 95% CI: 51.8-58.3), individuals with lower school-ing levels (31.1%; 95% CI: 30.1-32.2), individuals of black skin color/race (24.2%; 95% CI: 22.2-26.3) and people living in urban zones (21.7%; 95% CI: 21.0-22.3).13

Risk and protection factorsTotal Male Female

% 95% CI % 95% CI % 95% CIFoods

Consumption of fruits and vegetables 37.3 36.4-38.1 34.8 33.7-36.0 39.4 38.4-40.5Consumption of beans 71.9 71.2-72.6 76.8 75.8-77.7 67.6 66.6-68.5Consumption of meats with excess fat 37.2 36.4-38.0 47.2 46.0-48.4 28.3 27.3-29.2Consumption of soft drinks 23.4 22.7-24.1 26.6 25.6-27.6 20.5 19.7-21.3

Physical activityPracticing of physical activity during free time 22.5 21.8-23.1 27.1 26.1-28.0 18.4 17.5-19.2Insu�ciently active 46.0 45.2-46.8 39.8 38.7-40.8 51.5 50.5-52.5Watching television for three or more hours per day 28.9 28.2-29.6 25.5 24.5-26.6 31.9 31.0-32.8

AlcoholAbusive consumption of alcohol 13.7 13.1-14.2 21.6 20.7-22.5 6.6 6.1-7.1

SmokingSmokers 14.5 14.0-15.0 18.7 17.8-19.5 10.8 10.2-11.3Former smokers 17.5 16.9-18.0 21.2 20.3-22.1 14.1 13.4-14.8Passive smokers at home 10.7 10.2-11.3 9.5 8.8-10.3 11.7 10.9-12.4Passive smokers at work 13.5 12.6-14.4 16.9 15.5-18.2 10.4 9.3-11.5

Table 1. Risk factors for and protection against chronic non-transmissible diseases (CNTDs) according to sex, with 95% confidence intervals (95% CI)6

EDITORIAL | Malta DC, Szwarcwald CL

288 Sao Paulo Med J. 2015; 133(4):286-9

Self-reported diabetes was registered more frequently among women (7.0%; 95% CI: 6.5-7.5) than among men (5.4%; 95% CI: 4.8-5.9); and more frequently among people living in urban areas (6.5%; 95% CI: 6.1-6.9) than in rural areas (4.6%; 95% CI: 4.0-5.2). It has been estimated that a total of approximately 9 million Brazilians have diabetes, and around 3.5 million of them are 65 years of age or older.14

�e self-reported prevalence of chronic spinal problems was 18.5% (95% CI: 17.8-19.1) and this was greater among women (21.1%; 95% CI: 20.2-21.9) and individuals with low schooling levels (24.6%; 95% CI: 23.5-25.6). Among the individuals who reported having spinal problems, 16.4% (95% CI: 15.2-17.6) said that they had a high or very high degree of limitations in relation to their habitual activities, especially those in rural areas (20.3%; 95% CI: 17.5-23.0). �e prevalence of work-related musculoskel-etal disorders (WRMD) was 2.4% (95% CI: 2.2-2.7), and this was greater among women (3.3%; 95% CI: 2.9-3.7) and individuals with higher education (3.8; 95% CI: 3.0-4.7).15

Out of the total number of hypertensive individuals, 81.4% (95% CI: 80.1-82.7) were using medications to treat CNTDs, with greatest use in the southern region (83.6%; 95% CI: 80.8-86.4), by women (84.6%; 95% CI: 83.2-86.5) and by individuals over the age of 75 years (92.2%; 95% CI: 89.7-94.6). Among those who reported having diabetes and depression, 80.2% (95% CI: 78.0-82.5) and 52.0% (95% CI: 49.1-54.9) were using medica-tions, respectively, with greatest use in the southeastern region for both of these diseases (84.6% and 55.0%). Out of the total number of patients who reported having asthma, 81.5% (95% CI: 77.4-85.6) were using medications, and there were no di�erences in this regard between the Brazilian macroregions. �e role of the Brazilian National Health System (Sistema Único de Saúde, SUS) with regard to access to healthcare services and medications can

be highlighted, both through primary healthcare units and at public-service pharmacies. SUS facilitates access to medications precisely for the population of lower schooling and income levels and black skin color.16

In conclusion, PNS is the most extensive such survey ever car-ried out in Brazil, with good quality and reliability, and it provides a wealth of information for healthcare in this country. Its data are of inestimable value for planning and evaluating healthcare ser-vices, both in the public and in the private sector. Summarizing its �ndings, the Brazilian population presented high prevalence rates of risk factors for CNTDs in adults.17 �e prevalence of consump-tion of unhealthy foods, which are considered to be risk factors for CNTDs, was high. On the other hand, the survey also showed that there was high prevalence of consumption of beans, �sh and fruits and vegetables in the diet of the adult population of Brazil.6 Tobacco consumption presented a reduction of 20% in compari-son with the �ndings of the National Household Sampling Survey (PNAD) of 2008, thus showing that important advances in com-bating smoking have been achieved in Brazil.10

Regarding CNTDs, the results from the PNS are consistent with those of other surveys that have been conducted. They show that that a large group within the Brazilian population has been diagnosed with these diseases, especially in urban areas. The results also show that there is high use of medica-tions for treating the chronic diseases investigated, which may indicate that access to treatment for these diseases has been increasing, with a prominent role played by SUS in facilitating access to diagnosis and treatment among large portions of the Brazilian population.

Data relating to access and use of healthcare services have also been released, and information on life cycles, anthropom-etry, arterial blood pressure measurements and laboratory tests will shortly be available. �ere is no doubt that these results are going to support healthcare management and research and will improve Brazilians’ health.

REFERENCES1. Brasil. Ministério do Planejamento, Orçamento e Gestão. Instituto

Brasileiro de Geogra�a e Estatística - IBGE (Brasil). Pesquisa Nacional

de Saúde: Percepção do estado de saúde, estilos de vida e doenças

crônicas: 2013. Rio de Janeiro: IBGE; 2014.

2. Damacena GN, Szwarcwald CL, Malta DC, et al. O processo de

desenvolvimento da Pesquisa Nacional de Saúde no Brasil, 2013

[The Development of the National Health Survey in Brazil, 2013].

Epidemiol Serv Saúde. 2015;24(2):197-206.

3. Souza-Júnior PRB, Freitas MPS, Antonaci GA, Szwarcwald CL.

Desenho da amostra da Pesquisa Nacional de Saúde 2013 [Sampling

Design for the National Health Survey, 2013]. Epidemiol Serv Saúde.

2015;24(2)207-16.

Morbidity Total Male FemaleArterial hypertension 21.4 18.3 24.2Diabetes 6.2 5.4 7.0Asthma 4.4 3.6 5.1Depression 7.6 3.9 10.9Other mental disease 0.9 0.9 1.0Heart disease 4.2 3.9 4.4Stroke 1.5 1.6 1.4Arthritis 6.4 3.5 9.0Spinal problems 18.5 15.5 21.1WRMD 2.4 1.5 3.3Cancer 1.8 1.6 2.0Chronic kidney failure 1.4 1.4 1.5Lung disease 1.8 1.7 1.8

Table 2. Total number of individuals who reported having morbidities, according to sex, National Health Survey, 201312

WRMD = work-related musculoskeletal disease.

Lifestyles and chronic non-transmissible diseases of the Brazilian population according to the National Health Survey: balance of the main results | EDITORIAL

Sao Paulo Med J. 2015; 133(4):286-9 289

4. Szwarcwald CL, Malta DC, Pereira CA, et al. Pesquisa Nacional de

Saúde no Brasil: concepção e metodologia de aplicação [National

Health Survey in Brazil: design and methodology of application].

Ciênc Saúde Coletiva. 2014;19(2):333-42.

5. Jaime PC, Stopa SR, Oliveira TP, et al. Prevalência e distribuição

socidemográ�ca de marcadores de alimentação saudável, Pesquisa

Nacional de Saúde, Brasil 2013 [Prevalence and sociodemographic

distribution of healthy eating markers, National Health Survey, Brazil

2013]. Epidemiol Serv Saúde. 2015;24(2)267-76.

6. Malta DC, Andrade SSCA, Stopa SR, et al. Estilos de vida da população

brasileira: resultados da Pesquisa Nacional de Saúde, 2013 [Brazilian

lifestyles: National Health Survey results, 2013] Epidemiol Serv Saúde.

2015;24(2):217-26.

7. Claro RM, Santos MAS, Oliveira TP, et al. Consumo de alimentos

não saudáveis relacionados a doenças crônicas não transmissíveis

no Brasil: Pesquisa Nacional de Saúde, 2013 [Unhealthy food

consumption related to chronic non-communicable diseases

in Brazil: National Health Survey, 2013]. Epidemiol Serv Saúde.

2015;24(2):257-65.

8. Oliveira MM, Malta DC, Santos MAS, et al. Consumo elevado de

sal autorreferido em adultos: dados da Pesquisa Nacional de

Saúde, 2013 [Self-reported high salt intake in adults: data from

the National Health Survey, Brazil, 2013]. Epidemiol Serv Saúde.

2015;24(2):249-56.

9. Mielke GI, Hallal PC, Rodrigues GBA, et al. Prática de atividade física

e hábito de assistir à televisão entre adultos no Brasil: Pesquisa

Nacional de Saúde 2013 [Physical activity and television viewing

among Brazilian adults: National Health Survey 2013]. Epidemiol Serv

Saúde. 2015;24(2):277-86.

10. Malta DC, Oliveira TP, Vieira ML, Almeida L, Szwarcwald CL. Uso e

exposição à fumaça do tabaco no Brasil: resultados da Pesquisa

Nacional de Saúde 2013 [Use of tobacco and exposure to tobacco

smoke in Brazil: results from the National Health Survey 2013].

Epidemiol Serv Saúde. 2015;24(2):239-48.

11. Garcia LP, Freitas LRS. Consumo abusivo de álcool no Brasil: resultados

da Pesquisa Nacional de Saúde 2013 [Heavy drinking in Brazil: results

from the 2013 National Health Survey]. Epidemiol Serv Saúde.

2015;24(2):227-37.

12. Malta DC, Stopa SR, Barbosa, J et al. A Vigilância e o Monitoramento

das Principais Doenças Crônicas Não Transmissíveis no Brasil -

Pesquisa Nacional de Saúde, 2013. Rev Brasileira de Epidemiologia.

2015. Prelo.

13. Andrade SSA, Stopa SR, Brito AS, et al. Prevalência de hipertensão

arterial autorreferida na população brasileira: análise da Pesquisa

Nacional de Saúde, 2013 [Self-reported hypertension prevalence

in the Brazilian population: analysis of the National Health Survey,

2013]. Epidemiol Serv Saúde. 2015;24(2):297-304.

14. Iser BPM, Stopa SR, Chueiri PS, et al. Prevalência de diabetes

autorreferido no Brasil: resultados da Pesquisa Nacional de Saúde

2013 [Self-reported diabetes prevalence in Brazil: results from National

Health Survey 2013]. Epidemiol Serv Saúde. 2015;24(2):305-14.

15. Oliveira MM, Andrade SSCA, Souza CAV, et al. Problema crônico de

coluna e diagnóstico de distúrbios osteomusculares relacionados ao

trabalho (DORT) autorreferidos no Brasil: Pesquisa Nacional de Saúde,

2013 [Chronic back complaints and diagnosis of self-reported work-

related musculoskeletal disorders (WMSDs) in Brazil: National Health

Survey, 2013]. Epidemiol Serv Saúde. 2015;24(2):287-96.

16. Tavares NUL, Costa KS, Mengue SS, et al. Uso de medicamentos

para tratamento de doenças crônicas não transmissíveis no Brasil:

resultados da Pesquisa Nacional de Saúde, 2013 [Use of medication

for treatment of noncommunicable chronic diseases in Brazil: results

from the National Health Survey, 2013]. Epidemiol Serv Saúde.

2015;24(2):315-23.

17. Garcia LP. Primeiros resultados da Pesquisa Nacional de Saúde,

big data e relato de revisões sistemáticas. Epidemiol Serv Saúde.

2015;24(2):195-6.

Sources of funding: None

Con�ict of interest: None

Date of submission: July 28, 2015

Last received: August 3, 2015

Accepted: August 3, 2015

Address for correspondence:

Deborah Carvalho Malta

Departamento de Vigilância de Doenças e Agravos Não Transmissíveis e

Promoção da Saúde

Secretaria de Vigilância em Saúde, Ministério da Saúde

SAF Sul, Trecho 2, Lote 5/6, Torre I, Edifício Premium, Sala 16, Térreo

Brasília (DF) — Brasil

CEP 70070-600

Tel. (+55 61) 3315-7701

E-mail: [email protected]

290 Sao Paulo Med J. 2015; 133(4):290-7

ORIGINAL ARTICLE DOI: 10.1590/1516-3180.2014.8381508

WOMAC and SF-36: instruments for evaluating the health-related quality of life of elderly people with total hip arthroplasty. A descriptive studyWOMAC e SF-36: instrumentos para avaliar a qualidade de vida relacionada à saúde de idosos com artroplastia total de quadril. Um estudo descritivoMariana Kátia Rampazo-LacativaI, Ariene Angelini dos SantosII, Arlete Maria Valente CoimbraIII, Maria José D’ElbouxIV

Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil

ABSTRACTCONTEXT AND OBJECTIVES: Quality-of-life results have increasingly been evaluated among patients undergoing joint replacements. The objective of this study was to compare two assessment instruments for health-related quality of life (one generic and the other speci�c), among elderly patients undergoing total hip arthroplasty.DESIGN AND SETTING: Cross-sectional descriptive study in a reference hospital in the region of Campinas. METHODS: The subjects were 88 elderly outpatients aged 60 years or over who underwent primary to-tal hip arthroplasty. Two instruments for assessing health-related quality of life were applied: the generic Medical Study 36-item Short-Form Health Survey (SF-36) and the speci�c Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Cronbach’s alpha and the ceiling and �oor e�ects of the instru-ments were evaluated.RESULTS: The scores from both instruments showed that issues of a physical nature a�ected these elderly people’s quality of life most. The pain and sti�ness dimensions of WOMAC showed ceiling e�ects and only the functional capacity and pain dimensions of the SF-36 did not show the ceiling e�ect. The SF-36 pre-sented �oor e�ects in the dimensions of physical and emotional aspects. Cronbach’s alpha was considered satisfactory in both instruments (α > 0.70). CONCLUSIONS: The �oor and ceiling e�ects that were observed suggest that these instruments may present some limitations in detecting changes to the majority of the SF-36 dimensions, except for func-tional capacity and pain, and to the pain and sti�ness dimensions of WOMAC, when applied to elderly people with total hip arthroplasty.

RESUMOCONTEXTO E OBJETIVO: Os resultados sobre a qualidade de vida têm sido cada vez mais avaliados em pacientes submetidos a substituições articulares. Este estudo objetivou comparar dois instrumentos de avaliação de qualidade de vida relacionada à saúde (um genérico e outro especí�co), em pacientes idosos submetidos a artroplastia total de quadril. TIPO DE ESTUDO E LOCAL: Estudo descritivo transversal em hospital de referência da região de Campinas. MÉTODOS: Os sujeitos foram 88 pacientes idosos ambulatoriais, com 60 anos ou mais, submetidos a artroplastia total de quadril primária. Foram aplicados dois instrumentos de avaliação de qualidade de vida relacionada à saúde: Medical Study 36-item Short-Form Health Survey (SF-36) (genérico) e Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (especí�co). O coe�ciente alfa de Cronbach e os efeitos teto e chão dos instrumentos foram avaliados. RESULTADOS: Os escores de ambos os instrumentos mostraram que as questões de natureza física são as que mais afetam a qualidade de vida desses idosos. As dimensões dor e rigidez do WOMAC apresentaram efeito teto e apenas as dimensões capacidade funcional e dor do SF- 36 não mostraram o efeito teto. O SF-36 apresentou efeito de chão nas dimensões: aspectos físicos e aspectos emocionais. O coe�ciente alfa de Cronbach foi considerado satisfatório nos dois instrumentos (α > 0.70). CONCLUSÕES: A constatação dos efeitos chão e teto sugere que esses instrumentos podem apresentar algumas limitações, quando aplicados em idosos com artroplastia total de quadril, para detectar alte-rações na maioria das dimensões do SF-36, exceto capacidade funcional e dor, e nas dimensões dor e rigidez do WOMAC.

IMSc. Physiotherapist and Doctoral Student, School of Nursing, Universidade Estadual de Campinas (Unicamp) Campinas, São Paulo, Brazil. IIPhD. Nurse, School of Nursing, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.IIIPhD. Professor, Family Health Program, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.IVPhD. Professor, Postgraduate Gerontology Program, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.

KEY WORDS:Arthroplasty, replacement, hip.Osteoarthritis, hip.Aged.Quality of life.Health of the elderly.

PALAVRAS-CHAVE:Artroplastia de quadril.Osteoartrite do quadril.Idoso.Qualidade de vida.Saúde do idoso.

WOMAC and SF-36: instruments for evaluating the health-related quality of life of elderly people with total hip arthroplasty. A descriptive study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):290-7 291

INTRODUCTIONWith increasing aging of the population, there is ever-greater prevalence of non-transmissible chronic diseases. Among these, osteoarthritis stands out as one of the most common joint dis-eases in the elderly population, a�ecting more than one third of people over 60 years of age.1

In Brazil, it is the most common rheumatic disease, respon-sible for 7.5% of all absences from work, the second most fre-quent condition in relation to obtaining sickness bene�ts, and the fourth in determining retirement. Hip osteoarthritis has become a growing problem in Western societies and is a major cause of morbidity and disability among the elderly.2

Among the elderly population, there is high incidence of fractures of the proximal femur. It has been estimated that the incidence of this type of fracture will reach 6.3 million cases by 2050, with the growth of older age groups within the world population.3 Most hip fractures are caused by falls, and they are a major cause of morbidity and mortality among the elderly. Such fractures are responsible for most of the surgical proce-dures, including hip replacement, and for most bed occupancy in orthopedic wards.4-6

In the light of these hip disorders a�ecting the elderly and given the technological advance that have been achieved, total hip arthroplasty has become a widely used method for surgi-cal treatment. �is consists of replacing the hip joint and has the purposes of restoring function and promoting pain relief in this joint.2,7

Total hip arthroplasty is called primary when referring to the �rst surgery on the hip that will be replaced. It has become one of the most common and most successful orthopedic surgical pro-cedures performed today, providing great bene�ts, especially for the elderly population.8,9

In relation to outcomes used in analyzing the e�ective-ness of medical treatments or orthopedic surgery, a change has been seen over the last few years. Although clinical changes evaluated through physical and complementary examinations are used in such analyses, health-related quality of life, func-tion, pain scales and satisfaction scales have been emphasized as some of the outcomes from medical and surgical interven-tions, over recent years. �ese parameters enable analysis on health status and disease manifestations within an individual’s life from his own subjective perspective, thereby complement-ing the objective clinical data.10

�e improvement in health-related quality of life a�er pri-mary total hip arthroplasty has been documented in several studies.11-17 Concern regarding this issue among the elderly pop-ulation undergoing this surgical procedure has been highlighted over recent years,6,7,18-20 and this shows the importance of such evaluations and clinical research.

With regard to health-related quality of life, two groups of tools stand out: generic tools, which are intended for measuring broader dimensions of quality of life; and speci�c tools, which are designed for measuring the dimensions of quality of life in speci�c groups, such as individuals with deformities and dis-abilities. Both types have advantages and limitations. Among the tools used for evaluating the health-related quality of life in the population with total hip arthroplasty, the generic Medical Study 36-item Short-Form Health Survey (SF-36)21 and the spe-ci�c Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)22 stand out because of their high levels of use.

In the worldwide literature, studies designed to evaluate the psychometric properties of instruments for measuring health-related quality of life among patients with total hip arthroplasty are still at an incipient stage.23-25

With regard to WOMAC, in Brazil, it can be seen that there is a need for this tool to be used more widely in studies evaluating health-related quality of life among patients who undergo total hip arthroplasty, given that in comparison with SF-36, WOMAC has higher sensitivity to small changes in health status, when applied to populations that underwent this surgery.25 Furthermore, we found only two studies that assessed the quality of life and func-tion of patients with primary total hip arthroplasty.26,27

Use of a generic tool, complemented by application of a spe-ci�c tool to assess health-related quality of life when analyz-ing this type of condition, has the advantage of evaluating the patients’ perception of their general health status combined with the possibility of detecting speci�c clinical changes to health-related quality of life a�er primary total hip arthroplasty.8,10,28

�e performance characteristics of generic and speci�c tools used in the elderly and general populations di�er from each other.29 Concerning the SF-36, it is important to mention that one study found that this tool is a reliable way of assessing health-related quality of life among elderly patients undergoing primary total hip arthroplasty.8 Both SF-3630 and WOMAC31 have been culturally adapted and validated for the Brazilian context.

OBJECTIVE�e objective of this study was to evaluate the performance of the Brazilian versions of the SF-36 and WOMAC tools in the elderly population, with regard to ceiling and �oor e�ects and to their internal consistency, as assessed using Cronbach’s alpha.

METHODS�e subjects of this study were elderly patients of both sexes, aged over 60 years, who underwent primary unilateral total hip arthroplasty and were outpatients at two major referral hospitals in the state of São Paulo, Brazil. �e study was approved by the Ethics Committee of each institution and all participants signed a consent form.

ORIGINAL ARTICLE | Rampazo-Lacativa MK, Santos AA, Coimbra AMV, D’Elboux MJ

292 Sao Paulo Med J. 2015; 133(4):290-7

Patients were enrolled in the study on the day of their rou-tine outpatient medical visit that had previously been scheduled, to determine the preferences of patients and their companions or caregivers about the best time to make the assessment for the study, i.e. before or a�er the consultation. �rough this, a conve-nience sample was characterized. We included patients who had undergone unilateral primary total hip arthroplasty at least six months earlier and who were able to understand instructions and to communication verbally. Patients with visual de�cits, hemipa-resis or hemiplegia, or who had a history of other arthroplasty procedures in another joint that would distort the functioning of the joint now operated, were excluded in order to eliminate the in�uence of surgical interventions other than total hip arthro-plasty on the perception of health-related quality of life. Patients who refused to participate in the study were also excluded.

Data-gathering was performed by the �rst author of the study, from September 2007 to March 2008. �is consisted of consult-ing the medical records in order to obtain data referring to the patient’s clinical condition and conducting individual interviews to obtain sociodemographic characterizations and measure the health-related quality of life.

Measurement toolsA sociodemographic and clinical characterization instrument was used to record information on the interviewees relating to social characteristics, health and total hip arthroplasty. �is instrument was built speci�cally for this study and it passed through examination by a professional expert group (phys-iotherapist, nurse, rheumatologist and orthopedic surgeon). It sought the following sociodemographic data: sex, age, mari-tal status and living arrangements; and information about inter-viewees’ clinical characteristics: comorbidities, use of medicine, pain in the operated hip, other joint pain, use of walking aids and body mass index. �e total hip arthroplasty data included: reason for surgery, hip function evaluated by means of the Harris Hip Score, duration of clinical follow-up, length of post-operative period, type of prosthesis �xation and satisfaction with the results from the surgery.

�e Harris Hip Score tool32 is an internationally validated hip function evaluation instrument for patients with total hip arthroplasty.23 Inclusion of this tool was justi�ed because of its frequent use among local healthcare professionals for functional evaluations of the hip. It consists of a scale on which the total score ranges from 0 to 100 points and the dimensions include pain, function, deformity and range of motion. �e maximum score for the pain dimension is 44 points and for the function dimension, 47 points. �e latter is subdivided into activities of daily living (ADLs) and walking, with 14 and 33 points respec-tively. For the deformity dimension, up to four points can be

assigned and for the range of motion, up to �ve points. �e func-tional outcome is considered poor if the total Harris Hip score is less than 70 points. Fair scores are between 70 and 79, good scores are between 80 and 89 and excellent scores are between 90 and 100 points.

�e Medical Outcomes Study 36-item Short-Form Health Survey (SF-36)21 is a generic tool for assessing health-related quality of life that has been translated and validated for use in Brazil.30 It consists of 36 items divided into eight dimensions: functional capacity (ten items), physical aspects (four items), pain (two items), general health status (�ve items), vitality (four items), social aspects (two items), emotional aspects (three items) and mental health (�ve items), and one question making a comparative evaluation between current health conditions and the conditions one year ago. �e results are evaluated by assign-ing scores for each question and then transforming the scores into a scale from 0 to 100, on which zero corresponds to “worst health status” and 100 to “best health status”. �ere are no cuto� points and each dimension is evaluated separately.

�e Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)22 is a speci�c quality-of-life tool for patients with osteoarthritis of hip and knee that has been translated and adapted for use in Brazil.31 It is indicated for use in postoperative evaluations on total knee and hip arthro-plasty procedures.23,25 �is questionnaire was originally devel-oped to be self-administered, but it has been used in interviews and telephone surveys, and, most recently, a computerized ver-sion (via e-mail) has also been validated. It comprises 24 items, divided into three dimensions. �e pain dimension has �ve questions, the joint sti�ness dimension has two questions and the physical disability dimension has 17 questions. Each ques-tion has �ve possible answers, on a Likert scale (“not at all”, “slightly”, “somewhat”, “moderate” and “extremely”), which are graded 0, 1, 2, 3 and 4, respectively. �us, zero represents the absence of the symptom and 4 the worst result regarding to that symptom. �rough summing the scores, each dimen-sion receives a score that is transformed into a scale of 0 to 100 points, with zero representing the best health status and 100 the worst possible status.

Statistical analysis�e data were analyzed using SAS for Windows (Statistical Analysis System), version 8.02 (SAS Institute, Inc., Inc., Cary, NC, USA).

Descriptive statistics were used to present the frequency dis-tribution and to calculate the mean, standard deviation, median and range of the sociodemographic and clinical variables and of the data from the health-related quality of life evaluation. To cal-culate the ceiling and �oor e�ects of the instruments (SF-36 and


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WOMAC), the proportion of 10% of the best possible score for the tool dimensions was used for the ceiling e�ect and the pro-portion of 10% of the worst possible score for the tool dimensions was used for the �oor e�ect.33 Presence of a ceiling e�ect was con-�rmed when there was asymmetrical distribution of scores and a signi�cant percentage of the population in the study scored at the highest levels for the parameter. �us, for individuals whose scores were at the extremity of the range of improvement regard-ing perceptions of health-related quality of life (HRQoL), the instrument would not be able to detect this. �e �oor e�ect, in turn, re�ected the percentage of subjects whose scores were at the lowest level of the parameter. �is type of asymmetrical dis-tribution hampers detection of worsening of perceived HRQoL among the subjects evaluated. �is measurement property relates to the ability of the instrument to detect and estimate the magni-tude of changes in health condition over time.33,34

�e internal consistency was assessed by means of Cronbach’s alpha and α = 0.70 was considered to be satisfactory.35

�e signi�cance level for statistical tests was 5%, i.e. P < 0.05.

RESULTS

Sociodemographic and clinical characterizationOver the study period, 88 patients were enrolled. Among the patients studied, 54.6% were female, most were married and the mean age was 68.8 ± 7.4 years. �e average number of comor-bidities among the subjects was 3.3 ± 1.5. Forty-nine patients (55.6%) reported pain in the operated hip, but 82 (93.2%) reported pain in other joints. With regard to nutritional status, 23 patients (26.1%) were obese and 49 (55.7%) did not use any walking aid.

�e average Harris Hip score was 73.4 ± 19.0, which was con-sidered to be a functional result. However, a greater proportion of elderly patients (39.8%) scored fewer than 70 points, or pre-sented poor hip function (39.8%). It was noteworthy that the most common reason for undergoing surgery among the sam-ple was hip osteoarthritis (84.19%), and these patients remained under clinical follow-up for a mean time of 69.3 ± 55.7 months. �e type of �xation used for the prosthesis was most frequently cemented (58.0%) and the mean postoperative period was 59.6 ± 52.4 months (Table 1).

Health-related quality of life Table 2 shows the scores for each dimension of the assessment of health-related quality of life using the SF-36 and WOMAC. Regarding the SF-36, the patients showed higher scores in the dimensions that assess social aspects, vitality and general health status and lower averages in the dimensions that assess physical aspects, functional capacity and pain.

In relation to WOMAC, the patients had lower average scores in the dimensions of pain and sti�ness, which indicates that pain and sti�ness had a minor impact on the quality of life of these elderly people. Although the dimension relating to physical activity had a higher average than the other dimen-sions, it could be seen from analyzing the observed variation that this dimension did not reach higher scores than those achieved in the pain dimension.

Table 1. Sociodemographic and clinical characteristics of the total hip arthroplasty subjects studied (n = 88)

Variables n (%)Average

(SD)Median

Observed range

SexFemale 48 (54.6)Male 40 (45.4)

Age (in years) 68.8 (7.4) 67.0 60-87Marital status

Married 60 (68.2)Widow/single/divorced 28 (31.8)

Living arrangementsAlone 6 (6.8)With family/partner/children

82 (93.2)

Presence of comorbidities 87 (98.8) 3.3 (1.5) 3.0 0-7Body mass index ≥ 30 kg/m2 23 (26.1)Pain in operated hip 49 (55.6)Pain in other joints 82 (93.1)Use of medicine 83 (94.3) 2.8 (1.6) 3.0 0-8Use of walking aids 39 (44.3)Hip function* 88 (100.0) 73.4 (19.0) 74.8 21.1-100

Excellent 21 (23.9) Good 20 (22.7) Fair 12 (13.6) Poor 35 (39.8)

Reason for surgery Hip osteoarthritis 74 (84.1)Fracture of the proximal femur

11 (12.5)

Avascular necrosis of the femoral head

3 (3.4)

Duration of clinical follow-up (in months)

88 (100) 69.3 ± 55.7 48.0 8-252

Postoperative period (in months)

88 (100) 59.6 ± 52.4 45.5 6-216

Type of prosthesis �xationCemented 51 (58.0)Non-cemented 19 (21.6)Hybrid 18 (20.4)

Satisfaction with surgery High 68 (77.3)Moderate 16 (18.2)Low 4 (4.5)

SD = standard deviation; *Harris Hip Score.


294 Sao Paulo Med J. 2015; 133(4):290-7

Table 3 describes the mean SF-36 and WOMAC scores of this study and other studies that used these tools. In analyzing the ceiling and �oor e�ects, through measuring the proportion of 10% of the best and worst possible scores obtained on the scales,35 these two tools showed a ceiling e�ect in their dimensions.

WOMAC showed a ceiling e�ect in the pain and sti�ness dimensions, such that the largest population of the patients was concentrated within the sti�ness dimension. Only the functional capacity and pain dimensions of the SF-36 did not show the ceiling e�ect. Among the other dimensions, which presented the ceiling e�ect, higher proportions of patients were found in the dimensions of emotional, social and physical aspects and vital-ity. �e SF-36 also presented �oor e�ects regarding physical and emotional aspects (Table 4).

In comparing the ceiling and �oor e�ects of these two tools with the hip function of the Harris Hip Score, patients who scored within the ceiling e�ect, in both the WOMAC and the SF-36 tools, showed better hip function (P < 0.05). On the other hand, those who scored within the �oor e�ect of the SF-36 showed worse hip function (P = 0.01).

�e reliability of the WOMAC and the SF-36 tools, as eval-uated according to their internal consistency, was satisfactory. All the dimensions presented values greater than 0.7, except for the WOMAC sti�ness dimension (Table 4).

DISCUSSIONRegarding the SF-36, higher scores that indicated better quality of life were observed in the dimensions of social aspects, vitality, general

Table 2. Scores for the dimensions of the SF-36 and WOMAC, for 88 elderly patients with total hip arthroplasty

Dimensions nAverage

(SD)Median

Observed range

SF-36Functional capacity 88 45.4(21.9) 45.0 0-90

Physical aspects 88 39.0 (39.9) 25.0 0-100

Pain 88 50.1 (25.5) 51.0 0-100

General health status 88 65.9 (27.2) 77.0 0-100

Vitality 88 67.2 (22.7) 75.0 10-100

Social aspects 88 67.9 (27.4) 75.0 0-100

Emotional aspects 88 55.3 (41.9) 66.6 0-100

Mental health 88 62.2 (23.5) 66.0 12-96

WOMACPain 88 18.9 (19.5) 12.5 0-85.0

Sti�ness 88 7.6 (11.2) 0.0 0-50.0Physical activity 88 27.8 (16.9) 23.5 5.8-75.0

SF-36 = short-form health survey; SD = standard deviation; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; possible variation for each category: 0-100.

health and mental health status, while lower scores were observed in the dimensions of physical aspects and functional capacity.

In applying WOMAC in relation to the physical dimension, those who referred to physical activities of daily life showed a higher mean score for this than for the other dimensions, thus indicating that these patients’ quality of life seemed to be more related to the di�culty of performing everyday activities. �ese data were similar to those of a study in which the subjects also had higher scores in the physical activity dimension.24,36 Other studies have described similar results.12,13,37,38

Previous studies have described health-related quality of life among elderly people with total hip arthroplasty.8,18 While there are some results that resemble those of the present study, i.e. lower scores in the functional capacity and physical appearance dimensions,18 the authors Wood and McLauchlan found lower means for the general health and mental health status dimen-sions of the SF-36.8 Studies on elderly populations with other chronic diseases have described functional ability and physical aspects as the dimensions of the SF-36 that most a�ect health-related quality of life.39,40 �us, the �ndings from the present sur-vey show that, although this population had undergone a surgical intervention with the aim of functional improvement, physical problems were still the ones that most a�ected health-related quality of life among elderly patients with total hip arthroplasty.

In this study, WOMAC showed a ceiling e�ect in the pain and sti�ness dimensions, with a greater proportion than what was shown in another investigation that also found a ceiling e�ect in the physical activity dimension.16 Another similarity was the absence of �oor e�ects in all the dimensions of WOMAC.

In contrast, in a study on a sample of 469 subjects with total hip arthroplasty, WOMAC presented �oor e�ects in the sti�ness and pain dimensions and did not show ceiling e�ects in any of the three dimensions.24 �e presence of a ceiling e�ect in the pain and sti�ness dimensions may indicate that these dimensions are probably not capturing changes in the population studied, which suggests that the tool may be “unable to measure” or “measures very little of ” patients’ improvements in these dimensions.

With regard to the SF-36, �oor e�ects were found in the physical and emotional aspect dimensions. �ese data were sim-ilar to those of another study,24 but with smaller proportions of subjects. Ceiling e�ects occurred in the physical, social and emotional aspect dimensions in the earlier study a�er total hip arthroplasty, thus con�rming the data from the present study, which in addition to these dimensions, also showed ceiling e�ects in relation to the general health status and vitality dimen-sions. In another study, no e�ect was detected through the SF-12, which thus indicates that this tool had better performance with regard to picking up positive or negative changes in patients with total hip arthroplasty.16


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According to some authors,34 the existence of ceiling and �oor e�ects in the tools indicates that their items or scales may have di�culty in discriminating between the subjects and, therefore, present reduced sensitivity and responsiveness. Consequently, patients whose scores are within the �oor e�ect of a tool may be in “such a bad” condition that the tool is unable to detect wors-ening of their condition. On the other hand, patients whose scores are within the ceiling e�ect of a tool show little possibility of improvement, thus indicating that the tool is unable to detect improvement. In the present investigation, the �oor and ceiling e�ects obtained seemed to indicate that some issues among the population studied, namely elderly patients undergoing total hip arthroplasty, were handled inadequately.

By comparing the �oor and ceiling e�ects of the WOMAC and SF-36 with hip function evaluated using the Harris Hip Score, it was clear that patients with better functional scores showed a ceiling e�ect, and patients who were considered to be function-ally worse had scores within the �oor e�ect. �is result shows that patients with minor limitations were concentrated among

the best possible scores of the tools, while those with major limi-tations showed the worst possible scores of the tools.

�e internal consistency of the WOMAC and SF-36 tools was satisfactory. �e Cronbach’s alpha values were greater than 0.90 for the pain and physical activity dimensions of WOMAC. �ese data are similar to those of previous studies that showed satisfac-tory reliability for this tool; however, in the pain dimension, the alpha values were greater than 0.80.24,41

In the sti�ness dimension, the Cronbach’s alpha value was 0.48, which does not correspond with �ndings from other stud-ies,24,41 which presented values greater than 0.80. �is diver-gence may have occurred because the population of the present study was exclusively elderly, which would therefore indicate that this tool showed di�erent behavior for this population. �e inclusion criteria may also have contributed, since the sample consisted of subjects who theoretically had resolved their issue of sti�ness through the surgery. Moreover, these earlier stud-ies24,41 were not composed solely of elderly patients because age was not an inclusion criterion.

Table 4. Descriptive analysis of the �oor and ceiling e�ects obtained in this study Scale/Dimension Number of items Range Floor e�ect* (%) Ceiling e�ect† (%) Coe�cient‡

SF-36 – functional capacity 10 0-100 3.4 1.1 0.87SF-36 – physical aspects 4 0-100 37.5 22.7 0.84SF-36 – pain 2 0-100 0.0 7.9 0.84SF-36 – general health status 5 0-100 2.2 19.3 0.85SF-36 – vitality 4 0-100 1.1 21.5 0.80SF-36 – social aspects 2 0-100 1.1 26.1 0.72SF-36 – emotional aspects 3 0-100 28.4 39.7 0.80SF-36 – mental health 5 0-100 0.0 11.3 0.86WOMAC – pain 5 0-100 0.0 50.0 0.91WOMAC – sti�ness 2 0-100 0.0 60.2 0.48WOMAC – physical activity 17 0-100 0.0 7.9 0.94

SF-36 = short-form health survey; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; *Floor e�ect equivalent to 10% of the worst possible results of the scale; †Ceiling e�ect equivalent to 10% of the best possible results of the scale;33 ‡Cronbach’s alpha coe�cient for Likert scales.

Table 3. Average scores for SF-36 and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) obtained in this study and in other studies SF-36 dimensions Range In this study* Lavernia et al.12† Linsell et al.18* Wood et al.8*Functional capacity 0-100 45.4 10.5 43.8 65.8Physical aspects 0-100 39.0 33.7 44.3 75.3Pain 0-100 50.1 22.2 55.1 78.5General health status 0-100 65.9 60.2 51.2 49.5Vitality 0-100 67.2 5.87 68.8 73.8Social aspects 0-100 67.9 8.07 75.3 44.3Emotional aspects 0-100 55.3 62.7 76.9 79.1Mental health 0-100 62.2 40.1 59.1 61.7WOMAC dimensions Range In this study* Fernandes31† Quintana et al.24‡ Hamel et al.38*Pain 0-100 18.9 43.2 12.2 23.9Sti�ness 0-100 7.6 43.4 15.5 20.8Physical activity 0-100 27.8 37.9 22.3 24.8

SF-36 = short-form health survey; *Elderly individuals with total hip arthroplasty; †Adults and elderly people with hip osteoarthritis; ‡Adults and elderly people with total hip arthroplasty.


296 Sao Paulo Med J. 2015; 133(4):290-7

Regarding the SF-36, all its dimensions presented Cronbach’s alpha values greater than 0.70, as also seen in some other studies,23,24,41 except for the last these, which showed an alpha of 0.67 in the pain dimension, although this was close to the criterion of satisfactory. While investigating the internal consistency of this tool in different groups of elderly people, we found that it had presented satisfactory reliability when used among elderly patients on hemodialysis and among elderly patients with heart failure.38,42

Some limitations were identi�ed in this study. �e number of subjects was relatively small. �e criteria for inclusion and exclu-sion adopted reduced the chances of a larger sample, but selected a homogeneous group of subjects in relation to surgery. Another important point was that the descriptive nature of this study did not allow us to say which instruments for assessing health-related quality of life among elderly patients with total hip arthroplasty were the most appropriate. Further investigations with more sig-ni�cant numbers of subjects, longitudinal designs and deeper statistical approaches are needed, in order to achieve better understanding of the performance of the SF-36 and WOMAC instruments when applied to elderly patients a�er this surgery.

�e analysis accomplished in this study was consistent with the recommendations in the literature regarding concomitant use of speci�c and generic tools for measuring health-related quality of life. Furthermore, the physical, psychological and social particularities of aging should be taken into consideration in clinical practice, so as to choose tools capable of assessing health-related quality of life when investigating elderly populations with total hip arthroplasty.

CONCLUSION�e WOMAC and SF-36 tools presented satisfactory levels of reli-ability in this sample, However, only the functional capacity and pain dimensions of the SF-36 showed no ceiling e�ect, and �oor e�ects were detected in the dimensions of physical and emotional aspects. �ese �ndings show that these dimensions have little sen-sitivity for detecting changes in the group evaluated. �is study also con�rmed the presence of a ceiling e�ect relating to the WOMAC pain and sti�ness dimensions. �e observation of �oor and ceiling e�ects in using these tools suggests that they may present some limi-tations when applied to elderly patients with total hip arthroplasty.

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Date of �rst submission: February 10, 2014

Last received: August 12, 2014



Mariana Kátia Rampazo Lacativa

Rua Tessália Vieira de Camargo, 126

Barão Geraldo — Campinas (SP) - Brasil

CEP 13083-887

Tel. (+55 19) 3521-8820

Cel. (+55 16) 9788-0306


298 Sao Paulo Med J. 2015; 133(4):298-306


Relationship between the Brazilian version of the Montreal-Toulouse language assessment battery and education, age and reading and writing characteristics. A cross-sectional study Relação entre a bateria Montreal-Toulouse de avaliação da linguagem, versão brasileira, e escolaridade, idade e hábitos de leitura e escrita. Um estudo transversalKarina Carlesso PagliarinI, Gigiane GindriII, Karin Zazo OrtizIII, Maria Alice Mattos Pimenta ParenteIV, Yves JoanetteV, Jean-Luc NespoulousVI, Rochele Paz FonsecaVII

School of Psychology, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: There is growing concern about understanding how sociodemographic variables may interfere with cognitive functioning, especially with regard to language. This study aimed to investigate the relationship between performance in the Brazilian version of the Montreal-Toulouse language assessment battery (MTL-BR) and education, age and frequency of reading and writing habits (FRWH). DESIGN AND SETTING: Cross-sectional study conducted in university and work environments in Rio Grande do Sul, Brazil. METHOD: The MTL-BR was administered to a group of 233 healthy adults, aged 19 to 75 years (mean = 45.04, standard deviation, SD = 15.47), with at least �ve years of formal education (mean = 11.47, SD = 4.77). RESULTS: A stepwise multiple linear regression model showed that, for most tasks, the number of years of education, age and FRWH were better predictors of performance when analyzed together rather than separately. In separate analysis, education was the best predictor of performance in language tasks, especially those involving reading and writing abilities. CONCLUSION: The results suggested that the number of years of education, age and FRWH seem to in�uence performance in the MTL-BR, especially education. These data are important for making diagnoses of greater precision among patients su�ering from brain injuries, with the aim of avoiding false positives.

RESUMOCONTEXTO E OBJETIVO: Há uma preocupação crescente com o entendimento de como as variáveis sociodemográ�cas podem interferir no funcionamento cognitivo, especialmente na linguagem. Este estudo teve como objetivo investigar a relação entre o desempenho na Bateria Montreal-Toulouse de Avaliação da Linguagem, em sua versão brasileira (MTL-BR), e a escolaridade, a idade e a frequência de hábitos de leitura e escrita (FHLE). TIPO DE ESTUDO E LOCAL: Estudo transversal conduzido em ambientes universitários e de trabalho do Rio Grande do Sul, Brasil.MÉTODOS: A Bateria MTL-BR foi administrada em um grupo de 233 adultos saudáveis, de 19 a 75 anos de idade (M = 45,04, desvio padrão, DP = 15,47), com no mínimo cinco anos de estudo formal (M = 11,47, DP = 4,77). RESULTADOS: O modelo de regressão linear múltipla (stepwise) mostrou que, para a maioria das tarefas, os anos de escolaridade, de idade e FHLE são melhores preditores de desempenho quando analisados em conjunto do que separadamente. Quando analisada isoladamente, a escolaridade foi o melhor preditor para o desempenho nas tarefas linguísticas, principalmente nas tarefas que envolvem habilidades de leitura e escrita. CONCLUSÃO: Os resultados mostraram que os anos de escolaridade, idade e FHLE parecem in�uenciar o desempenho na MTL-BR, principalmente a escolaridade. Esses dados são relevantes para a realização de diagnóstico mais preciso de pacientes que sofreram lesão cerebral a �m de evitar falsos positivos.

IPhD. Postdoctoral student, Speech Pathology and Audiology Department, Universidade Federal de Santa Maria (UFSM), Santa Maria, Rio Grande do Sul, Brazil.IIPhD. Speech Therapist at Hospital Nossa Senhora da Conceição, Porto Alegre, Rio Grande do Sul, Brazil.IIIPhD. Speech Therapist and Associate Professor, Speech Pathology and Audiology Department, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil. IVPhD. Senior Professor, Psychology Department, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.VPhD. Speech Therapist and Professor, Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal (CRIUGM), Faculté de Médecine, Université de Montréal, Montreal, Canada.VIPhD. Emeritus Professor in Language Sciences, Laboratoire Jacques-Lordat, Université de Toulouse-Le Mirail, Toulouse, France.VIIPhD. Speech Therapist, Psychologist and Associate Professor, Psychology Department, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil.

KEY WORDS:Language tests. Educational status. Age factors. Aphasia. Adult.

PALAVRAS-CHAVE:Testes de linguagem. Escolaridade. Fatores etários. Afasia.Adulto.

Relationship between the Brazilian version of the Montreal-Toulouse language assessment battery and education, age and reading and writing characteristics. A cross-sectional study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):298-306 299

INTRODUCTIONInterpretations on the �ndings from neuropsychological assess-ments of language tend to have signi�cant bias because of dif-�culty in distinguishing between cognitive e�ects due to brain damage and biological and sociocultural traits, in patients exam-ined.1,2 �us, there is growing concern about understanding how age, gender, race, education and socioeconomic status, among other factors, may interfere with cognitive functioning.3-6

Among the abovementioned factors, education level and age are the ones highlighted in the literature as the core in�uences on cognition. Overall, old age and low education level have been correlated with decreased performance.7-11 However, this relationship is not always linear, given that there may be interactions between these factors, such as in naming and verbal �uency tasks, in which the e�ect of age is canceled when individuals are highly educated.12-14 In addition, although education is considered to be the cultural factor that has the greatest in�uence on cognition, there are limitations in analyses on this variable. Education level is generally based on the number of years of study, which addresses di�erences in the duration and not the quality of education.

One alternative that has been suggested is to use read-ing level15 as a predictor of cognitive function. Since partici-pants who have higher frequency of reading and writing hab-its (FRWH) are more pro�cient in these skills and therefore score better in cognitive and language tests,6,10,16-18 reading per-formance has been regarded as equally or more important than education level. It is also worth noting that the practice of writ-ing can in�uence reading comprehension: people who read more write better and vice versa.19,20

�e e�ects of age and education level on healthy samples have been investigated in Brazilian research studies using the two main language assessment batteries: Boston Diagnostic Aphasia Examination (BDAE)21 and Montreal-Toulouse Language Assessment Battery.22 �ese studies have aimed to demonstrate the strong impact of these two factors on tasks involving oral and written comprehension, reading aloud, spelling, naming, written naming, reading numbers and copying. �e results have revealed that older individuals with lower education levels are the ones who underperform. However, no studies investigat-ing the independent e�ects of age, education and FRWH and their interactions in aphasia batteries have been conducted in Brazilian populations.8,9,23

Several tools designed to assess language among patients with aphasia have been described in the international litera-ture. �e BDAE,21 Aachen Aphasia Test (AAT)24 and Western Aphasia Battery (WAB)25 are the ones that stand out. Although not as widely used, another battery of Francophone origin that is used for language assessment is the Montreal-Toulouse

Language (MTL) Assessment Battery.22 �e Brazilian Portuguese adaptation of this battery (MTL-BR)26 has been seen to present interesting advantages with regard to evalua-tion and clinical interpretation of the di�erent components of oral and written language. In particular, this adapted version has made it possible to analyze dissociations between di�erent inputs and outputs, and di�erent levels of complexity (word, sentence and discourse).26 �e psychometric measurements were veri�ed in a previous study27 that found evidence of valid-ity (Cronbach’s alpha 0.79-0.90) and reliability (mean test-retest score of 0.52) for the battery. Nevertheless, there is still a lack of research on healthy participants, with the aim of comprehend-ing the e�ect of each sociocultural and/or biological factor on linguistic and language-related abilities.

OBJECTIVEIn this context, this study aimed to investigate the relationship between the Montreal-Toulouse language assessment battery and education, age and FRWH, using a sample of neurologically healthy adults.

METHODS

Participants�e study included 233 neurologically healthy adults from south-ern Brazil: 151 females and 82 males. �eir ages ranged from 19 to 75 (mean = 45.04; standard deviation, SD = 15.47) and educa-tion level ranged from 5 to 23 years of formal schooling (mean = 11.47; SD = 4.77).

�e exclusion criteria included: a) impaired vision and/or hearing that was not corrected by means of visual and/or hearing aids; b) signs suggestive of neurological/psychiatric conditions; c) signs of moderate to severe depression (scores above 19 points), as measured using the Beck Depression Inventory (BDI-II);28 and d) signs of cognitive decline, as measured using the clock-draw-ing test29 in association with the Mini-Mental State Examination (MMSE),30 with scores below 22 points for individuals with 5 to 8 years of schooling and below 24 points for more than 8 years.31 In addition, participants who had a history of alcoholism and/or current or previous abuse of illicit drugs or benzodiazepines and antipsychotics, except for atypical neuroleptics (data collected through a questionnaire on the sociocultural aspects of health),32 were not included in the study.

Materials and procedure�e participants were recruited from university environments and work centers (convenience sample). A�er receiving clari�ca-tions about the study, all participants signed a consent form and participated as unpaid volunteers. It is important to state that all

ORIGINAL ARTICLE | Pagliarin KC, Gindri G, Ortiz KZ, Parente MAMP, Joanette Y, Nespoulous JL, Fonseca RP

300 Sao Paulo Med J. 2015; 133(4):298-306

ethical procedures were respected, with a guarantee that partici-pation in the study would be voluntary. �e study was conducted under approval by the research ethics committee of a higher-edu-cation institution (Ponti�cal Catholic University of Rio Grande do Sul; under approval no. 04908/09).

�e FRWH was evaluated using an inventory that included questions about reading habits (magazines, newspapers, books and other materials) and writing habits (text messages, let-ters and other materials), and the frequency of each activ-ity was scored as follows: 4 points for every day; 3 for several days a week; 2 for once a week; 1 for rarely; and 0 for never, with a maximum frequency score of 28 points.33 In this sample, the 14-point band was regarded as the median. Scores higher and lower than 14 were thus denominated high FRWH or low FRWH, respectively.

Finally, the participants were evaluated using the MTL-BR battery.26 �is tool enables characterization of the subjects’ oral and written language expression and comprehension behavior. �e tasks used for this study were: 1. Directed interview: Includes 13 open-ended questions to

analyze speech and auditory comprehension. However, only comprehension is scored, with a maximum score of 26 points: 13 items with maximum score of two points each.

2. Automatic speech: Assesses the ability to evoke automatisms such as numbers, days of the week and the birthday song. �is task involves formal factors (occurrences of phonemic errors), which are scored with a maximum of six points, and content factors (occurrences of omissions), also with a maxi-mum score of six points.

3. Auditory comprehension: Measures the ability to identify images that represent words and phrases from auditory input. �e task consists of a total of 19 items, �ve words (plates with six stimuli comprising one target and �ve distracters: one phonological, one semantic, one visual and two neutral) and 14 sentences (both simple and complex). �e maximum score is �ve points for words and 14 points for phrases, with one point for each correct answer.

4. Oral narrative task: Evaluates the ability to tell a story from visual inputs. �e task consists of describing a picture depicting a bank robbery. �e narrative is analyzed for the number of words produced and the information units (IU) produced (microstructure): bank, robbery, thieves, guard, car, running, waiting, calling, people and money. Each word gets one IU point. Furthermore, three major elements of the scene (macrostructure) are scored: the robbery itself (main scene), someone waiting for the thieves and someone telling the police. �e maximum score for the components of the microstructure (IU) is 10 points and for the macrostructure (main elements of the scene), three points.

5. Written comprehension: Assesses the ability to identify the input from visual images corresponding to words and written sentences. The task consists of a total of 13 items, five words (plates with six stimuli comprising one tar-get and five distracters: one orthographic, one semantic, one visual and two neutral) and eight phrases (both sim-ple and complex). The maximum score is five points for words and eight points for phrases, with one point for each correct answer.

6. Sentence copying: Assesses the ability to recognize and repro-duce letters. �e task consists of a sentence made of eight words. �e maximum score is eight points, with one point for each word spelled correctly. Verbatim or servile copying is not considered to be correct.

7. Dictation: Assesses the individual’s ability to understand the auditory stimulus and search the corresponding writ-ten representation. �e task consists of nine words (regular, irregular, foreign words and non-words) and two sentences. �e maximum score is 22 points, with one point for each word written correctly, including phrases.

8. Repetition: Measures the individual’s ability to reproduce auditory stimulus orally, following verbal models. �e task consists of 11 words (regular, irregular and non-words) and three sentences. �e maximum scores are 11 and 22 points for words and phrases respectively, with one point for each word produced correctly.

9. Reading: Assesses the ability to recognize letters and pro-duce the appropriate phonological sounds corresponding to 12 words (regular, irregular, foreign words and non-words) and three target sentences. �e maximum scores are 12 and 21 points for words and phrases respectively, with one point for each correct answer.

10. Semantic verbal �uency: Evaluates spontaneous production of words in the category “animals” within a time period of 90 seconds. Each word correctly selected from this class is equivalent to one point, ignoring repetitions, morphologi-cal derivatives of the same word and other words that do not match the requested category.

11. Naming: Measures the ability to identify and name pictures that refer to nouns and verbs, from a visual input. Fi�een pic-tures are presented (12 nouns and three actions), placed on individual boards. �e maximum score is 30 points, compris-ing 15 items with a maximum score of two points each.

12. Nonverbal praxis: Assesses the ability to produce isolated gestures and movement sequences involving the face and tongue, requested by the evaluator through verbal instruc-tions. The task consists of a total of six items with maxi-mum scores of four points each, giving a maximum total of 24 points.


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13. Object manipulation: Assesses the ability to understand sim-ple and complex commands. �e individual is instructed to perform six commands given by the clinician, using physical objects (key, comb, cup, pen and paper). �e complexity of orders increases gradually. �e maximum score is 16 points.

14. Phonological verbal �uency: Evaluates spontaneous produc-tion of words that start with the letter M within a time period of 90 seconds. Each correct word equals one point, ignoring repetitions, morphological derivatives of the same word and proper names.

15. Body part recognition and le�-right orientation: Assesses the individual’s ability to identify parts of the body and their laterality. �e maximum score is eight points, of which four points are given for each body part (limbs) and the other four are given for the right-le� orientation.

16. Written naming: Assesses the ability to identify and indi-cate 15 figures referring to 12 nouns and three actions (verbs), from visual input. The examiner presents each of the figures on different boards. The maximum score is 30 points, comprising 15 items with a maximum score of two points each.

17. Oral text comprehension: Assesses the ability to understand auditory input from a text read by the clinician. �e individ-ual must answer six questions orally or in writing a�er lis-tening to the text (three open-ended and three closed-ended questions). �e maximum score is nine points: a maximum of 2 points for each of the three open-ended questions and one point for each of the closed-ended questions.

18. Number dictation: Assesses the ability to understand the auditory stimulus and write down the corresponding num-ber. �e task consists of six numbers. Each number written correctly gets one point, with a maximum score of six points.

19. Reading of numbers: Assesses the ability to recognize numeri-cal and visual stimuli and reproduce them orally. �e maximum score is six points: one point for each number read correctly.

20. Written narrative: Involves an individual’s ability to write a story from visual input. �e task consists of a picture depicting a robbery at a bakery. We analyzed the number of words produced and information units (IU) produced (microstructure): bakery, robbery, robbers, guard, car, run-ning, waiting, calling and gun (one point for each word). In addition, three major elements of the scene (macrostruc-ture) are scored: the robbery itself (main scene), someone waiting for the bandits and someone telling the police. �e maximum score is 10 points for IU and three points for elements of the scene.

21. Written text comprehension: Evaluates the ability to decode and interpret linguistic signs in a written text. �e task consists of six questions (three open-ended and three

closed-ended) that can be answered orally or in writing a�er reading. �e maximum score is nine points: a maximum score of two points each for the three open-ended questions and one point each for the closed-ended questions.

22. Calculation: Evaluates the ability to perform the numerical operations of addition, subtraction, multiplication and divi-sion, as well as mental and written mathematical problems. �e maximum score is 12 points: one point for each correctly solved calculation (four mental and four written) and two math problems.

�e participants were evaluated in a single 90-minute ses-sion, by properly trained and quali�ed healthcare professionals who had completed or were in the process of completing addi-tional training in language neuropsychology. �e MTL-BR score was determined by two reviewers, and the �nal score was estab-lished by consensus.

Statistical analysis�e data were analyzed using SPSS 17.0. Initially, Pearson corre-lation analysis was used to investigate the relationship between age, education and FRWH and the scores from the MTL-BR tasks. Next, multiple linear regression analysis using the step-wise method was performed in order to identify which variables provided the best explanatory models. A signi�cance level of P ≤ 0.05 was applied.

RESULTS�e scores from 17 out of the 22 tasks were signi�cantly corre-lated with education, while the scores from nine subtests (oral narrative task, written comprehension, dictation, reading, semantic and phonological verbal �uency, written naming, writ-ten narrative and calculation) achieved moderate positive corre-lations. Ten tasks were negatively correlated with age (directed interview, auditory comprehension, oral narrative task total number of words, written comprehension, repetition, semantic verbal �uency, naming, written naming, written narrative total number of words and oral text comprehension). Performance in the oral narrative task, dictation, reading, semantic and phono-logical verbal �uency, written naming, written narrative and cal-culation presented signi�cant moderate positive correlation with FRWH. �e highest correlation was found between the written narrative task (total number of written words) and education variables, followed by the association between semantic verbal �uency and education (Table 1).

Table 2 displays the results from the regression analysis on the predictive model for performance in language tasks, con-sidering education, age and FRWH as predictors. As the results show, education was a signi�cant predictor (P < 0.01) for


302 Sao Paulo Med J. 2015; 133(4):298-306

most tasks, with explanatory power ranging from 6% to 28%. Interestingly, it was also the only signi�cant predictive factor in seven subtests: automatisms (form), oral narrative task (total number of IU), reading, number dictation, reading of num-bers, written narrative (total number of scenes) and written text comprehension. �e FRWH was a signi�cant predictor only for automatisms (content), while age was the only predictor for the guided interview.

In general, among the tests in which education was com-bined with other variables, the variable FRWH contributed 2-3% to the explanatory model. In contrast, age contributed 3-6% to the explanatory power when combined with education in some tasks.

With regard to the explanatory models for each dependent variable, education level and FRWH jointly explained 32% of the variance of performance in the semantic verbal �uency and writ-ten narrative task (total number of words) and 30% of the vari-ance relating to dictation. Education and age explained 25% of the scores for written naming. �ese three variables combined showed the greatest explanatory power (33%) for the semantic verbal �uency task. �ese �ndings corroborate the results pre-sented in Table 1 (signi�cant correlations).

DISCUSSION�e results from this study revealed that the MTL-BR is mainly in�uenced by education, such that higher education level was correlated with better performance. Likewise, other studies have shown the importance of the number of years of formal educa-tion in language tasks, with �ndings similar to those observed in the present study.1,6,8-10,33

As seen in the results, in this study there was a moderate posi-tive correlation with education in tasks that involve dictation, writ-ten naming, written comprehension, auditory comprehension and written narrative. �ese tasks require reading-writing abilities that are developed over the course of education. However, educa-tion was not a predictor of the tasks relating to the guided inter-view, repetition, automatic speech (content) and oral narrative task (total number of words) (Table 2). Previous research has shown that tasks involving graphic stimuli (written comprehension, dicta-tion, reading, written naming, number dictation, reading of num-bers, written narrative and written text comprehension) tend to be more sensitive to the in�uence of education.6,8,11

�e importance, albeit weaker, of FRWH in linguistic perfor-mance deserves to be highlighted, given that it increases the predic-tive power of the education variable. Regularly practicing reading and writing can compensate for low education levels in linguistic performance,17,33 and the quality of what is read is one of the big-gest predictors of cognitive performance.16,34 Despite the relevance of FRWH in this study, although this variable had signi�cant posi-tive correlations with various tasks of the MTL-BR (Table 1), it did not show strong explanatory power in comparison with a model composed only by education (Table 2). �e main hypothesis for this �nding relates to the information obtained from FRWH, since this was restricted to measurement of the frequency of the mate-rial that was read and produced, but not the quality, level of com-plexity or resulting potential for neurocognitive stimulation of this material. However, Pawlowski et al.33 used this same questionnaire to verify the in�uence of FRWH combined with education level on performance in neuropsychological tasks among adults and noted that frequent practice of reading and writing among individuals with low education promoted an improvement in cognitive perfor-mance, as well as in language tasks.

Education Age FRWHEducation - -0.04 0.58*

Age -0.04 - -0.09FRWH 0.58* -0.09 -Task 1. Directed interview 0.11 -0.20* 0.10Task 2. Automatic speech

2.1. form 0.29* -0.06 0.24*

2.2 content 0.15† 0.09 0.27*

Task 3. Auditory comprehension 0.29* -0.22* 0.29*

Task 4. Oral narrative task 4.1. total number of words 0.31* 0.21* 0.32*

4.2. total number of information units 0.36* -0.11 0.0*

4.3 total number of scenes 0.33* -0.09 0.21*

Task 5. Written comprehension 0.35* -0.24* 0.29*

Task 6. Copying 0.11 -0.03 0.05Task 7. Dictation 0.51* -0.08 0.46*

Task 8. Repetition 0.13† -0.21* 0.17*

Task 9. Reading 0.45* -0.11 0.35*

Task 10. Semantic verbal �uency 0.53* -0.16† 0.47*

Task 11. Nonverbal praxis 0.13 0.11 0.06Task 12. Naming 0.29* -0.28* 0.28*

Task 13. Objects manipulation 0.07 0.09 0.23*

Task 14. Phonological verbal �uency 0.52* 0.06 0.44*

Task 15. Body part recognition and left-right orientation

0.09 0.00 0.05

Task 16. Written naming 0.44* -0.29* 0.33*

Task 17. Written narrative 17.1. total number of words 0.55* -0.14† 0.44*

17.2. total number of information units 0.48* -0.11 0.39*

17.3. total number of scenes 0.45* -0.13 0.36*

Task 18. Oral text comprehension 0.29* -0.16† 0.28*

Task 19. Number dictation 0.18* 0.04 0.03Task 20. Reading of numbers 0.14† -0.05 0.12Task 21. Written text comprehension 0.26* -0.07 0.25*

Task 22. Calculation 0.50* 0.02 0.40*

Table 1. Correlations between education level, age and frequency of reading and writing habits (FRWH) and the tasks of the Montreal-Toulouse language assessment battery, Brazilian version (MTL-BR)

*P ≤ 0.001; †P ≤ 0.05.


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IU = information units; FRWH = frequency of reading and writing habits; ANOVA = analysis of variance; F = F-statistics; P = P-value; R² = coe�cient of determination (R squared); R²a = adjusted R squared.

Dependent variablesIndependent

variables (selected model)t-value P (ANOVA)

ModelF P R² R²a

Directed interview Age -3.140 0.002 9.861 0.002 0.041 0.037Automatic speech (form) Education 4.564 < 0.001 20.829 < 0.001 0.083 0.079Automatic speech (content) FRWH 4.336 < 0.001 18.801 < 0.001 0.075 0.071

Auditory comprehensionEducation 2.207 0.028 21.398 < 0.001 0.085 0.081

Education and age -3.235 0.001 10.416 0.001 0.124 0.117Education, age and FRWH 2.348 0.020 5.514 0.020 0.145 0.134

Oral narrative (total number of words)FRWH 2.911 0.004 27.241 < 0.001 0.105 0.102

FRWH and age 4.023 < 0.001 14.617 < 0.001 0.159 0.152FRWH, age and education 2.717 0.007 7.384 0.007 0.185 0.175

Oral narrative (total number of IU) Education 5.805 < 0.001 33.696 < 0.001 0.127 0.124Oral narrative (total number of scenes) Education 5.244 < 0.001 27.502 < 0.001 0.106 0.103

Written comprehensionEducation 5.656 < 0.001 33.729 < 0.001 0.127 0.124

Education and age -3.460 0.001 11.970 0.001 0.171 0.163

DictationEducation 5.388 < 0.001 82.640 < 0.001 0.263 0.260

Education and FRWH 3.452 0.001 11.913 0.001 0.300 0.294

RepetitionAge -3.196 0.002 10.887 0.001 0.045 0.041

Age and FRWH 2.468 0.014 6.089 0.014 0.070 0.062Reading Education 7.624 < 0.001 58.128 < 0.001 0.201 0.198

Semantic verbal �uencyEducation 5.675 < 0.001 92.244 < 0.001 0.285 0.282

Education and FRWH 3.557 < 0.001 12.610 < 0.001 0.323 0.317Education, FRWH and age -2.145 0.033 4.601 0.033 0.336 0.327

NamingEducation 2.336 0.020 21.378 < 0.001 0.085 0.081

Education and age -4.23 < 0.001 17.818 < 0.001 0.151 0.143Education, age and FRWH 12.107 0.036 4.441 < 0.001 0.167 0.156

Phonological verbal �uencyEducation 5.651 < 0.001 83.700 < 0.001 0.266 0.263


Written namingEducation 7.421 < 0.001 56.083 < 0.001 0.195 0.192

Education and age -4.509 < 0.001 20.330 < 0.001 0.261 0.254

Oral text comprehensionEducation 2.260 0.025 20.548 < 0.001 0.082 0.078

Education and age -2.168 0.031 4.722 0.031 0.100 0.092Education, age and FRWH 2.156 0.032 4.647 0.032 0.118 0.107

Number dictation Education 2.708 0.007 7.333 0.007 0.031 0.027Reading of numbers Education 2.171 0.031 4.714 0.031 0.020 0.016

Written narrative (total number of words)Education 6.613 < 0.001 100.503 < 0.001 0.303 0.300


Written narrative (total number of IU)Education 5.261 < 0.001 67.566 < 0.001 0.226 0.223

Education and FRWH 2.317 0.021 5.368 0.021 0.244 0.237Written narrative (total number of scenes) Education 7.696 < 0.001 59.223 < 0.001 0.204 0.201Written text comprehension Education 4.076 < 0.001 16.613 < 0.001 0.067 0.063

CalculationEducation 5.755 < 0.001 77.590 < 0.001 0.251 0.248


Table 2. Results from multiple regression analysis on the tasks of the Montreal-Toulouse language assessment battery, Brazilian version (MTL-BR), considering the study variables and the total number of participants

�e greater explanatory power found in joint education-FRWH models is based on the combination of these two sociocultural variables: the higher the education level and the frequency of reading and writing habits are, the better the scores in language tasks will be. On the other hand, people with low education levels are less motivated to perform tasks that require

reading and writing in their day-to-day lives,17,35 which can hamper understanding in some subtests involving increasing complexity and may cause lower performance.

It has been shown that not only education level, but also reading scores are predictors in the verbal �uency test, naming task and comprehension.10,17,18 �is is mainly because anyone


304 Sao Paulo Med J. 2015; 133(4):298-306

who reads and writes more o�en possesses a richer vocabu-lary, and makes use of attention, mnemonic and executive skills. People who tend to read less may present cognitive decline and worse outcomes in reading tasks, especially the elderly.

�e habits of reading and writing are also considered to be one of the factors that contribute towards formation of a cogni-tive reserve, thereby preventing the e�ects of aging on cognition.36 �e �ndings from this study are in agreement with results relating to the e�ects of age, in a study on performance in the subtests of oral narrative, repetition, verbal �uency, auditory comprehension (sentences), written narrative, reading, written text and sentence comprehension, in which older individuals had lower scores than younger subjects did.37 Like in other studies with similar tasks and batteries,1,6,10 age had little e�ect on task performance. Despite the decline in task performance found among older age groups, it has been shown that in narrative tasks the elderly have better scores and higher production of words and sentences to express picto-rial information,38,39 thus corroborating the �ndings in our study. �is is because the elderly tend to have more repetitions, although these are not necessarily o�-topic.40 In speech, it is possible that repetitions are intentional, produced in order to emphasize certain information,41 or even to make time for organization of thought.42 Moreover, they may be due to the changes in communication style that occur naturally as a result of aging.

During the guided interview, age was the only predictor, contributing 3% to performance. In conversations with autobi-ographical topics, elderly people may have more personal obser-vations, with frequent remembrance of the past. Moreover, with the aging process, narratives tend to have a complex plot, with more episodes and better management of resources, so as to maintain the interest of communicative interaction by mak-ing linguistic and extra-linguistic adjustments.43 It is important to pay special attention to the heterogeneity of communicative performance, which is greater in the elderly population.44,45

Some limitations of this study should be taken into consideration in order to make better use of its �ndings. �e fact that illiterate or functionally illiterate patients were not included may have contrib-uted towards the predictive outcome of models, with a maximum of 28% for the education level variable. Since the e�ect of education is not linear in cognitive tests (mainly because of lower education lev-els), a di�erence of one or two years of schooling interferes with per-formance.6 In addition, it should be pointed out that both education level and FRWH were used as quantitative measurements, thus not covering speci�c measurements of education quality or the quality of the material read and/or written.18 �us, additional studies are needed in order to analyze these factors, so as to better understand the in�uence of these variables on language performance.

�ese data are important with regard to making correct diagnoses among patients su�ering from neurological injuries,

because of the potential for avoiding false positives. In addition, the variables studied are important because they establish norma-tive data for clinical populations, especially aphasic individuals.

CONCLUSION�ese results show the in�uence of sociodemographic variables, especially education and its association with FRWH, among the MTL-BR tasks. Examiners should take these variables into con-sideration when evaluating language performance, especially in clinical populations.

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Sources of funding: Coordenação de Aperfeiçoamento de Pessoal de

Nível Superior (CAPES), grant number: 12247/12-0

Con�ict of interest: none


Last received: September 15, 2014

Accepted: October 16, 2014


Karina Carlesso Pagliarin

Rua Coronel Scherer, 09

Centro — São Pedro do Sul (RS) — Brasil

CEP 97400-000

Tel. (+55 55) 3220-8659


Sao Paulo Med J. 2015; 133(4):307-13 307

ORIGINAL ARTICLEDOI: 10.1590/1516-3180.2014.8792210

Hierarchy of evidence referring to the central nervous system in a high-impact radiation oncology journal: a 10-year assessment. Descriptive critical appraisal studyHierarquia de evidência referindo-se ao sistema nervoso central em um jornal de radioterapia de alto impacto: uma avaliação de 10 anos. Estudo descritivo de avaliação críticaFabio Ynoe MoraesI, Lorine Arias BonifacioI, Gustavo Nader MartaII, Samir Abdallah HannaIII, Álvaro Nagib AtallahIV, Vinícius Ynoe MoraesV, João Luis Fernandes SilvaVI, Heloísa Andrade CarvalhoVII

Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: To the best of our knowledge, there has been no systematic assessment of the classi�cation of scienti�c production within the scope of radiation oncology relating to central nervous system tumors. The aim of this study was to systematically assess the status of evidence relating to the central nervous system and to evaluate the geographic origins and major content of these published data. DESIGN AND SETTING: Descriptive critical appraisal study conducted at a private hospital in São Paulo, Brazil. METHODS: We evaluated all of the central nervous system studies published in the journal Radiotherapy & Oncology between 2003 and 2012. The studies identi�ed were classi�ed according to their method-ological design and level of evidence. Information regarding the geographical location of the study, the institutions and authors involved in the publication, main condition or disease investigated and time of publication was also obtained. RESULTS: We identi�ed 3,004 studies published over the 10-year period. Of these, 125 (4.2%) were con-sidered eligible, and 66% of them were case series. Systematic reviews and randomized clinical trials accounted for approximately 10% of all the published papers. We observed an increase in high-quality evidence and a decrease in low-quality published papers over this period (P = 0.036). The inter-rater reliability demonstrated signi�cant agreement between observers in terms of the level of evidence.CONCLUSIONS: Increases in high-level evidence and in the total number of central nervous system pa-pers were clearly demonstrated, although the overall number of such studies remained relatively small.

RESUMOCONTEXTO E OBJETIVO: Até onde sabemos, não há avaliação sistemática da classi�cação da produção cientí�ca no âmbito da radioterapia de tumores de sistema nervoso central. O objetivo deste estudo foi avaliar sistematicamente o estado das evidências relativas ao sistema nervoso central e avaliar origem geográ�ca e a temática envolvida nestas publicações.TIPO DE ESTUDO E LOCAL: Estudo descritivo de avaliação crítica, realizado em um hospital privado em São Paulo, Brasil.MÉTODOS: Foram avaliados todos os estudos publicados em sistema nervoso central na revista Radio-therapy & Oncology, entre 2003 e 2012. Os estudos identi�cados foram classi�cados de acordo com o desenho metodológico e nível de evidência. Informações sobre a localização geográ�ca do estudo, insti-tuições e os autores envolvidos nas publicações, a principal condição ou doença estudada e o período de publicação também foram obtidos. RESULTADOS: Foram identi�cados 3.004 estudos publicados no período de 10 anos. Destes, 125 (4,2%) foram considerados como elegíveis, e 66% destes eram séries de casos. As revisões sistemáticas e ensaios clínicos randomizados foram responsáveis por cerca de 10% de todas as publicações. Observou-se um aumento das evidências de alta qualidade e uma diminuição das publicações de baixa qualidade durante o período (P = 0,036). A con�abilidade entre avaliadores demonstrou concordância signi�cativa para níveis de evidência.CONCLUSÕES: Um aumento nas evidências de alto nível, assim como no número absoluto de artigos em siste-ma nervoso central foi claramente demonstrado, apesar de o número global ser ainda relativamente pequeno.

IMD. Physician, Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.IIMD. Radiation Oncologist, Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo and Radiation Oncologist, Department of Radiation Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil. IIIMD, PhD. Radiation Oncologist. Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.IVMD, PhD. Full professor and head of the Discipline of Emergency Medicine and Evidence-Based Health of Universidade Federal de São Paulo - Escola Paulista de Medicina. Director of the Brazilian Cochrane Center, São Paulo, Brazil. VMD. Orthopedic Surgeon, Department of Orthopedics and Hand Surgery, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, Brazil.VIMD. Radiation Oncologist and Head of the Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil. VIIMD, PhD. Radiation Oncologist, Radiotherapy Service, Institute of Radiology, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, and Radiation Oncologist, Department of Radiation Oncology Hospital Sírio-Libanês, São Paulo, Brazil.

KEY WORDS:Radiotherapy. Central nervous system neoplasms. Epidemiologic methods. Research design. Evidence-based medicine.

PALAVRAS-CHAVE:Radioterapia. Neoplasias do sistema nervoso central. Métodos epidemiológicos.Projetos de pesquisa.Medicina baseada em evidências.

ORIGINAL ARTICLE | Moraes FY, Bonifacio LA, Marta GN, Hanna SA, Atallah AN, Moraes VY, Silva JLF, Carvalho HA

308 Sao Paulo Med J. 2015; 133(4):307-13

INTRODUCTION Evidence-based medicine has become essential to clinical and research actions since it was formally proposed in 1990.1 �e importance of evidence-based medicine concepts was highlighted in an article published in the British Medical Journal in 2007, in which the editors described the emergence of evidence-based med-icine as one of the 15 most important milestones since the foun-dation of the British Medical Journal (1870).2,3 Henceforth, critical evaluation of evidence has become an important tool for assessing research quality and progress. Clinical research can be classi�ed into levels of evidence, which are based on evaluating and inter-preting evidence. �e level of evidence is closely related to the likeli-hood that a piece of research will produce valid and reliable results.

Radiotherapy is no di�erent in this regard. �e pursuit of the best evidence is changing and is beginning to follow the trends reported in the 1990s.4 As an example, conducting a quick Medline search associating “randomized trials” and “radiation oncology”, 211, 144, 27 and 5 studies for the years 2012, 1996, 1981 and 1970 are identi�ed, respectively. �is �nd-ing demonstrates the evolution and intensi�cation of research applied to radiotherapy, with a 40-fold increase in publications, over this time period.

Moreover, high-quality studies play a fundamental role in medical journals. From a broader perspective, the methodologi-cal quality and level of evidence of published articles are impor-tant determinants of how many times an article is cited, which therefore a�ects the impact factor of that journal and can also play a major role in the clinical transfer of knowledge.5,6 �is has become an essential aspect of the evaluation of scienti�c journals.6 In 2003, prominent journals began to use evidence hierarchies to rank the published studies.7,8 As a result, evidence-based medi-cine concepts were adopted by the conferences and symposia of the main specialties. Following this paradigm, great e�orts have been applied within radiation oncology to follow the evidence-based medicine trend. Nevertheless, to date, there has been no systematic assessment of the quality of scienti�c production in several areas of radiation oncology.4,5

OBJECTIVE�e aim of this study was to identify central nervous system studies published in Radiotherapy & Oncology (Elsevier Ireland) over the last decade (2003-2012), classify the type of study and evidence levels according to evidence-based medicine criteria and observe the inter-rater agreement in the classi�cation of the studies included.

METHODS Using electronic databases, two researchers independently evalu-ated all studies published in all editions of the major European

radiation oncology-speci�c journal (Radiotherapy & Oncology, Elsevier Ireland, accessed at http://www.thegreenjournal.com) between 2003 and 2012. �is journal was chosen because it is important in the �eld of radiation oncology �eld; it is indexed in at least one major international database; and it is, so far, the radi-ation oncology journal with the highest impact factor. We con-ducted a descriptive critical appraisal study.

Studies in this journal were initially screened based on their titles and were classi�ed as eligible, potentially eligible or not eligible. �e sole inclusion criterion was that they needed to be clinical studies relating to the central nervous system that were published between 2003 and 2012. �us, presence of the follow-ing topics in the title counted for this initial screening: metastatic central nervous system; low-grade glioma; high-grade glioma; pediatrics and central nervous system (medulloblastoma, epen-dymoma or astrocytoma); central nervous system lymphoma; benign tumors (meningioma, schwannoma or arterial venous malformations); spinal cord, orbital and skull-base tumors; and experimental central nervous system studies. A�er this initial screening, the selected studies (eligible and potentially eligible) were �rst reassessed using their abstracts and then by using their full texts. All studies relating only to dosimetry were excluded. A third evaluator resolved any disagreements.

�e studies thus identi�ed were assessed by two examiners and were subsequently classi�ed according to the methodological design: 1. systematic reviews; 2. randomized or non-randomized clinical trials; 3. cohort studies; 4. case-control studies; 5. case series; and 6. basic science studies. �e studies were also classi�ed accord-ing to their level of evidence using the guidelines of the Oxford Centre for Evidence-based Medicine: systematic reviews of ran-domized clinical trials, level I; randomized clinical trials, level II; cohort and case-control studies, level III; case series, level IV; and narrative reviews and other designs, level V. �is is a widely used classi�cation method that has been adapted for use within the radi-ation oncology literature.9 �is categorization was done a�er read-ing the full texts of the eligible studies.

For all the studies ultimately included, we also obtained information regarding the geographical location at which the study was performed, institutions/departments and authors involved in the publication, main condition studied, main dis-ease investigated and time of publication. We also examined the productivity relating to radiotherapy for the central ner-vous system in each department over the 10-year period cov-ered by this analysis. �e following parameters were strati�ed using the following parameters: time of publication (period 1: 2003-2007; and period 2: 2008-2012); geographical loca-tion; level of evidence; and Scienti�c Journal Rankings index (www.scimagojr.com). �is index measures the impact that a single published paper has, and hence the scienti�c in�uence

Hierarchy of evidence referring to the central nervous system in a high-impact radiation oncology journal: a 10-year assessment. Descriptive critical appraisal study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):307-13 309

of an average article in a journal. It thus expresses the extent to which an average journal article is central to the global scien-ti�c discussion.

Statistical analysis �e assumption of normal distribution in the sample was assessed using the Kolmogorov-Smirnov test. Cohen’s kappa test was used to assess reliability and to evaluate the internal consis-tency of the inter-rater classi�cations. �e magnitude of agree-ment was determined based on the proposal of Landis and Koch: I. < 0, no agreement; II. 0 to 0.20, slight agreement; III. 0.21 to 0.40, fair agreement; IV. 0.41 to 0.60, moderate agreement; V. 0.61 to 0.80, signi�cant agreement; and VI. 0.81 to 1.00 almost perfect agreement.10,11 �e chi-square test was used to evaluate the pro-portions of papers at evidence levels I, II and III between the two periods. We considered P-values from two-sided tests < 0.05 to be statistically signi�cant.

RESULTS We identi�ed 3,004 studies published over the 10-year period evaluated. Of these, 135 were initially selected (central ner-vous system disease), from which 10 were then excluded. �us, 125 studies (4.2%) were considered eligible and were included in this analysis (Figure 1). �ere was an average of 300.4 pub-lications per year during the study period (which included an average of 13.5 publications per year relating to the central ner-vous system). We noted an absolute increase in the number of

published papers of 33% overall and 41% in relation to the central nervous system, from period 1 to period 2 (Table 1).

Table 2 shows the distribution of the central nervous system studies according to the geographical location at which they were conducted. European studies accounted for more than 60% of the published data over the entire period and, in comparison with the rest of the world, this di�erence was statistically signi�cant (P = 0.0306).

Strati�cation according to disease classi�cation showed that the majority (74%) of the studies were related to central nervous system metastasis, followed by high-grade gliomas and benign tumors (Table 2).

We also noted that the average numbers of authors and departments involved in the studies were 6.86 and 3.29, respec-tively; 67% of the �rst authors were radiation oncologists (Table 2), and 85% of the �rst authors only had a single arti-cle published in Radiotherapy & Oncology as the �rst author. Twelve institutions (University Hospital of Heidelberg, Institute of Southern Switzerland, University Hospital Zurich, University Hospital Groningen, Tata Memorial Hospital, University of Wisconsin Medical School, McGill University Health Center, ‘‘S. Maria” Hospital, VU University Medical Center, St. Jude Children’s Research Hospital, Ludwig-Maximilians-University Munich and San Ra�aele Scienti�c Institute) (13.3% of the total) were responsible for 40 published papers (32% of the total) and 78 institutions were responsible for the other 68% of publications over this 10-year period.

Figure 1. Flow diagram.

Excluded after secondary analysis (n = 10)

Excluded (n = 2869) Did not meet study inclusion criteria

Secondary analysis (n = 135)

Assessed for initial analysis (n = 3004)

Considered for the �nal analysis (n = 125)


310 Sao Paulo Med J. 2015; 133(4):307-13

Among these studies, 66.5% were case series (prospective and retrospective; number published (n) = 81 articles); 8% were pro-spective controlled studies (not randomized) (n = 10); 1% were cohort studies (n = 1); 1% were case-control studies (n = 1); 6% were cross-sectional studies (n = 8); and 3% were review articles (n = 5). Systematic reviews (n = 5) and randomized clinical tri-als (n = 7) accounted for approximately 10% of all the published papers. Other studies, which included case reports, were respon-sible for 5% of the publications (n = 7). In analyzing the level of evidence according to year, we observed that there were greater numbers of published papers with evidence levels I, II and II and lower numbers with evidence levels IV and V in period 2 (2008-2012) than in period 1 (2003-2007) (P = 0.036).9

�e Scienti�c Journal Rankings index showed average val-ues of 1.38 and 1.89 for periods 1 and 2, respectively. �is higher index for period 2 presented a tendency towards a statistically signi�cant di�erence in relation to period 1 (P = 0.0528). �e inter-rater reliability for the classi�cation of study type accord-ing to the kappa statistic demonstrated signi�cant agreement between the observers (kappa = 0.69).

DISCUSSIONIn this 10-year single-journal analysis, we found that the stud-ies published within the scope of the central nervous system increased in quality and number, although signi�cant rep-resentation in the journal Radiotherapy & Oncology is still lacking (< 4.5% of published papers). We also found that case

series (retrospective and prospective) represented the major-ity of central nervous system papers published in this journal. Furthermore, level of evidence was found to be a reproducible tool, and secondary tumor (metastasis) research was well rep-resented in this journal. �e major strength of our data is that they represent, to the best of our knowledge, an original study with a representative period of evaluation in a single journal. Moreover, this analysis was based on formal and systematic data-gathering and evaluation, and our results present sequen-tial assessment, including formal statistical analysis and inter-reliability analysis based on Cohen’s kappa test.

In the United States, according to the national database, pri-mary central nervous system tumors account for less than 3% of all diagnosed neoplasms.12 Similarly, primary and metastatic central nervous system tumors, together with benign central nervous system diseases, represent vast opportunities for treat-ment improvements, with implementation of new markers and prognostic factors. �is is an important �eld for radiotherapy research, including newer approaches using stereotactic radio-surgery. In the �eld of central nervous system tumors, radiother-apy plays a major role in the management of almost all types of malignant brain tumors. Moreover, a high level of evidence can play a major role in treatment decisions.

Among patients diagnosed with cancer (all anatomical sites), approximately 54% of all of them will require some radiation treatment during their lifetime, and 12% will require re-irradi-ation.13 Based on evidence-based guidelines, the central nervous

Published papers per region Published papers per diagnosis First author specialty Europe* 78 Metastasis 40 Rad Onc 84North America 22 HGG 35 Others† 13Asia 11 Benign 31 Neurologist 10Multiple regions 9 Other 9 Clin Onc 9Oceania 4 Pediatrics 8 Med Phys 9Africa 1 LGG 2Total 125

*Chi-square test, P = 0.03 (when comparing Europe versus all other regions). †Others: radiologist, palliative care specialist, epidemiologist, nuclear medicine specialist, pediatrician and not speci�ed. Abbreviations: HGG = high-grade glioma; LGG = low-grade glioma; Rad Onc = radiation oncologist; Clin Onc = clinical oncologist; Med Phys = medical physicist.

Table 2. Central nervous system papers published, according to region, diagnosis and �rst author over the 10-year period

Level of evidenceLevel I n (%)

Level II n (%)

Level III n (%)

Level IV n (%)

Level V n (%)

Period2003-2007 0 (0) 3 (5.6%) 5 (9.3%) 35 (64%) 11 (20%)2008-2012 5 (7%) 10 (14%) 7 (9.9%) 46 (64%) 3 (4.2%)

Region

Europe 5(4%) 5 (4%) 10 (8%) 52 (41%) 6 (4,8%)Americas 0 3 (2.4%) 1 (0.8%) 14 (11%) 4 (3.2%)

Asia 0 0 0 8 (6.4%) 3 (2.4%)Oceania 0 2 (1.6%) 1 (0.8%) 1 (0.8%) 0

Africa 0 0 0 1 (0.8%) 0Multiple region 0 3 (2.4%) 1 (0.8%) 4 (3.2%) 1 (0.8%)

Table 1. Frequencies of the hierarchy of evidence, grouped according to the period and region of origin


Sao Paulo Med J. 2015; 133(4):307-13 311

system shows a highly recommended overall optimal radiother-apy utilization rate (approximately 92-93%).13 In a comprehen-sive analysis in which the objective was to estimate the ideal pro-portion of patients with newly diagnosed central nervous system neoplasms who could bene�t from external-beam radiotherapy, most of the recommendations were based on evidence level III.14 For tumors at other sites, such as cervical tumors (62% presenting levels IV/V), hematological malignancies (majority presenting level III) and gastrointestinal tumors (mainly presenting levels II/III), the clinical recommendation for radiotherapy was based on low/moderate level of evidence.15-18 Based on our analysis, most of the studies presented low-level evidence, such as prospective and retrospective case series (66%). Higher evidence levels such as systematic reviews and randomized clinical trials represented only approximately 10% of all central nervous system published papers. In comparison with case series, randomized trials involve greater numbers of ethical issues and higher costs. �e incidence of primary central nervous system tumors, combined with the tendency to treat them in large specialized centers, may explain the �ndings of this study. It also needs to be taken into consid-eration that the journal Radiotherapy & Oncology accepts phys-ical contributions, dosimetry studies, molecular biology assays and other types of non-formal clinical publications. In addition to the important role of such articles with regard to development of radiation oncology, they are classi�ed as presenting evidence levels IV or V according to the Oxford Criteria.9 Nevertheless, there was an increase in the evidence level of published central nervous system articles (in our data) over the years, particularly in the more recent period.

In a manner similar to our study, Yarascavitch et al. (at McMaster University, Hamilton, Canada) quanti�ed the level of evidence in 660 eligible articles in the neurosurgical literature in order to determine the changes over time and the predictive factors for higher-level evidence.19 Levels I and II accounted for only 1 in 10 neurosurgical clinical papers in top journals, and papers with larger sample sizes were signi�cantly associ-ated with higher level of evidence. �ese authors concluded that there is a need for better evidence in papers published within this �eld and that patient management and the publication of prospective studies may be improved by education and the adoption of level of evidence. In addition, other analyses have suggested that improvements in the evidence of published stud-ies are possible, although most of the published papers in many �elds remain at evidence level IV.6,20-24

Similarly, it is important to note that level of evidence can be correlated with journal impact factor and that increasing num-bers of studies with high-level evidence have been observed in palliative and orthopedic settings.22,25,26 �is �nding empha-sizes that there is an urgent need to expand the data relating

to evidence-based oncology. Regarding the origin of the arti-cles included in this study, in comparison with the rest of the world, Europe showed the largest number of published papers within the �eld of the central nervous system (60%). Because Radiotherapy & Oncology is a journal based and supported in Europe, this could represent a bias of our study. However, we did not �nd any previous data evaluating the regions in which central nervous system radiation oncology publications are pro-duced. �is may re�ect the tendency to centralize more special-ized procedures in reference centers that can better address cen-tral nervous system diseases. We also found that most authors published just one article as �rst author and then either ceased to be involved in research or acquired greater independence and became senior researchers. However, this was not evaluated in the present study. In addition, Morgan et al. evaluated sci-enti�c production relating to radiation oncology in the United States27 and observed that there was an average of one peer-reviewed �rst-author publication and one �rst-author abstract presentation at an annual meeting of the American Society for �erapeutic Radiology and Oncology (ASTRO) per resident during their four years of training. We consider that this sort of analysis is important for future studies and for knowledge of referral centers for future postgraduate training.

�e limitations of the current analysis lie in the fact that cen-tral nervous system articles may not be well represented in the journal chosen for analysis here because other radiation oncol-ogy journals that were not included in the electronic search also publish articles relating to the central nervous system. In addi-tion, speci�c journals and higher-impact journals may account for signi�cant numbers of published papers relating to the central nervous system. �ese were not assessed in the present analysis but may have had an impact on the data presented. Furthermore, a wider search of the literature might lead to a more optimistic outlook regarding the proportion of high-quality studies.

In this study, a training workshop on manuscript classi�ca-tion was conducted initially. �e Oxford system of levels of evi-dence seemed to be a feasible instrument for evaluating stud-ies, with a signi�cant degree of consistency.9 �ese �ndings and those in other studies emphasize the importance of speci�c training for individuals who are responsible for determinations relating to the quality of evidence.28 Finally, our study represents a possible landmark for future studies and other evidence-based assessments on the central nervous system within the �eld of radiation oncology research. Moreover, the present study may result in new research opportunities, such as assessment of the internal and external validity of other study features and evalu-ations on high-impact and specialized journals. In particular, it would be interesting to evaluate how radiation oncologists man-age and comprehend evidence-based medicine.


312 Sao Paulo Med J. 2015; 133(4):307-13

CONCLUSION Both the number and the level of evidence of published papers relating to the central nervous system have increased in the jour-nal Radiotherapy & Oncology. However, between 2003 and 2012, central nervous system papers still represented less than 5% of all publications with evidence levels I and II and accounted for only 10% of the papers published in this speci�c journal. Our analy-sis also encourages the use of levels of evidence, which is a useful tool with signi�cant inter-rater reliability.

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rating imply high quality of reporting in orthopaedic randomised

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23. Wasserman JM, Wynn R, Bash TS, Rosenfeld RM. Levels of evidence

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24. Thoma A, Ignacy TA, Li YK, Coroneos CJ. Reporting the level of

evidence in the Canadian Journal of Plastic Surgery: Why is it

important? Can J Plast Surg. 2012;20(1):12-6.

25. Amiri AR, Kanesalingam K, Cro S, Casey AT. Level of evidence of

clinical spinal research and its correlation with journal impact factor.

Spine J. 2013;13(9):1148-53.

26. Tieman J, Sladek R, Currow D. Changes in the quantity and level of

evidence of palliative and hospice care literature: the last century. J

Clin Oncol. 2008;26(35):5679-83.

27. Morgan PB, Sopka DM, Kathpal M, et al. First author research

productivity of United States radiation oncology residents: 2002-

2007. Int J Radiat Oncol Biol Phys. 2009;74(5):1567-72.

28. Turpen RM, Fesperman SF, Sultan S, et al. Levels of evidence ratings in

the urological literature: an assessment of interobserver agreement.

BJU Int. 2010;105(5):602-6.


Sao Paulo Med J. 2015; 133(4):307-13 313

Presented at the 15th Congress of the Brazilian Society of Radiotherapy,

São Paulo, 2013, and in the Annals of the 15th Congress of the

Brazilian Society of Radiotherapy, 2013. Fortaleza: Brazilian Society of

Radiotherapy, 2013



Date of �rst submission: April 22, 2014

Last received: October 17, 2014

Accepted: October 22, 2014


Fabio Ynoe Moraes

Hospital Sírio-Libanês

Radiation Oncology Department

Rua Dona Adma Jafet, 91

São Paulo (SP) — Brasil

CEP 01308-050

Tel. (+55 11) 3155-0558

Fax. (+55 11) 3155-0983

Email: [email protected]

314 Sao Paulo Med J. 2015; 133(4):314-9


Neuroprotective body hypothermia among newborns with hypoxic ischemic encephalopathy: three-year experience in a tertiary university hospital. A retrospective observational studyHipotermia corpórea neuroprotetora em recém-nascidos com encefalopatia hipóxico-isquêmica: três anos de experiência em hospital universitário terciário. Um estudo observacional retrospectivoMauricio MagalhãesI, Francisco Paulo Martins RodriguesII, Maria Renata Tollio ChopardIII, Victoria Catarina de Albuquerque MeloIV, Amanda MelhadoIV, Inez OliveiraV, Clery Bernardi GallacciVI, Paulo Roberto PachiVI, Tabajara Barbosa Lima NetoIV

Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: Neonatal hypoxic-ischemic encephalopathy is associated with high morbid-ity and mortality. Studies have shown that therapeutic hypothermia decreases neurological sequelae and death. Our aim was therefore to report on a three-year experience of therapeutic hypothermia among asphyxiated newborns.DESIGN AND SETTING: Retrospective study, conducted in a university hospital.METHODS: Thirty-five patients with perinatal asphyxia undergoing body cooling between May 2009 and November 2012 were evaluated.RESULTS: Thirty-nine infants ful�lled the hypothermia protocol criteria. Four newborns were removed from study due to refractory septic shock, non-maintenance of temperature and severe coagulopathy. The median Apgar scores at 1 and 5 minutes were 2 and 5. The main complication was infection, diagnosed in seven mothers (20%) and 14 newborns (40%). Convulsions occurred in 15 infants (43%). Thirty-one patients (88.6%) required mechanical ventilation and 14 of them (45%) were extubated within 24 hours. The duration of mechanical ventilation among the others was 7.7 days. The cooling protocol was started 1.8 hours after birth. All patients showed elevated levels of creatine phosphokinase, creatine phospho-kinase-MB and lactate dehydrogenase. There was no severe arrhythmia; one newborn (2.9%) presented controlled coagulopathy. Four patients (11.4%) presented controlled hypotension. Twenty-nine patients (82.9%) underwent cerebral ultrasonography and 10 of them (34.5%) presented white matter hyper-echo-genicity. Brain magnetic resonance imaging was performed on 33 infants (94.3%) and 11 of them (33.3%) presented hypoxic-ischemic changes. The hospital stay was 23 days. All newborns were discharged. Two patients (5.8%) needed gastrostomy. CONCLUSION: Hypothermia as therapy for asphyxiated newborns was shown to be safe.

RESUMOCONTEXTO E OBJETIVO: A encefalopatia hipóxico-isquêmica neonatal apresenta alta morbi-mortalidade. Estudos com hipotermia comprovam diminuição de sequelas neurológicas e morte. Nosso objetivo foi então relatar experiência de três anos da hipotermia terapêutica em recém-nascidos (RN) as�xiados.TIPO DE ESTUDO E LOCAL: Estudo restrospectivo, conduzido em hospital universitário.MÉTODOS: Trinta e cinco pacientes com as�xia perinatal submetidos a resfriamento corporal entre maio de 2009 e novembro de 2012 foram avaliados. RESULTADOS: Trinta e nove RN preencheram os critérios do protocolo de hipotermia. Quatro RN foram excluídos devido a choque séptico refratário, não manutenção da temperatura e coagulopatia grave. A mediana do Apgar de 1o e 5o minutos foi de 2 e 5. A maior complicação foi infecção, diagnosticada em sete mães (20%) e 14 RN (40%). Convulsão ocorreu em 15 RN (43%). 31 pacientes (88,6%) necessitaram da ventilação mecânica e 14 (45%) foram extubados em 24 horas. O tempo de ventilação mecânica dos demais foi de 7,7 dias. O início do resfriamento ocorreu com 1,8 horas de vida. Todos os pacientes apre-sentaram níveis elevados de creatinofosfoquinase, creatinofosfoquinase-MB e desidrogenase lática. Não se observou arritmia grave; um RN (2,9%) apresentou coagulopatia controlada. Quatro pacientes (11,4%) tiveram hipotensão controlada. Realizou-se ultrassonogra�a cerebral em 29 pacientes (82,9%), 10 (34,5%) com hiperecogenicidade da substância branca. 33 RN (94,3%) �zeram ressonância magnética cerebral, 11 (33,3%) com alterações hipóxico-isquêmicas. O tempo de internação foi de 23 dias e todos receberam alta. Dois pacientes (5,8%) necessitaram de gastrostomia. CONCLUSÃO: A hipotermia como terapêutica para RN as�xiados demonstrou ser segura.

IMD, MSc. Head, Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil. IIMD, PhD. Assistant Professor, Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.IIIMD, MSc. Instructor Professor, Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.IVMD. Instructor Professor, Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.VMD. Resident, Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.VIMD, PhD. Assistant Professor, Division of Neonatology, Department of Pediatrics, Santa Casa de São Paulo, São Paulo, Brazil.

KEY WORDS:Infant, newborn.Hypoxia, brain.Hypothermia.Asphyxia neonatorum.Magnetic resonance imaging.

PALAVRAS-CHAVE:Recém-nascido.Hipóxia encefálica.Hipotermia.As�xia neonatal.Imagem por ressonância magnética.

Neuroprotective body hypothermia among newborns with hypoxic ischemic encephalopathy: three-year experience in a tertiary university hospital. A retrospective observational study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):314-9 315

INTRODUCTIONPerinatal asphyxia consists of decreased metabolic and nutri-tional intake from mother to fetus, thereby causing low fetal tissue perfusion, hypoxia, hypercapnia and acidosis. One of its main consequences is hypoxic-ischemic encephalopathy (HIE), which occurs in one to three cases per 1000 full-term new-borns.1-2 �e outcomes from HIE range from intact survival to death. �e spectrum of long-term morbidity among survi-vors ranges from mild motor and cognitive de�cits to cerebral palsy and severe cognitive de�cits.3 It used to be believed that HIE was caused by intrapartum events and umbilical cord pro-lapse, breech presentation, forceps delivery and maternal fever.4 However, intrapartum factors have been found to be the cause of HIE in only 4% of a�ected newborns, while 69% of such cases have shown evidence of antenatal risk factors such as severe preeclampsia, maternal thyroid disease, viral infection, moder-ate to severe vaginal bleeding during pregnancy and maternal hypertension.5,6 Restriction of primary and secondary intrauter-ine growth has also presented a strong association with HIE.4 However, little evidence of antenatal damage has been observed on brain magnetic resonance imaging (MRI) performed at an early stage on neonates su�ering from HIE.7

Until recently, clinical HIE treatment consisted basically of neonatal intensive care support, correction of metabolic respi-ratory and hemodynamic disorders and use of anticonvulsants. However, studies published over the last eight years have indi-vidually or collectively shown the e�ectiveness of using body hypothermia for HIE treatment, thereby promoting increased survival without neurological sequelae, with lower morbidity and mortality.8,9

Since the time of Hippocrates, therapeutic hypothermia has been applied to various clinical conditions. In a book written by Sir John Floyer, a physician and writer in the 17th century, a procedure in which a stillborn infant was immersed in cold water to induce spontaneous breathing is described.10 �e his-tory of modern science has included periodic attempts to stan-dardize the use of therapeutic hypothermia for a range of cere-bral injury; this movement has been accelerated by advances in cardiopulmonary resuscitation.10,11 Randomized controlled trials on the e�ectiveness of therapeutic hypothermia in adult patients a�er cardiac arrest have shown improvements in sur-vival and neurological outcomes. 12

Hypothermia reduces brain injury through its impact on several biological processes. It reduces vasogenic edema, hem-orrhage and neutrophil in�ltration. It limits the release of excit-atory neurotransmitters and the accumulation of intracellular calcium. �e production of free radicals is restricted by hypo-thermia, and thus cells and organelles are protected from oxida-tive damage during reperfusion. Also, it reduces the activation

of cytokine and coagulation cascades by increasing the concen-tration of interleukin-10, an anti-in�ammatory cytokine, and reducing tumor necrosis factor-alpha. Furthermore, hypother-mia helps to maintain cerebral metabolism during and a�er cerebral attacks by decreasing the metabolic rate of glucose and oxygen. �rough reducing caspase-3 activity and increasing the expression of the anti-apoptotic protein BCL-2, hypothermia limits neuronal apoptotic death.13

Among newborns, this therapy consists of reducing body temperature by three to four degrees Celsius (moderate hypo-thermia), starting within six hours of birth and continuing for 72 hours. �e e�cacy and safety of this treatment have been con-�rmed in other studies and meta-analyses, and this has led to the introduction of hypothermia therapy protocols in daily clinical practice in many neonatal units worldwide.14-16 Our neonatology service has been using hypothermia as a routine clinical thera-peutic practice since 2009 and was the pioneer in introducing a hypothermia protocol to Brazilian neonatal units, with e�ective participation by all the professionals involved in high-risk new-born care, from birth in the obstetric delivery room to proce-dures in the neonatal intensive care unit.

OBJECTIVEOur aim in this study was therefore to report on our experience of three years of hypothermia therapy on asphyxiated newborns in a tertiary university hospital, demonstrating the characteris-tics of the newborn population undergoing this therapy, birth conditions, clinical complications, adverse e�ects, features of body temperature control and follow-up during the stay in the neonatal unit.

METHODS�is was a retrospective observational study on a cohort of new-borns with HIE who ful�lled the criteria for inclusion in a total body cooling protocol at a neonatology service in a tertiary-level university hospital (Chart 1) and were treated between May 2009 and November 2012. �e laboratory tests indicative of perina-tal asphyxia comprised gas analysis (pH and base excess, BE) on samples collected from cord blood or from the newborn within the �rst hour of life and assays on the enzymes creatine phospho-kinase (CPK), creatine phosphokinase-MB (CK-MB) and lac-tate dehydrogenase (LDH) collected from the infant before the sixth hour of life. Furthermore, we analyzed the time required to reach the target temperature of 34 °C. �e possible adverse e�ects evaluated were cardiac arrhythmias, hypotension, coagulopathy, infection and death.

We performed the following imaging studies: cerebral ultra-sonography (US) on �rst day of life and brain computed tomog-raphy (CT) and/or magnetic resonance imaging (MRI) between

ORIGINAL ARTICLE | Magalhães M, Rodrigues FPM, Chopard MRT, Melo VCA, Melhado A, Oliveira I, Gallacci CB, Pachi PR, Lima Neto TB

316 Sao Paulo Med J. 2015; 133(4):314-9

the 5th and 21st days. We took into consideration changes in the analyses that were consistent with hypoxic-ischemic injury.

We used the following assessments to determine the �nal outcome during the hospitalization period: length of hospital stay, mortality and need for gastrostomy.

For the statistical analysis, we �rstly performed descrip-tive analysis on the data. Qualitative variables were represented as absolute and relative frequencies. Numerical variables were expressed as mean, median, standard deviation (SD) and mini-mum and maximum values. In cases in which we found great variability in the samples, we chose to use the median. We used the chi-square test to compare qualitative variables and the non-parametric Kruskal-Wallis test to compare the Apgar variable. P-values (P) ≤ 0.05 were considered statistically signi�cant. We used the Minitab-15 statistical so�ware.

�e study was approved by our institution’s Ethics Committee for Human Research.

RESULTS�irty-nine infants met the criteria for inclusion in the hypo-thermia protocol during the study period. Four of them had to be withdrawn from the study: two developed refractory septic shock, one failed to maintain a temperature below 34 °C and one evolved with severe coagulopathy. �e perinatal characteristics of the 35 patients studied are shown in Table 1.

With regard to the type of delivery (vaginal or cesarean), we did not �nd any statistically signi�cant di�erence between the sexes (P = 0.42). Comparing the type of delivery with the Apgar scores at 1 and 5 minutes, there were no statistical dif-ferences (P = 0.096 and 0.287). �ere were no statistical di�er-ences in the Apgar scores at 1 and 5 minutes in relation to sex (P = 0.847 and 0.296).

Nine pregnant women (25.7%) had no complications dur-ing pregnancy. �e main maternal complication was infection, diagnosed in seven patients (20%). Infection was also the most commonly diagnosed complication in the newborns, found in 14 of them (40%). Five of these (35.7%) had positive blood cultures. Seizures were diagnosed in 15 newborns (43%): 11 of them (73.3%) received monotherapy treatment (phenobarbital) and four (27%) received diphenylhydantoin in association with phenobarbital.

�irty-one patients (88.6%) required mechanical ventilation and 14 (45%) of these patients were extubated within 24 hours of life. Among the other 17 infants, the duration of mechanical ven-tilation was 7.7 days (SD = 5.6), with a median of six days.

Body cooling began on average 1.8 hours (SD = 1.8) a�er birth (median of 1 hour). �e target temperature was attained, on average, 1.2 hours a�er the beginning of the protocol, and 21 infants (60%) achieved this temperature within 1 hour.

Chart 1. Total body cooling protocol for infants with hypoxic-ischemic encephalopathy

Inclusion criteriaGestational age ≥ 35 weeksPerinatal hypoxic ischemic event or suspected eventSix hours of life or lessEvidence of moderate or severe encephalopathy (clinical seizure) or presence of three or more of six categories: 1. Level of consciousness: lethargy (moderate); stupor/coma (severe) 2. Spontaneous activity: decreased (moderate); absent (severe) 3. Posture: distal �exion, full extension (moderate); decerebration (severe) 4. Tonus: focal or generalized hypotonia (moderate); sagging (severe) 5. Primitive re�exes: weak or incomplete (moderate); absent (severe) 6. Autonomic system: miosis, bradycardia, and periodic breathing (moderate), mydriasis, heart rate variable, apnea (severe)Associated with two of the following criteria:

Apgar score ≤ 5 in the 5th minuteVentilatory support with 5 minutes of life (orotracheal intubation or positive pressure ventilation)pH < 7.1 or base excess > -12 in cord blood gases or from arterial blood of baby in �rst hour of life

Exclusion criteria> 6 hours of lifeBirth weight < 2 kgMajor congenital malformationsInevitable death (judged by the neonatology team)

Cooling

Start within the �rst 6 hours of lifeRecord the time of the beginning of the protocolIn delivery room:

Turn o� the heated cribTransportation to the intensive care unit (ICU) in an incubator o�

In neonatal ICU:Turn o� the heated cribInstall rectal temperature monitor at 5 cm from the anal verge and �x; continuous monitoringMaintain rectal temperature between 33-34 ºC. Use ice packsRecord temperature every 30 minutes

Urinary catheter: strict control of diuresis until the end of rewarming

Safe vascular accessFasting during period of hypothermiaFentanyl: 1 mcg/kg/min throughout the procedure and increase the dose according to pain scoresSkin care

Stop cooling if:Persistence of hypoxemia with 100% FiO2

Cardiac arrhythmia requiring drug treatment (not sinus)Inform parents of the risks of hypoxic-ischemic encephalopathy (HIE), the procedure and the possible bene�ts

Reheating

Start 72 hours after the beginning of coolingHeat from 0.2 to 0.5 ºC per hour until rectal temperature reaches 36.5 ºCContinuous control of rectal temperature and record every hour until 24 hours after reaching 36.5 ºCAttention to the need for �uids during rewarming


Sao Paulo Med J. 2015; 133(4):314-9 317

All patients from whom CPK, CK-MB and LDH enzyme samples were obtained showed elevated levels. �ere was only one patient without enzyme samples. �e initial laboratory abnormalities are shown in Table 2.

Considering the possible adverse e�ects resulting from hypo-thermia, no patient had any arrhythmia other than sinus brady-cardia and only one patient (2.9%) had coagulopathy requiring intervention (Table 3). Four (11.4%) of the initial 35 newborns presented hypotension requiring vasoactive drugs.

�e cases prior to March 2011 (16 children) underwent ultraso-nography and/or computed tomography (CT) and two cases did not undergo magnetic resonance imaging (MRI) before discharge. From March 2011 onwards, all the patients underwent MRI. �e data relating to the hospital outcomes are reported in Table 3. Cerebral ultrasonography was performed on 29 patients (82.9%): 19 (65.5%) were normal and 10 (34.5%) had hyperechogenicity of white matter. Brain MRI was performed on 33 infants, and 11 of them (33.3%) had signs suggestive of hypoxic-ischemic encephalopathy.

All the infants were discharged from the neonatal unit. Only two patients (5.8%) were discharged with gastrostomy.

DISCUSSION�is study reports on a three-year experience of administer-ing hypothermia therapy to asphyxiated newborns in a tertiary-level university hospital. �e criteria for infant inclusion and exclusion were based on previous studies on safety. �e ges-tational age for inclusion in the study (more than 35 weeks) made it possible to di�erentiate encephalopathy attributed to perinatal hypoxia from other problems relating to prematu-rity.17 Hypothermia is applied within the �rst six hours of life because this is the therapeutic window within which the neu-roprotective e�ect relating to reduction of cerebral metabo-lism, reduction of excitatory neurotransmitter activity, suppres-sion of free radical release, inhibition of the apoptotic process and reduction of the release of in�ammatory mediators is most e�ective. In general, the e�cacy of the neuroprotective e�ect diminishes if the cooling period starts a�er the therapeutic win-dow, but evidence suggests that the neurological injury in HIE cases continues beyond this period.18

�e fact that no signi�cant complications attributed to thera-peutic hypothermia were observed, with successful maintenance of body temperature within 72 hours, shows that this therapy is safe and easy to control and maintain when a multidisciplinary team is involved with the main aim of reducing neurological sequelae among infants with HIE. Regarding sedation, given that it is di�cult to determine the degree of pain or discomfort in newborns with HIE who undergo hypothermia, and that opioids appear to boost the neuroprotective e�ect of this therapy, we con-sidered that it would be bene�cial to use systematic sedation with low doses of opioids in this group of infants.9

All the patients with HIE who underwent hypothermia were kept fasting for 72 hours, in accordance with the protocols of pre-viously published clinical trials.8-14 Hypothermia could increase the already-present risk of occurrences of necrotizing enteroco-litis secondary to intestinal ischemia and hypoxia. �is approach contributed towards the absence of gastrointestinal complica-tions in our patients, as also seen in the results from the above-mentioned studies.8,9

Table 1. Perinatal characteristics of patients

Categorical variablesAbsolute

frequency%

SexMale 25 71Female 10 29

Type of deliveryNormal 16 45.7Cesarean section 10 28.6Forceps 9 25.7

ResuscitationPPV with mask 2 5.7OTI 31 88.6Cardiac massage 0 0Drugs 2 5.7

Numerical variables Median Mean (SD) Minimum-maximumApgar score

1st minute 2 0-35th minute 5 2-7

Birth weight (g) 3290 3362 (302) 2925-4340

PPV = pressure ventilation; OTI = orotracheal intubation; SD = standard deviation.

Table 2. Laboratory abnormalitiesLaboratory tests Mean (SD) Median Minimum-maximumpH 7.04 (0.19) 7.00 6.60-7.40BE -15.8 (5.49) -15.0 -28.80 to -3.0CK-MB (U/L) 450 (939) 232 80-5670CPK (U/L) 4226 (3618) 3265 329-16895LDH (U/L) 3666 (4141) 2261 1045-24020

BE = base excess; CPK = creatine phosphokinase; CK-MB = creatine phosphokinase-MB; LDH = lactate dehydrogenase.

Table 3. Adverse e�ects and outcome during hospitalizationAdverse e�ects n %Arrhythmia 0/35 0Thrombocytopenia 0/35 0Coagulopathy 1/35 2.9Outcome during hospitalizationGastrostomy 2/35 5.8US changes 10/29 34.5CT changes 3/8 37.5MRI changes 11/33 33.3Death 0 0

Mean (SD) MedianLength of hospital stay (days) 23 (23) 14.5

US = Ultrasonography; CT = brain computed tomography; MRI = magnetic resonance imaging.

ORIGINAL ARTICLE | Magalhães M, Rodrigues FPM, Chopard MRT, Melo VCA, Melhado A, Oliveira I, Gallacci CB, Pachi PR, Lima Neto TB

318 Sao Paulo Med J. 2015; 133(4):314-9

Although we used cold packs rather than thermal mat-tresses, we did not record any difficulties in maintaining the temperature within the established goals. Use of gel packs has been reported to reduce death or developmental delays at six months of age among infants with HIE, without increasing the adverse events,19 although use of servo control systems can avoid temperature fluctuations.20 Moreover, we had no diffi-culties during reheating.

We did not �nd any serious side e�ects or complications that were directly related to hypothermia. As in other stud-ies,9-14 we had cases of sinus bradycardia without hemodynamic e�ects. Cooling induces QTc prolongations in hypoxic full-term newborns that become normal with rewarming.21 In our study, no patient had severe arrhythmia requiring antiarrhyth-mic intervention.

We had clinical diagnoses of seizures in 15 infants, rep-resenting 43% of the study group. Electrographic seizures are common and o�en nonconvulsive, and their onset occurs over a broad range of times within the �rst days of life.22 Unfortunately, amplitude-integrated electroencephalograms (aEEGs) available for continuous electroencephalographic monitoring were not available to us. aEEGs might have provided greater accuracy in diagnosing seizures, since it is known that asphyxiated new-borns can present neuronal hyperexcitability without evidence on clinical examination. �e changes found on brain US are not speci�c to HIE, but changes seen on MRI are more reliable, especially for demonstrating changes to the basal ganglia and thalamus. �e development and severity of motor de�cits due to perinatal asphyxia correlate with the pattern of brain injury seen on MRI. MRI provides valuable prognostic information on hypothermia-treated infants.23 �ere may be a selective neuro-protective e�ect on the cerebral cortex from hypothermia, with improved neurocognitive functioning.24 �e ideal time to per-form MRI is between the ��h and eleventh days of life, because the imaging �ndings have a better relationship to the neuro-logical prognosis.25 We observed seizures in only 43% of the newborns, and there were no deaths, which may have demon-strated that the pro�le of the group studied was more similar to patients with moderate HIE. However, we cannot rule out the hypothesis that hypothermia is an e�ective form of therapy for reducing neurological injuries.

We succeeded in reducing the newborns’ body temperature, at the beginning of and during hypothermia therapy, and suc-cessfully performed rewarming. We did not have any potentially serious complication relating to this therapy. �e patients had favorable outcomes during the hospitalization period, given the high degree of neurological sequelae in this group of patients.

In most infants with HIE, feeding impairments are pres-ent from the neonatal period onwards or started within the

first six months.26 Most of our patients were discharged with oral feeding, which provided hope, both for us and for the parents, that the neurological outcomes among these patients will be quite satisfactory, with a better quality of life. It is necessary to follow this group of newborns clini-cally and neurologically, in order to better assess the results from this therapy.

More studies involving hypothermia are needed, with longer exposure, lower temperatures and selective or whole-body hypo-thermia, and using other related therapies such as erythropoie-tin, xenon, melatonin, topiramate and stem cell therapy.27,28

CONCLUSIONWe concluded that the use of body hypothermia for neuro-protection among neonates with HIE within daily practice in our hospital did not lead to any problems when performed with a specific protocol and a trained multidisciplinary team. Hypothermia as a form of therapy for asphyxiated newborns was shown to be safe.

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with mild systemic hypothermia after neonatal encephalopathy:

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12. Arrich J, Holzer M, Havel C, Müllner M, Herkner H. Hypothermia for

neuroprotection in adults after cardiopulmonary resuscitation.

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hypothermia for neonates with hypoxic-ischemic encephalopathy. N

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15. Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA.

Hypothermia for neonatal hypoxic ischemic encephalopathy: an

updated systematic review and meta-analysis. Arch Pediatr Adolesc

Med. 2012;166(6):558-66.

16. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with

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21. Lasky RE, Parikh NA, Williams AL, Padhye NS, Shankaran S. Changes

in the PQRST intervals and heart rate variability associated with

rewarming in two newborns undergoing hypothermia therapy.

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seizures during therapeutic hypothermia for neonatal hypoxic-

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adc.bmj.com/content/97/Suppl_2/A20.4. Accessed in 2014 (May 30).

24. Inder TE, Hunt RW, Morley CJ, et al. Randomized trial of systemic

hypothermia selectively protects the cortex on MRI in term hypoxic-

ischemic encephalopathy. J Pediatr. 2004;145(6):835-7.

25. Massaro AN, Kadom N, Chang T, et al. Quantitative analysis

of magnetic resonance images and neurological outcome in

encephalopathic neonates treated with whole-body hypothermia. J

Perinatol. 2010;30(9):596-603.

26. Martinez-Biarge M, Diez-Sebastian J, Wustho� CJ, et al. Feeding and

communication impairments in infants with central grey matter

lesions following perinatal hypoxic-ischaemic injury. Eur J Paediatr

Neurol. 2012;16(6):688-96.

27. Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment

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28. Gonzalez FF, Ferriero DM. Neuroprotection in the newborn infant.

Clin Perinatol. 2009;36(4):859-80, vii.



Date of �rst submission: September 26, 2013

Last received: June 16, 2014

Accepted: June 24, 2014


Francisco Paulo Martins Rodrigues

Rua Barão do Triunfo 756 — apto 72

Brooklin Paulista — São Paulo (SP) — Brasil

CEP 04602-003

Tel. (11) 2176-7000, ramal 5667


320 Sao Paulo Med J. 2015; 133(4):320-5


Retrospective cohort of trisomy 18 (Edwards syndrome) in southern BrazilCoorte retrospectiva de trissomia do cromossomo 18 (síndrome de Edwards) no sul do BrasilDaniela DenardinI, Fabíola Elizabete SavarisI, André Campos da CunhaII, Rosilene da Silveira BetatII, Jorge Alberto Bianchi TellesIII, Luciano Vieira TargaIV, Aline WeissV, Paulo Ricardo Gazzola ZenVI, Rafael Fabiano Machado RosaVII

Hospital Materno Infantil Presidente Vargas (HMIPV) and Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: Trisomy 18 (T18), or Edwards syndrome, is a chromosomal disease character-ized by a broad clinical picture and a poor prognosis. Our aim was to describe clinical, radiological and survival data of a cohort of patients prenatally diagnosed with T18.DESIGN AND SETTING: Retrospective single cohort in the Fetal Medicine Service of Hospital Materno Infantil Presidente Vargas (HMIPV).METHODS: All sequential patients with T18 registered at the Fetal Medicine Service of HMIPV between January 2005 and September 2013 were considered. We gathered their clinical, radiological and survival data and used the Kaplan-Meier test for survival analysis. RESULTS: Ten patients were diagnosed with T18, of whom seven (70%) were female. The majority (90%) were referred due to malformations seen on ultrasound. The mean gestational age at the �rst evaluation was 25.5 weeks. At karyotyping, the defects were considered multiple in only four patients (40%). All the fetuses presented full trisomy of chromosome 18. The main abnormality observed was congenital heart disease (n = 7). Intrauterine death occurred in half of the patients (50%). All live patients (n = 5) were born through cesarean section presenting low weight and low Apgar scores. The median length of survival after birth was 18 days. CONCLUSIONS: T18 is associated with a high risk of fetal and neonatal death. The majority of the patients present major malformations identi�ed through ultrasound, such as congenital heart defects, which could help in identifying such cases prenatally.

RESUMOCONTEXTO E OBJETIVO: A trissomia do cromossomo 18 (T18), ou síndrome de Edwards, é uma doença cromossômica caracterizada por um quadro clínico amplo e prognóstico pobre. Nosso objetivo foi descrever os dados clínicos, radiológicos e de sobrevida de uma coorte de pacientes com diagnóstico pré-natal de T18.TIPO DE ESTUDO E LOCAL: Coorte única retrospectiva no Serviço de Medicina Fetal do Hospital Materno Infantil Presidente Vargas (HMIPV).MÉTODOS: Foram considerados todos os pacientes consecutivos com T18 registrados no Serviço de Me-dicina Fetal do HMIPV entre janeiro de 2005 e setembro de 2013. Foram coletados os seus dados clínicos, radiológicos e de sobrevida. Foi utilizado o teste de Kaplan-Meier para análise de sobrevida.RESULTADOS: 10 pacientes foram diagnosticados com T18, 7 (70%) do sexo feminino. A maioria (90%) foi encaminhada devido a malformações detectadas no ultrassom. A média da idade gestacional na primeira avaliação foi de 25,5 semanas. Ao cariótipo, os defeitos foram considerados múltiplos em apenas 4 pacien-tes (40%). Todos apresentaram trissomia livre do cromossomo 18. A principal anormalidade observada foi a cardiopatia congênita (n = 7). Morte intraútero ocorreu em metade dos pacientes (50%). Todos os pacientes vivos (n = 5) nasceram através de parto cesáreo, apresentando baixo peso e baixos escores de Apgar. A mediana de sobrevida após o nascimento foi de 18 dias. CONCLUSÕES: A T18 associa-se a risco elevado de morte fetal e neonatal. A maioria dos pacientes apre-senta malformações identi�cadas através do ultrassom, como cardiopatias congênitas, que poderiam au-xiliar na sua identi�cação pré-natal.

IMD. Physician, Residency Program on Obstetrics and Gynecology, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, Rio Grande do Sul, Brazil.IIMD. Obstetrician, Fetal Medicine, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, Rio Grande do Sul, Brazil.IIIMD. Fetologist, Fetal Medicine, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, Rio Grande do Sul, Brazil.IVMD. Pediatric Radiologist, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, Rio Grande do Sul, Brazil.VMD. Neonatologist, Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, Rio Grande do Sul, Brazil.VIPhD. Adjunct Professor of Clinical Genetics and of the Postgraduate Program on Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), and Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.VIIPhD. Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA) and Hospital Materno Infantil Presidente Vargas (HMIPV), Porto Alegre, Rio Grande do Sul, Brazil.

KEY WORDS:Trisomy.Chromosomes, human, pair 18. Karyotype.Prenatal diagnosis.Survival analysis.

PALAVRAS-CHAVE:Trissomia.Cromossomos humanos par 18.Cariótipo.Diagnóstico pré-natal.Análise de sobrevida.

Retrospective cohort of trisomy 18 (Edwards syndrome) in southern Brazil | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):320-5 321

INTRODUCTIONTrisomy 18 (T18) was one of the �rst chromosomal abnormali-ties to be described. It was �rst reported by Edwards et al. in 1960 and, therefore, is also known as Edwards syndrome. Nowadays, it is considered to be the second most common chromosomal abnormality involving the autosomes, only behind trisomy 21 (Down syndrome).1,2 It has an estimated prevalence of approxi-mately 1:3,600-8,500 live births.3 T18 is clinically characterized by a broad clinical picture, with more than 130 di�erent �nd-ings already described, and a prognosis that is considered poor.2,4 Most fetuses diagnosed during gestation are spontaneously aborted and, among those that are born alive, most die within the �rst six months.1,2,4

In Brazil, prenatal identi�cation of patients with T18 is important in determining issues relating to their evolution and prognosis, as well as their birth and clinical management. Many countries have also adopted a more interventionist stance and have made more investment in cases that come to birth, thereby increasingly respecting family autonomy in decision-making.1,2 However, in Brazil, there is a paucity of studies evaluating both the prenatal diagnosis and the natural history of patients with T18, especially from the beginning of pregnancy.4,5

OBJECTIVEOur aim was to describe clinical, radiological and survival data from a cohort of patients prenatally diagnosed with T18.

METHODSAll sequential patients with T18 registered at the Fetal Medicine Service of Hospital Materno Infantil Presidente Vargas between January 2005 and September 2013 were considered. We gath-ered clinical, radiological and survival data on the patients from their medical records. �is project was approved by the hospital’s Research Ethics Committee.

�e information retrieved from medical records consisted of the reason for referral; gestational age at �rst assessment; maternal and paternal ages; maternal pregnancy history; presence of diseases and threatened abortion in the current pregnancy; results from �rst-trimester sonographic screening, echocardiography and karyotyping; delivery and perinatal features; and postnatal evaluation, survival and autopsy results.

Gestational age was determined according to the earlier ultrasound. �e main reasons for fetal karyotyping were catego-rized as described by Kessler et al.6 �e patients were classi�ed according to the number of major and minor sonographic mark-ers observed before and a�er puncturing for fetal karyotyping in accordance with Raniga et al.7 Abnormalities identi�ed through imaging studies performed during prenatal care were also clas-si�ed as single or multiple defects, in accordance with Staebler

et al.,8 before and a�er performing fetal karyotyping. To deter-mine the congenital heart defect observed, we used the classi�ca-tion suggested by Botto et al.9

�e Kaplan-Meier test was used to construct the survival curve, by means of the BioEstat 5.0 so�ware.

RESULTSOver this period of about nine years, ten patients were diagnosed with T18. �e majority of them (90%) had been referred due to presence of malformations in an ultrasound evaluation (only one patient presented increased nuchal translucency). �e mean gesta-tional age at the �rst evaluation was 25.5 weeks. �e maternal age ranged from 20 to 45 years (mean of 34.4 years) and the paternal age ranged from 30 to 40 years (mean of 33.9 years). Advanced maternal age (≥ 35 years) was observed in six cases (60%) (Table 1).

All the cases in the sample were singleton pregnancies. Regarding the maternal history of pregnancy, two mothers were primiparous (20%). One of them (10%) presented gestational diabetes. �ere were no cases of preeclampsia or even threatened abortion. �ree mothers (30%) had family histories of malforma-tions, and two of them had had malformed fetuses in a previous pregnancy. Half of the patients underwent �rst-trimester sono-graphic screening. �ree of these screenings (60%) were consid-ered normal. Two patients (40%) presented a cystic hygroma. In one of them, the nasal bone was not identi�ed and there was tricuspid regurgitation. Abnormalities were seen in all cases in evaluations through obstetric and morphological ultrasound. Six patients (70%) underwent echocardiography and additional heart abnormalities were observed in three cases (all of these were ventricular septal defects) (Table 1 and 2).

At the time of making the puncture for fetal karyotype analy-sis, the number of major markers was 1.8 per case and the num-ber of minor markers was 0.3 per case. �e defects were consid-ered multiple in only four patients (40%). All the fetuses presented full trisomy of chromosome 18 in the karyotype analysis. By the end of the pregnancy, all the cases were characterized by multi-ple defects, i.e. in the six cases previously diagnosed as present-ing isolated defects, additional major abnormalities were detected. �e abnormalities observed can be seen in Table 2. According to Botto et al.,9 the main groups of heart malformations observed were septal (42.9%) and conotruncal defects (42.9%). �e con-genital heart defects observed in the present study consisted of ventricular septal defects (n = 3), double outlet of the right ventri-cle (n = 2), tetralogy of Fallot (n = 1) and hypoplastic le� ventricle (n = 1). None of our cases tried to legally terminate the preg-nancy. Intrauterine death occurred in half of the patients (50%) (Figure 1 and Table 1). By the end of the pregnancy, the number of major markers observed was 2.5 per case and the number of minor markers was 0.5 per case (Table 2).

ORIGINAL ARTICLE | Denardin D, Savaris FE, Cunha AC, Betat RS, Telles JAB, Targa LV, Weiss A, Zen PRG, Rosa RFM

322 Sao Paulo Med J. 2015; 133(4):320-5

Out of all the patients, 7 (70%) were female. All the live patients (n = 5) were born through cesarean section. Pelvic presen-tation was observed in two cases (40%). Only one was premature. Low birth weight (< 2,500 grams) was observed in all cases: the weight ranged from 1,460 to 2,475 grams, with a mean of 2,030 grams. �e length ranged from 36 to 44.5 cm (mean of 41.3 cm) and the head circumference from 30 to 34.5 cm (mean of 32.7 cm) (Table 1). All patients (n = 5) presented Apgar score < 7 at �rst minute, and 3 at the ��h minute. Additional �nd-ings observed during the postnatal period and potentially iden-ti�ed through ultrasound during the prenatal period consisted

Table 1. Gestational, perinatal and survival �ndings observed among the patients of the sample

FeaturesPatients

Total/range1 2 3 4 5 6 7 8 9 10

Sex M M F F M F F F F F 3M/7FMaternal age (years) 37 36 43 28 28 38 20 27 42 45 20 - 45Singleton pregnancies + + + + + + + + + + 10/10Radiological exams

First-trimester ultrasound + + + + + 5/10Obstetric ultrasound + + + + + + + + + 9/10Morphological ultrasound + + + + + + + 7/10Echocardiography + + + + + + 6/10

Intrauterine death + + + + + 5/10Pelvic presentation + NA NA NA NA NA + 2/5Cesarean section + NA + + NA NA NA NA + + 5/5Premature birth NA + NA NA NA NA 1/5Low birth weight + NA + + NA NA NA NA + + 5/5Postnatal survival (days) 1 NA 18 11 NA NA NA NA 73 378 1 - 378

M = male; F = female; NA = not applicable.

Table 2. Prenatal �ndings among the patients of the sample by the end of the pregnancy, divided into minor and major markers as described by Raniga et al.7

FeaturesPatients

Total1 2 3 4 5 6 7 8 9 10

Minor markers (n) 1 0 0 1 0 0 0 1 1 1 0-1Single umbilical artery + + + 3/10Short long bones + + 2/10

Major markers (n) 2 4 3 2 3 2 3 1 3 2 1-4Congenital heart defect + + + + + + + 7/10Cystic hygroma + + 2/10Micrognathia + + 2/10Omphalocele + + 2/10Corpus callosum agenesis + 1/10Ventriculomegaly + 1/10Microcephaly + 1/10Cleft lip/palate + 1/10Esophageal atresia + 1/10Diaphragmatic hernia + 1/10Radial anomaly + 1/10Clenched �sts with overlapping �ngers + 1/10Club foot + 1/10Myelomeningocele + 1/10Ambiguous genitalia + 1/10Intrauterine growth restriction + 1/10

of ambiguous genitalia (n = 2), clenched �sts with overlapping �ngers (n = 2) and micrognathia (n = 1). �e survival of these patients ranged from 1 to 378 days (median of 18 days). �ree patients (60%) died within the �rst month. Only one completed the �rst year of life. In none of the cases did the family authorize an autopsy (Figure 1 and Table 1).

DISCUSSION�e Fetal Medicine Service of HMIPV is considered to be a ref-erence in the state of Rio Grande do Sul for evaluation of preg-nant women with fetuses suspected to have or diagnosed with


Sao Paulo Med J. 2015; 133(4):320-5 323

some type of malformation, who have been attended within the Brazilian national health system (Sistema Único de Saúde, SUS). As seen from the results, the number of cases with prena-tal diagnosis of T18 at this service is about one per year, which corresponds to about 10% of the demand from live births in the state (taking the year 2005 as the reference point, which had noti�cations of 11 cases). We believe that many cases of T18 were diagnosed only during the postnatal period. �is is in accordance with the results obtained by Rosa et al. in the other study conducted in Brazil.4

�ere was a high rate of maternal age ≥ 35 years in our study, seen in 60% of the cases. �e average maternal age observed (34.4 years) was similar to that described by Rosa et al.4 (33.9 years). �e maternal age was similar to the paternal age (mean of 33.9 years). Diseases of pregnancy have been described among patients with T18.4 Rosa et al.4 observed a higher prev-alence of preeclampsia. Sugayama et al.5 also described a high rate of unspeci�ed hypertension in pregnancies of individuals with T18. A threat of abortion was also reported in 20% of the cases evaluated by Rosa et al.4 However, there were no cases of preeclampsia or threatened abortion in our sample. We cannot rule out the possibility that these �ndings may be related to our small sample size.

The first cases of prenatal diagnosis of T18 date from the 1970s.2 Today, diagnostic suspicion of T18 may be raised dur-ing the prenatal period through fetal ultrasonography, with measurement of nuchal translucency in the first trimester. This can be confirmed by fetal chromosome analysis through

procedures such as puncturing the chorionic villi and amnio-centesis.2 The finding of increased nuchal translucency is con-sidered to be the most sensitive finding for diagnosing T18 up to the 16th week of gestation.10 However, it was notewor-thy in our sample that only one of the five patients (20%) who underwent this evaluation presented increased nuchal trans-lucency. Moreover, this was the only case referred to our ser-vice due to this finding. This feature may have been related to our small sample size. On the other hand, it is interesting to note that only half of the sample was assessed by means of ultrasound during first trimester, thus showing that many patients are coming in late for evaluation.

Fetal echocardiography can also detect a congenital heart defect that may suggest the presence of T18. �e sonographic �nding of congenital heart disease is considered to be the most sensitive feature for diagnosing T18 a�er the 16th week of preg-nancy.10 In our sample, congenital heart disease was the main anomaly found during pregnancy (it was identi�ed in 70% of the patients), and use of fetal echocardiography allowed detection of additional defects that had not been identi�ed through morpho-logical and obstetric ultrasound. �is highlights the importance of performing echocardiography in these cases. �e main defects, as observed in our sample, are of septal type, especially ventric-ular septal defects. Conotruncal defects, such as a double outlet of the right ventricle and tetralogy of Fallot, and le� obstructive defects, such as hypoplastic le� heart, are considered less com-mon among patients with T18.11

Other common manifestations reported during pregnancy include intrauterine growth restriction and polyhydramnios. �e latter has been described in 9-52% of pregnancies,5,12,13 and it seems related to abnormalities of sucking and swallowing presented by the fetus. However, despite its frequency, intra-uterine growth restriction and polyhydramnios were uncom-mon in our sample. Polyhydramnios was observed only in the case with esophageal atresia (patient 4) (Table 1). We believe that in this case, the polyhydramnios was secondary to the digestive tract malformation presented by the fetus, which pre-vented adequate swallowing of amniotic �uid and hence led to accumulation around it.

It is important to highlight that the association between intra-uterine growth restriction and major malformation consistent with the phenotype of T18 o�en leads to prenatally diagnosing it a�er the 20th week of gestation. According to Viora et al.,14 modern ultrasound examinations clearly present high sensitivity (greater than 90%) for detecting fetuses with T18. �is �nding is also in agreement with the observations made by Yeo et al.,15 who found that multiple abnormalities were usually observed in fetal sonog-raphy, typically involving the brain, heart and upper limbs.16 In the study by Yeo et al.,15 all the fetuses had four or more abnormalities.

Figure 1. Kaplan-Meier curve showing the survival presented by the patients during the prenatal and postnatal periods. Note especially that half of them presented intrauterine death and that out of those who were born alive, three died within the �rst month of life and only one patient lived for longer than one year.

10

8

6

4

2

Freq

uenc

y

20 40 40 80 100

Time intervals - weeks

Prenatal PostnatalBirth

ORIGINAL ARTICLE | Denardin D, Savaris FE, Cunha AC, Betat RS, Telles JAB, Targa LV, Weiss A, Zen PRG, Rosa RFM

324 Sao Paulo Med J. 2015; 133(4):320-5

In our sample, using the method of Raniga et al.,7 the number of major markers was 1.8 per case and the number of minor markers was 0.3 per case, at the time of karyotyping. Another important aspect of our sample was that at the time of fetal karyotyping, only four patients had multiple defects. �us, it is important to have a high degree of suspicion in cases with malformations presenting a greater association with T18, such as omphalocele, diaphragmatic hernia, myelomeningocele and esophageal atresia.1,2

�e most common chromosomal abnormality observed in these patients is full trisomy of chromosome 18,1,2 and all the patients of our sample presented this �nding. Full trisomy of chromosome 18 has a relationship with advanced maternal age, due to the phenomenon of non-disjunction of chromosomes.2 In our sample, as pointed out earlier, we found a high rate of mothers aged over 35 years (60%). However, it is important to be aware that T18 can be secondary to other chromosomal abnormalities such as translocations, which may have impor-tant implications regarding genetic counseling for the patients and their families.2

We found that females predominated in our sample (70%). �is �nding is in accordance with the literature, which shows that the proportion of females has ranged from 56 to 78%.4,5,17-19 However, it is noteworthy that some authors have found equal frequencies of the sexes in evaluations performed during the pre-natal period,20 especially before the 18th week of gestation.21 �ese features may perhaps be related to the fact that female patients have been associated with a greater chance of being born alive and surviving for longer periods than boys.2

In our series, all the live patients were born through cesarean section. �ese high rates of cesarean section have also been fre-quently described in the literature (50 to 90%).4,5,13,17,19,20 It is note-worthy that there are some studies speci�cally drawing attention to this �nding.17 In our sample, we believe that this feature was related to prenatal detection of major malformations, which thus in�uenced the choice of cesarean section as the delivery route.

Several studies have drawn attention to the high rate of pre-maturity described among patients with T18 (48%).4,5,13,19,20 However, in our series only one patient (20%) was premature. Regarding low birth weight, our frequency of 100% was similar to that described in the literature,13,19,20 including studies devel-oped in Brazil.4,5 Regarding Apgar scores, the high rate of patients presenting scores below 7 (suggestive of some degree of anoxia) at the �rst and ��h minute that we observed in our study was similar to what was described by Lin et al.19 and Rosa et al.4

A signi�cant proportion of the fetuses with T18 die while still in utero, as observed in our sample (50%). According to Morris and Savva,22 it is estimated that 72% of pregnancies with fetuses with T18 end in miscarriage or stillbirth between the 12th week and full term. �e median survival a�er birth among patients

with T18 that has been reported in the literature has usually ranged from 2.5 to 14.5 days,3,13,18-20,23,24 and we obtained a simi-lar value (18 days). It is noteworthy that the value described in the other study developed in Brazil, by Rosa et al.,4 was higher (31 days). �ose authors associated this �nding with possi-ble postnatal selection, since most of the patients in their study had been referred by other medical units within the state and had not been born in the hospital. �ey did not rule out the possi-bility that patients with greater severity of disease may not have survived to the point of being referred to their hospital for eval-uation and diagnosis. Interestingly, one of our patients (10%) presented survival longer than one year, and some other stud-ies have reported that about 5-10% of the patients live longer this age.1,2 Some authors have also reported, as pointed out earlier, that female patients were more likely to be born alive and survive for a longer period of time than males.3,19,24 Moreover, the only patient who lived longer than one year was a female.

�e birth of a child with T18 may represent a great chal-lenge, with complex ethical implications. Even though termina-tion of pregnancy in cases of fetuses with T18 is not permitted by Brazilian law, prenatal identi�cation of such cases is of great importance to the family and the medical team, since it provides important information regarding prognosis and management for these patients. A multidisciplinary approach is usually nec-essary not only during pregnancy but also a�er birth. Moreover, diagnosing T18 is of critical importance for appropriate genetic counseling for families, so that correct risk calculation for future pregnancies can be made. Recurrence in cases of full trisomy of chromosome 18 is considered rare.

CONCLUSIONST18 is a chromosomal disease associated with a high risk of fetal and neonatal death. �e majority of the patients present major malformations identi�ed through ultrasound, such as congen-ital heart defects, and this could help in prenatally identifying this condition. Among the live births, most have low birth weight and low Apgar scores. We believe that further studies, especially involving a larger number of individuals and di�erent regions of the country, are required in order to better delineate the current setting of the prenatal diagnosis and natural history of patients with T18 in Brazil.

REFERENCES1. Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis.

2012;7:81.

2. Rosa RF, Rosa RC, Zen PR, Graziadio C, Paskulin GA. Trissomia 18:

revisão dos aspectos clínicos, etiológicos, prognóstico e éticos

[Trisomy 18: review of the clinical, etiologic, prognostic, and ethical

aspects.] Rev Paul Pediatr. 2013;31(1):111-20.


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3. Rasmussen SA, Wong LY, Yang Q, May KM, Friedman JM. Population-

based analyses of mortality in trisomy 13 and trisomy 18. Pediatrics.

2003;111(4 Pt 1):777-84.

4. Rosa RF, Rosa RC, Lorenzen MB, et al. Trisomy 18: experience of a

reference hospital from the south of Brazil. Am J Med Genet A.

2011;155A(7):1529-35.

5. Sugayama SMM, Kim CA, Leone CR, et al. História natural de 24

pacientes com trissomia 18 (síndrome de Edwards) e de 20 pacientes

com trissomia 13 (síndrome de Patau) [Natural history of 24 patients

with trisomy 18 (Edwards’ syndrome) and 20 patients with trisomy 13

(Patau’s syndrome)]. Pediatria (São Paulo). 1999;21(1):69-77.

6. Kessler RG, Sanseverino MTV, Leistner-Segal S, Magalhães JAA,

Giugliani R. Prenatal diagnosis of fetal chromosomal abnormalities:

Report of an 18-year experience in a Brazilian public hospital. Genet

Mol Biol. 2008;31(4):829-33.

7. Raniga S, Desai PD, Parikh H. Ultrasonographic soft markers of

aneuploidy in second trimester: are we lost? MedGenMed. 2006;8(1):9.

8. Staebler M, Donner C, Van Regemorter N, et al. Should determination

of the karyotype be systematic for all malformations detected by

obstetrical ultrasound? Prenat Diagn. 2005;25(7):567-73.

9. Botto LD, Correa A, Erickson JD. Racial and temporal variations in the

prevalence of heart defects. Pediatrics. 2001;107(3):E32.

10. Yang JH, Chung JH, Shin JS, et al. Prenatal diagnosis of trisomy 18:

report of 30 cases. Prenat Diagn. 2005;25(2):119-22.

11. Rosa RF, Rosa RC, Lorenzen MB, et al. Trisomy 18: frequency, types, and

prognosis of congenital heart defects in a Brazilian cohort. Am J Med

Genet A. 2012;158A(9):2358-61.

12. Moerman P, Fryns JP, Goddeeris P, Lauweryns JM. Spectrum of

clinical and autopsy �ndings in trisomy 18 syndrome. J Genet Hum.

1982;30(1):17-38.

13. Young ID, Cook JP, Mehta L. Changing demography of trisomy 18.

Arch Dis Child. 1986;61(10):1035-6.

14. Viora E, Zamboni C, Mortara G, et al. Trisomy 18: Fetal ultrasound

�ndings at di�erent gestational ages. Am J Med Genet A.

2007;143(6):553-7.

15. Yeo L, Guzman ER, Day-Salvatore D, et al. Prenatal detection of fetal

trisomy 18 through abnormal sonographic features. J Ultrasound

Med. 2003;22(6):581-90; quiz 591-2.

16. Bronsteen R, Lee W, Vettraino IM, Huang R, Comstock CH.

Second-trimester sonography and trisomy 18. J Ultrasound Med.

2004;23(2):233-40.

17. David TJ, Glew S. Morbidity of trisomy 18 includes delivery by

caesarean section. Lancet. 1980;2(8207):1295.

18. Goldstein H, Nielsen KG. Rates and survival of individuals with trisomy

13 and 18. Data from a 10-year period in Denmark. Clin Genet.

1988;34(6):366-72.

19. Lin HY, Lin SP, Chen YJ, et al. Clinical characteristics and survival of

trisomy 18 in a medical center in Taipei, 1988-2004. Am J Med Genet

A. 2006;140(9):945-51.

20. Embleton ND, Wyllie JP, Wright MJ, Burn J, Hunter S. Natural history of

trisomy 18. Arch Dis Child Fetal Neonatal Ed. 1996;75(1):F38-41.

21. Niedrist D, Riegel M, Achermann J, Rousson V, Schinzel A. Trisomy

18: changes in sex ratio during intrauterine life. Am J Med Genet A.

2006;140(21):2365-7.

22. Morris JK, Savva GM. The risk of fetal loss following a prenatal diagnosis

of trisomy 13 or trisomy 18. Am J Med Genet A. 2008;146(7):827-32.

23. Brewer CM, Holloway SH, Stone DH, Carothers AD, FitzPatrick

DR. Survival in trisomy 13 and trisomy 18 cases ascertained from

population based registers. J Med Genet. 2002;39(9):e54.

24. Niedrist D, Riegel M, Achermann J, Schinzel A. Survival with trisomy

18--data from Switzerland. Am J Med Genet A. 2006;140(9):952-9.



Date of �rst submission: November 20, 2013

Last received: April 22, 2014

Accepted: July 11, 2014


Rafael Fabiano Machado Rosa

Genética Clínica, Universidade Federal de Ciências da Saúde de Porto

Alegre (UFCSPA) - Complexo Hospitalar Santa Casa de Porto Alegre

(CHSCPA)

Rua Sarmento Leite, 245/403

Centro — Porto Alegre (RS) — Brasil

CEP 90050-170

Tel. (+55 51) 3303-8771


326 Sao Paulo Med J. 2015; 133(4):326-35

ORIGINAL ARTICLE DOI:10.1590/1516-3180.2014.8800711

Frequency of nutritional disorders and their risk factors among children attending 13 nurseries in São Paulo, Brazil. A cross-sectional studyFrequência de distúrbios nutricionais e de seus fatores de risco entre crianças de 13 creches de São Paulo, Brasil. Um estudo transversalTulio KonstantynerI, José Augusto Aguiar Carrazedo TaddeiII, Thais Cláudia Roma Oliveira KonstantynerIII, Laura Cunha RodriguesIV

Department of Pediatrics, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: Nutritional disorders are associated with health problems earlier in life. The objective here was to estimate the frequency of nutritional disorders and their risk factors among children.DESIGN AND SETTING: Cross-sectional study in nurseries at 13 day-care centers in São Paulo, Brazil.METHODS: The mothers of 482 children were interviewed, with anthropometry on these children. Chil-dren whose anthropometric indices for weight and height were greater than two standard deviations were considered to have nutritional disorders. RESULTS: Children in families with lower per capita income (odds ratio [OR]: 2.25; 95% con�dence interval, CI: 1.08-4.67) and who presented neonatal risk (OR 8.08; 95% CI: 2.29-28.74), had incomplete vaccinations (OR 3.44; 95% CI: 1.15-10.31) or were male (OR 3.73; 95% CI: 1.63-8.56) were more likely to be malnourished. Children in families with lower per capita income were also less likely to be overnourished (OR 0.40; 95% CI: 0.19-0.88). Children who were exclusively breastfed for less than two months (OR 2.95; 95% CI: 1.35-6.44) or who were male (OR 2.18; 95% CI: 1.02-4.65) were also at greater risk of being overnourished. Children who presented neonatal risk (OR 3.41; 95% CI: 1.04-11.23), had incomplete vaccinations (OR 3.18; 95% CI: 1.30-7.76), or were male (OR 2.76; 95% CI: 1.56-4.90) were more likely to have a nutritional disorder. CONCLUSIONS: Nutritional disorders remain present in children attending nurseries in São Paulo. Actions should focus on boys, children who were exclusively breastfed for less than two months and those without up-to-date vaccinations.

RESUMOCONTEXTO E OBJETIVO: Distúrbios nutricionais estão associados a problemas de saúde mais cedo na vida. O objetivo foi estimar a frequência dos distúrbios nutricionais e seus fatores de risco entre crianças.DESENHO E LOCAL: Estudo transversal em berçários de 13 creches em São Paulo, Brasil.MÉTODOS: Foram realizadas entrevistas com as mães e antropometria de 482 crianças. Foram considera-das com distúrbios nutricionais as crianças com valores dos índices antropométricos para peso e estatura maiores do que dois desvios-padrão.RESULTADOS: Crianças de famílias com menor renda per capita (OR 2,25; intervalo de con�ança de 95%, IC 95%: 1,08-4,67), de risco neonatal (OR 8,08; IC 95%: 2,29-28,74), com vacinação incompleta (OR 3,44; IC 95%: 1,15-10,31) ou do sexo masculino (OR 3,73; IC 95%: 1,63-8,56) apresentaram maior risco de estarem desnutridas. Crianças de famílias com menor renda per capita apresentaram menor risco de estarem hiper-nutridas (OR 0,40; IC 95%: 0,19-0,88) e crianças que receberam amamentação exclusiva por menos de dois meses (OR 2,95; IC 95%: 1,35-6,44) ou do sexo masculino (OR 2,18; IC 95%: 1,02-4,65) apresentaram maior risco de estarem hipernutridas. Crianças de risco neonatal (OR 3,41; IC 95%: 1,04-11,23), com vacinação incompleta (OR 3,18; IC 95%: 1,30-7,76), ou do sexo masculino (OR 2,76; IC 95%: 1,56-4,90) apresentaram maior risco de terem um distúrbio nutricional.CONCLUSÕES: Distúrbios nutricionais permanecem presentes em crianças frequentadoras de creches em São Paulo. Ações devem focar meninos, crianças que foram amamentadas exclusivamente por menos de dois meses e aquelas com vacinação incompleta.

IMD, MSc, PhD. Professor, Department of Health Sciences, Universidade de Santo Amaro (Unisa), São Paulo, Brazil.IIMD, MSc, PhD. A�liated Professor, Department of Pediatrics, Escola Paulista de Medicina-Universidade Federal de São Paulo (EPM-Unifesp), São Paulo, Brazil.IIIMSc, PhD. Professor, Department of Epidemiology, Faculdade de Saúde Pública, Universidade de São Paulo (FSP-USP), São Paulo, Brazil.IVMD, MSc, PhD. Head of Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

KEY WORDS:Risk factors. Child day care centers. Nutritional status. Infant. Health promotion.

PALAVRAS-CHAVE:Fatores de risco. Creches. Estado nutricional. Lactente. Promoção da saúde.

Frequency of nutritional disorders and their risk factors among children attending 13 nurseries in São Paulo, Brazil. A cross-sectional study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):326-35 327

INTRODUCTIONNutritional disorders caused by a nutritional imbalance, consisting of either malnutrition or overnutrition, are associated with seri-ous health problems and the risk of premature illness and earlier death.1,2 Both factors have been used as indicators of child health status, since children’s health has multifactorial determinants, including socioeconomic status, food consumption, healthcare conditions, infectious diseases and biological factors.3,4

During the �rst years of life, anthropometric measurements, i.e. length/height, weight and/or age, that are two standard devia-tions (SDs) below (malnutrition) or two SDs above (overnutri-tion) the mean value for the reference (healthy) population have been correlated with negative e�ects on health, development and behavior, with subsequent medical and physiological con-sequences in adult life.2,3,5 �e distribution of the frequency of nutritional disorders, which has an in�nite range, is widely used by healthcare professionals and researchers to classify the nutri-tional status of children around the world.6

�e rates of nutritional disorders among children, both in developing and in developed countries, constantly change.1,2,7 For example, recent representative sampling studies in Brazil have shown a decrease in stunting, wasting and underweight and an increase in overweight among children under �ve years of age.8,9 �ese �ndings characterize a nutritional transition that has occurred over recent decades in many places throughout the world. �is transition has been a result from globalization relat-ing to the characteristics of family lifestyle and food consump-tion at all socioeconomic levels.10 However, this change has not consistently improved children’s health, and this re�ects the chal-lenges faced by social and healthcare systems in aiming to meet the global commitment de�ned in the United Nations’ health-related Millennium Development Goals (MDGs).7,11

Understanding the risk factors involved in malnutrition and overnutrition has helped healthcare professionals identify chil-dren who are vulnerable to nutritional disorders, thus determin-ing the priorities for prevention and control action plans. Although the multiple determinants of nutritional disorders are interlinked and form a system of in�uences,4 the results relating to malnutri-tion and overnutrition have usually been reported separately in the literature. In addition, studies have not identi�ed risk factors that could lead to either type of nutritional disorder (malnutrition or overnutrition) and have not provided guidance for preventing all the concomitant nutritional disorders.4,12

Educational institutions also have a responsibility in relation to concern about nutritional disorders during the �rst years of life. �e numbers of children attending nurseries in day-care cen-ters in Brazil, as an initial and alternative educational environ-ment for the children of working women, has been increasing. Currently, more than 6.7 million Brazilian children are enrolled in day-care centers and kindergartens.13

To gain insight into this setting and inform healthcare strate-gies and policies that might more e�ectively protect children in a changing world, we conducted a study on children attending day-care centers in the city of São Paulo, in order to estimate the pro-portion of children with nutritional disorders and identify individ-ual and combined risk factors for malnutrition and overnutrition.

OBJECTIVE�e objective of this study was to estimate the frequency of nutri-tional disorders and to determine the risk factors for these dis-eases among children at 13 nurseries in São Paulo.

METHODS�e present study was part of “Projeto CrechE�ciente” (E�cient Nursery Project), and the methods have been reported elsewhere.14

In brief, we used data from two surveys (2004 and 2007) on infant populations attending nurseries (ages 0 – 2 years) that were located in public day-care centers (directly administrated by the city) and philanthropic day-care centers (indirectly adminis-trated, through philanthropic institutions) that abided by admis-sion rules guaranteeing care for low-income families.

Survey 1 was undertaken in 54 day-care centers located in the central region of the city of São Paulo, Brazil, and survey 2 was conducted in 36 day-care centers in the subdistrict of Santo Amaro in the same city. �e managers of the day-care centers were contacted by telephone to identify which ones were eligi-ble. Of these, 47 day-care centers were excluded because they did not have a nursery, 4 were excluded because they refused to par-ticipate and 8 were excluded because they had been involved in a previous healthcare study. �is resulted in 13 and 18 day-care centers included in surveys 1 and 2, respectively.

�e 31 day-care centers were visited by the project’s �eld sta�, and a questionnaire asking for information about the school’s operations, the characteristics of their human resources and the numbers and ages of the children attending was completed. A�erwards, these day-care centers were ranked according to the characteristics of interest for the project.

�e following criteria were prioritized in order of decreasing value: number of children in the nursery, number of nursery teach-ers, safety of the area for the researchers (because some day-care cen-ters were located in areas with high rates of violence) and ease of transportation and access to the premises. Accordingly, �ve day-care centers from survey 1 and eight from survey 2 were selected for the �nal stage of data collection, thus totaling 13 day-care centers.

�e initial population of the 13 day-care centers selected con-sisted of 498 children, aged 4 to 29 months, who were enrolled at and were regularly attending the nurseries. �e following children were excluded: four children who were not present during the �eld activities, �ve children who had acute diseases at the time of the surveys, �ve disabled children with chronic conditions (two with

ORIGINAL ARTICLE | Konstantyner T, Taddei JAAC, Konstantyner TCRO, Rodrigues LC

328 Sao Paulo Med J. 2015; 133(4):326-35

Down’s syndrome, one with another genetic syndrome and two with cerebral palsy) and two children whose guardians refused to participate or did not sign the informed consent statement.

Seventeen other children were excluded only from the mul-tivariate analysis because some of the data for the variables were missing. �erefore, 482 children were selected and included in the univariate analysis, and 465 children were included in the multi-variate analysis, with sample losses of 3.2% and 6.6%, respectively.

A structured and pre-encoded questionnaire was used to col-lect individual data on the children, including demographic, clini-cal, epidemiological, socioeconomic and environmental variables. To ensure uniformity in the �eldwork procedures carried out by the interviewers, a manual of norms and de�nitions was created.15

Data collection was conducted in the day-care centers by interviewing the mothers or guardians, performing anthropom-etry and collecting blood samples from the children by means of digital puncture. All procedures were standardized and tested at the pretest stage of the project by an interdisciplinary �eld team consisting of postgraduate students.

�e completed questionnaires were evaluated for their inter-nal consistency before data entry. �e information was tran-scribed into databases using double entry and subsequent valida-tion to correct errors.

�e children were weighed on a digital pediatric scale (BP Baby model, Filizola) and their lengths/heights were measured using an anthropometric ruler with a movable cursor. Both of these were made by Brazilian manufacturers with international quality certi�cation. �e anthropometric procedures used were in accordance with international recommendations.6 Z-scores were used to express nutritional status, in conformity with the Multicentre Growth Reference Study (MGRS) standards for age and sex, as recommended by the World Health Organization (WHO) in 2006.6

Stunting was de�ned as a situation with length/height-for-age z-scores < -2 SD; wasting as weight-for-height < -2 SD; under-weight as weight-for-age < -2 SD; and overweight as weight-for-height or body mass index-for-age > 2 SD.3,5 To measure hemoglobin (Hb) levels, a portable Hb photometer (HemoCue hemoglobin photometer) was used.16

�e outcomes investigated were malnutrition (stunting, wasting or underweight), overnutrition (overweight) and nutri-tional disorders (stunting, wasting, underweight or overweight), based on the WHO 2006 standards.3,6

To investigate the associations between categorical variables, the chi-square (x2) test was used.17 �e cuto� points for the dichot-omous variables were based on the o�cial recommended values or on the average value of the variables in the study sample.6,15

To adjust for confounding factors, multivariate analysis was performed using the “stepwise forward” technique. �e selection criterion for the explanatory variables for inclusion in the three

logistic models was presence of an association with the outcomes at the level of P < 0.20.18

In addition to inclusion of the variables with statistically sig-ni�cant associations in relation to the logistic model outcomes (maximum level of P = 0.05), we also included the following con-trol variables: age, hemoglobin level and per capita family income.

Children who had not received the vaccine doses expected for their age, in accordance with the Brazilian basic vaccina-tion calendar, were considered to have incomplete vaccination. We also created the variable “neonatal risk”, to include children who were premature (gestational age less than 37 weeks), had low birth weight (less than 2.5 kg) and were kept in hospital at the neonatal stage for reasons relating to these conditions.

Finally, to verify the �t of the logistic regression models, we used the Hosmer-Lemeshow goodness-of-�t test.18 �e statisti-cal package used was the Stata so�ware, version 11.0 (StataCorp, College Station, TX, USA).

Children identi�ed as having a nutritional disorder, includ-ing anemia, were referred for outpatient care at the nutritional specialty unit in the Department of Pediatrics of the same uni-versity. Children with incomplete vaccinations were referred to healthcare centers for appropriate immunizations. �is study was approved by the university’s research ethics committee.

�is study was conducted in accordance with the guide-lines laid down in the Declaration of Helsinki, and all procedures involving human subjects were approved by the research ethics committee. Written informed consent was obtained from the parents of all of the children.

RESULTSOut of the 482 children, 248 (51.4%) were boys and 234 (48.6%) were girls. Sixty-two percent of them were enrolled at philan-thropic day-care nurseries, and 38% were enrolled at public day-care nurseries. �e average age was 17.2 months (95% con�dence interval, CI, 16.7 - 17.8), and the average duration of exclusive breastfeeding was 2.1 months (95% CI: 1.9 - 2.3).

�e prevalences of prematurity, low birth weight and neo-natal hospitalization were 10.8% (95% CI: 8.0 - 13.6), 9.8% (95% CI: 7.1 - 12.5) and 4.8% (95% CI: 2.9 - 6.7), respectively. �e proportion of children who presented neonatal risk was 3.0% (95% CI: 1.4 - 4.5); and 6.2% (95% CI: 4.1 - 8.4) of the children had incomplete vaccination.

We found that 7.7% (95% CI: 5.5 - 10.5) of the children were malnourished, 7.3% (95% CI: 5.2 - 10.0) were overnourished and 14.1% (95% CI: 11.2 - 17.6) had at least one nutritional disor-der. All children who presented wasting (n = 2; 0.4%) were also underweight (n = 11; 2.3%), and the most frequent type of mal-nutrition was stunting (n = 31; 6.4%). Figure 1 presents the prev-alence and overlapping nutritional disorders (stunting, wasting, underweight and/or overweight).


Sao Paulo Med J. 2015; 133(4):326-35 329

Table 1 presents the unadjusted and adjusted odds ratios (ORs) and 95% CI for the risk factors for malnutrition. Among the socio-economic variables, per capita family income of less than half the minimum monthly wage (MW) was the �rst one identi�ed to form part of the logistic model. �ree other variables indicating individ-ual child processes, “incomplete vaccination status”, “neonatal risk” and “male sex”, were also selected to form part of the �nal model. �erefore, children who had these characteristics were 2.2, 3.4, 8.1 and 3.7 times more likely to be malnourished, respectively.

Table 2 presents the unadjusted and adjusted ORs and 95% CIs for the factors associated with overnutrition. �e multiple logistic model showed that children who had shorter periods of exclusive breastfeeding (less than two months) and those who were male were 3.0 and 2.2 times more likely to be overnourished,

respectively. On the other hand, children of families with lower per capita income were at lower risk of developing overnutrition (OR: 0.4). �ese three variables were independently associated with this outcome.

Table 3 presents the unadjusted and adjusted ORs and 95% CIs for the factors associated with the set of nutritional disorders. Children who presented neonatal risk (OR: 3.4), had incomplete vaccinations (OR: 3.1) or were male (OR: 2.7) presented inde-pendent associations with higher risk of nutritional disorders (stunting, wasting, underweight or overweight).

In the three logistic regressions, other variables met the selection criteria for inclusion in the logistic model (P < 0.20). However, these were not kept in the analysis because they lost their statistical signi�cance when included in the �nal model.

Figure 1. Prevalence and numerical intersection of groups of children with nutritional disorders (stunting, wasting, underweight or overweight) in public and philanthropic day-care nurseries in the municipality of São Paulo, from two surveys (2004 and 2007).

Malnutrition7.7% (37/482)

Nutrition disorders 14.1% (68/482)Overnutrition 7.3% (35/482)

Underweight2.3% (n = 11)

Stunting6.4% (n = 31)

Wasting0.4% (n = 2)

n = 482Overweight

7.3% (n = 35)

4

2

0

5

22

04

31

+ =

0

0

0

00


330 Sao Paulo Med J. 2015; 133(4):326-35

Risk factors nMalnutrition (stunting, wasting or underweight)

OR (95% CI)* P-value OR (95% CI)† P-valueSocioeconomic factors

Slum housing (wooden structure) Yes 482 1.37 (0.39-4.73) 0.623No 1.00

Unsuitable sewage system Yes 482 0.92 (0.27-3.13) 0.892No 1.00

Per capita family income < 0.5 MW Yes 477 2.39 (1.21-4.71) 0.012 2.25 (1.08-4.67) 0.030No 1.00 1.00

Per capita family income < 1 MW Yes 477 1.52 (0.62-3.75) 0.363No 1.00

Mother unemployed Yes 475 1.50 (0.63-3.57) 0.364No 1.00

Maternal education (years) < 8 479 0.90 (0.44-1.82) 0.768≥ 8 1.00

Maternal age (years) < 28 479 0.73 (0.37-1.45) 0.371≥ 28 1.00

Food intakeExclusive breastfeeding (months) ≤ 2 470 1.16 (0.57-2.39) 0.678

> 2 1.00Child’s healthcare conditions

Exposure to day care (months) < 6 481 1.66 (0.85-3.26) 0.139≥ 6 1.00

Day-care nurseries Philanthropic 482 0.62 (0.38-1.21) 0.167Public 1.00

Incomplete vaccination Yes 482 3.40 (1.29-8.92) 0.013 3.44 (1.15-10.31) 0.027No 1.00 1.00

One or more siblings < 3 years Yes 482 2.43 (1.15-5.15) 0.021No 1.00

Prenatal (visits) < 4 480 2.65 (0.85-8.22) 0.092≥ 4 1.00

Use of oral iron supplementation Yes 481 1.88 (0.95-3.72) 0.069No 1.00

Child’s morbidityHemoglobin (g/dl) < 11 482 0.99 (0.50-1.94) 0.967

≥ 11 1.00Avoidable hospitalization Yes 482 0.73 (0.34-1.59) 0.428

No 1.00Neonatal conditions

Prematurity Yes 474 3.75 (1.68-8.26) 0.001No 1.00

Weight at birth (kg) < 2.5 479 3.55 (1.56-8.10) 0.003≥ 2.5 1.00

Neonatal hospitalization Yes 482 3.71 (1.29-10.63) 0.015No 1.00

Neonatal risk‡ Yes 474 7.69 (2.43-24.34) 0.001 8.08 (2.29-28.74) 0.001No 1.00 1.00

Biological characteristicsChild’s age (months) < 17 482 1.06 (0.54-2.07) 0.865

≥ 17 1.00Sex Male 482 3.74 (1.67-8.36) 0.001 3.73 (1.63-8.56) 0.002

Female 1.00 1.00

Table 1. Unadjusted and adjusted odds ratios (ORs) with their respective con�dence intervals (95% CIs) for the risk factors for malnutrition (stunting, wasting or underweight) among children in public and private day-care nurseries in the municipality of São Paulo, from two surveys (2004 and 2007)

CI = con�dence interval; MW = minimum monthly wage; *Unadjusted OR; †OR adjusted for the variables making up the �nal multiple logistic model (P < 0.001); ‡low birth weight (less than 2.5 kg) + prematurity (gestational age less than 37 weeks) + neonatal hospitalization; control variables: age and hemoglobin level.


Sao Paulo Med J. 2015; 133(4):326-35 331

Risk factors nOvernutrition (overweight)


Slum house (wooden structure) Yes 482 0.63 (0.19-2.12) 0.454No 1.00


Per capita family income < 0.5 MW Yes 477 0.88 (0.42-1.81) 0.720No 1.00

Per capita family income < 1 MW Yes 477 0.52 (0.25-1.08) 0.079 0.40 (0.19-0.88) 0.022No 1.00 1.00




Food intakeExclusive breastfeeding (months) ≤ 2 470 2.61 (1.22-5.58) 0.014 2.95 (1.35-6.44) 0.007

> 2 1.00 1.00Child’s healthcare conditions



Incomplete vaccination Yes 482 1.46 (0.42-5.07) 0.553No 1.00


Prenatal (visits) < 4 480 0.54 (0.07-4.12) 0.552≥ 4 1.00








Neonatal risk‡ Yes 474 0.96 (0.12-7.59) 0.972No 1.00


≥ 17 1.00Sex Male 482 2.17 (1.04-4.54) 0.039 2.18 (1.02-4.65) 0.043

Female 1.00 1.00

Table 2. Unadjusted and adjusted odds ratios (ORs) with their respective con�dence intervals (95% CIs) for the risk factors for overnutrition (overweight) among children in public and private day-care nurseries in the municipality of São Paulo, from two surveys (2004 and 2007)

CI = con�dence interval; MW = minimum monthly wage; *Unadjusted OR; †OR adjusted for the variables making up the �nal multiple logistic model (P = 0.003); ‡low birth weight (less than 2.5 kg) + prematurity (gestational age less than 37 weeks) + neonatal hospitalization; control variables: age and hemoglobin level.


332 Sao Paulo Med J. 2015; 133(4):326-35

Table 3. Unadjusted and adjusted odds ratios (ORs) with their respective con�dence intervals (95% CIs) for the risk factors for nutritional disorders (stunting, wasting, underweight or overweight) among children in public and private day-care nurseries in the municipality of São Paulo, from two surveys (2004 and 2007)

Risk factors NNutritional disorders (stunting, wasting, underweight or overweight)


Slum house (wooden structure) Yes 482 0.66 (0.20-2.24) 0.507No 1.00


Per capita family income < 0.5 MW Yes 477 1.41 (0.84-2.37) 0.198No 1.00

Per capita family income < 1 MW Yes 477 0.76 (0.42-1.37) 0.364No 1.00




Food intakeExclusive breastfeeding (months) ≤ 2 470 1.65 (0.96-2.84) 0.069

> 2 1.00Child’s healthcare conditions



Incomplete vaccination Yes 482 2.85 (1.25-6.53) 0.013 3.18 (1.30-7.76) 0.011No 1.00 1.00


Prenatal (visits) < 4 480 1.25 (0.41-3.77) 0.695≥ 4 1.00








Neonatal risk‡ Yes 474 3.57 (1.16-10.99) 0.027 3.41 (1.04-11.23) 0.043No 1.00 1.00


≥ 17 1.00Sex Male 482 2.79 (1.56-4.90) < 0.001 2.76 (1.56-4.90) 0.001

Female 1.00 1.00

CI = con�dence interval; MW = minimum monthly wage; *Unadjusted OR; †OR adjusted for the variables making up the �nal multiple logistic model (P < 0.001); ‡low birth weight (less than 2.5 kg) + prematurity (gestational age less than 37 weeks) + neonatal hospitalization; control variables: age, hemoglobin level and per capita family income.


Sao Paulo Med J. 2015; 133(4):326-35 333

DISCUSSIONOverweight and stunting were the most common nutritional disorders in children in day-care centers in Brazil. Four factors were independently and signi�cantly associated with malnutri-tion: low per capita family income, neonatal risk, incomplete vac-cination status and male sex. Meanwhile, three factors were asso-ciated with overnutrition: high per capita family income, short exclusive breastfeeding and male sex. Furthermore, three factors were associated with the set of nutritional disorders: neonatal risk, incomplete vaccination status and male sex.

Childhood overnutrition is a complex condition that is in�uenced by our evolutionary genetic legacy interacting with a technologically advanced and consumerist society, thereby gen-erating multiple associated risk factors.12 �ese determinants appear to be closely related to perinatal conditions, early wean-ing and high purchasing power, and they lead to excess energy intake and consumption of manufactured food.12,19

Similarly, child malnutrition is a process involving many risk factors relating to lower economic resources (poverty), lower food availability and lower maternal education, which leads to lack of energy and protein intake.4

�e risk factors identi�ed in the present study were indepen-dent of the funding source of the day-care centers (public or phil-anthropic), thus indicating that they are important for children in low per capita income families attending both day-care center systems. However, it is worth noting that even though the study was conducted using rigorous data collection and analysis, the selection of day-care centers was based on ease/convenience, giv-ing priority to centers with a large number of children and to those that were located in poor but safe areas. Additionally, it is possible that the numbers of subjects and day-care centers used in this study were not large enough to provide a broad perspec-tive of the risk of nutritional disorders among children attend-ing this level of schooling. Consequently, it may not be possible to generalize these results to all Brazilian day-care centers, and the external validity and possibility of generalizing these results to children who are not in day care or to children attending day-care nurseries that function in other contexts must be considered only with caution.

Since the analysis was conducted on an existing dataset, we were limited to the use of variables that were collected for the “Projeto CrechE�ciente”. For instance, our study did not investi-gate maternal state of health or the food consumption character-istics (quality and quantity of nutrient intake), which are known to be associated with both overnutrition and malnutrition in both developed and developing countries.3,4,12

Consistent with our study, other researchers have found higher rates of overweight and stunting than of wasting and under-weight in Brazil.9,11,19,20 However, the prevalence of malnutrition was similar to that of overnutrition among children attending

day-care nurseries. �is result suggests that the Brazilian health and education systems are unable to meet their goals of keeping the anthropometric indices of children attending day-care cen-ters close to the average for the general population of the same age, and thus these children are not protected from nutritional disorders.

�e only factor present in all three �nal models was male sex, thus indicating that boys are more likely to develop overnu-trition, malnutrition and the set of nutritional disorders. Some studies reported that there was no relationship between sex and child nutrition indices.21 However, another study reported that nutritional states were worse among males,19 while others reported that females are nutritionally disadvantaged.22 Similarly, some researchers have not found associations between being overweight and sex,12 while others reported that male sex was a determinant of childhood obesity.23 �is controversy appears to be the result of sex only being one component of a more complex system of linked in�uences. Speci�cally, there is evidence that the relationship between sex and nutrition is modulated by a variety of factors, including cultural values, birth order, number of male and female children in the family, household and the day-care centers’ decisions regarding allocation of food resources.4,24

Being up-to-date with vaccinations has been reported to be negatively associated with malnutrition.25 �is probably re�ects a common determinant of parental education/knowledge and accessibility to primary healthcare services, thus suggesting that a lack of preventive healthcare during the �rst years of life can result in infant malnutrition. However, the literature has not shown any association between being overweight and incomplete vaccination status.12 Consistently, in the present study, vaccina-tion status was associated with malnutrition, but not with being overweight. Nonetheless, incomplete vaccination status had the largest impact on the set of nutritional disorders.

Children with a history of being weaned from breastfeed-ing before two months of age showed a higher risk of overnu-trition, which was consistent with another study.26 In contrast, two reviews concluded that breastfeeding is unlikely to be pro-tective of early childhood obesity because associations might be explained largely by residual confounding and/or publication bias.12,27 However, short exclusive breastfeeding was not associ-ated with malnutrition, as reported in many other studies.4,25

Low per capita family income has also been reported to be associated with malnutrition4,19,20 and overnutrition.8,12,19 �is is likely to be indicative of a parent’s ability to appropriately care for their children by providing more and adequate feeding.

Despite the fact that we analyzed children from low-income families and not from the general community, our results showed that children of families with lower per capita income had a higher risk of malnutrition, whereas those with higher per capita income had increased risk of overweight, similar to the results


334 Sao Paulo Med J. 2015; 133(4):326-35

from other studies conducted in various Brazilian regions.8,20 As expected, the association between the nutritional disor-ders was not as strong. �is �nding emphasizes the importance of appropriate use of available socioeconomic resources and of improving socioeconomic conditions in the poorest groups, so as to prevent and control these nutrition imbalances.

Nevertheless, the traditional explanation that child nutri-tional de�ciencies are simply due to food scarcity or a lack of family economic resources has been increasingly questioned by researchers.4 Furthermore, the roles of three caregiver/parent characteristics (education, intelligence and good mental health) have been considered to be important determinants linked to characteristics such as culture, maternal input into family eco-nomic decisions and social support networks.4

In contrast to some other studies,4,8,19,22 the present investi-gation did not identify any statistically signi�cant association between malnutrition or overnutrition (or a combination of them) and maternal employment, age or education. �is may have resulted from the lack of diversity of these variables in the study population.

Infants born prematurely, who were of low birth weight or who were hospitalized during the neonatal period were found to be more likely to acquire nutritional disorders in the �rst months of life.28 However, we did not �nd any association between neo-natal risks and being overweight, although neonatal risk was associated with malnutrition and with the set of nutritional dis-orders, even a�er controlling for age, hemoglobin level and per capita family income.

�ese �ndings gain greater validity through inclusion of other factors that can in�uence nutritional status in multivari-ate analysis, thereby providing a broad perspective for events that are triggered by multiple risk factors.18 As such, the e�ects were shown to be statistically signi�cant when controlling for the other variables in the multifactorial model, including hemoglobin level, as an essential indicator of iron status, and adequacy of food intake.

Governments in developing countries have considered strat-egies, such as visits to vulnerable households and integrated care across emergency and primary care services, to be methods for improving the nutritional status of children.11 However, it is also important to recognize the potential for day-care nurseries to improve the health of children under their care during weekdays and to ensure adequate nutrition for them. Nurseries are con-sidered to be spaces for implementing programs to control and prevent infant sociobiological vulnerability to parents. Managers and healthcare professionals believe that healthcare actions at day-care centers and health education programs directed towards children’s caregivers can improve a child’s health.30

Furthermore, this study highlights that there are risk factors associated with the set of nutritional disorders, which is a new

perspective for nutritional strategies. Identi�cation of the prevalence of overnutrition and malnutrition, individually and in combination, along with the associated factors, suggests that opportunities to keep children nutritionally healthy, as demonstrated through anthropo-metric measurements, are being missed.

Finally, we emphasize the need for comprehensive health and nutritional interventions in day-care centers that address nutri-tional disorders and also the importance of keeping children’s anthropometric patterns close to the average for the population.

We recommend that future studies should use qualitative and quantitative methods to study the determinants of nutritional disorders based on a comprehensive sample of children attend-ing day-care centers, in order to generate further epidemiological evidence to inform health and educational interventions for pre-venting nutritional disorders.

CONCLUSIONBased on the results from this study, we conclude that nutritional disorders remain present among children attending nurseries in São Paulo. Knowledge of the risk factors for overnutrition, mal-nutrition and the set of nutritional disorders can potentially help healthcare professionals develop strategies to prevent and control these nutrition imbalances. Actions to enhance the nutritional status of children should focus on boys, children who were exclu-sively breastfed for less for than two months and those without up-to-date vaccinations. Identi�cation of risk factors for a set of nutritional disorders seems useful as a new approach for sup-porting health promotion actions.

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Acknowledgements: The present study forms an integral part of

“Projeto CrechE�ciente”. The authors thank the principals of the day-care

centers for their assistance in obtaining informed consent and in data

collection. Moreover, the authors thank the research ethics committee of

Universidade Federal de São Paulo

Sources of funding: This study was �nanced by Fundação de Amparo

à Pesquisa do Estado de São Paulo (Fapesp), under procedural number

2006/02597-0. Fapesp had no role in the design, analysis or writing of

this article


Date of �rst submission: April 23, 2014

Last received: December 22, 2014

Accepted: December 23, 2014


Tulio Konstantyner

Disciplina de Nutrologia do Departamento de Pediatria

Escola Paulista de Medicina-Universidade Federal de São Paulo

(EPM-Unifesp)

Rua Loefgreen, 1.647

Vila Clementino — São Paulo (SP) — Brasil

CEP 04040-032

Tel. (+55 11) 5539-1783


336 Sao Paulo Med J. 2015; 133(4):336-42


Greater expression of the human leukocyte antigen-G (HLA-G) and interleukin-17 (IL-17) in cervical intraepithelial neoplasia: analytical cross-sectional study Aumento da expressão do antígeno leucocitário humano-G (HLA-G) e interleucina-17 (IL-17) em neoplasia intraepitelial cervical: estudo transversal analíticoLidyane Neves MirandaI, Fernanda Priscila Santos ReginaldoII, Daliana Maria Berenice Oliveira SouzaIII, Christiane Pienna SoaresIV, Tarsia Giabardo Alves SilvaV, Keyla Borges Ferreira RochaVI, Carlos André Nunes JatobáVI, Eduardo Antonio DonadiVII, Joanlise Marco Leon AndradeVIII, Ana Katherine Silveira GonçalvesIX, Janaína Cristiana Oliveira CrispimX

Department of Toxicology and Clinical Analysis, School of Pharmaceutical Sciences, Universidade Federal do Rio Grande do Norte, Natal (UFRN), Rio Grande do Norte, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: Impaired local cell immunity seems to contribute towards the pathogen-esis and progression of cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms promoting its progression remain unclear. Identi�cation of new molecular markers for prognosis and di-agnosis of early-stage CIN may aid in decreasing the numbers of CIN cases. Several novel immunoregula-tory molecules have been discovered over the past few years, including the human leukocyte antigen G (HLA-G), which through interaction with its receptors exerts important tolerogenic functions. Several lines of evidence suggest that T-helper interleukin-17 (IL-17)-producing cells (Th17 cells) may play a role in antitumor immunity. However, recent reports have implicated Th17 cells and their cytokines in both pro and anti-tumorigenic processes. The aim of the study was to evaluate the roles of HLA-G and Th17 in the immunopathogenesis of CIN I.DESIGN AND SETTING: Analytical cross-sectional study with a control group using 58 cervical specimens from the �les of a public university hospital providing tertiary-level care. METHODS: We examined HLA-G and IL-17 expression in the cervical microenvironment by means of im-munohistochemistry, and correlated these �ndings with clinical and pathological features.RESULTS: There was a greater tendency towards HLA-G and IL-17 expression in specimens that showed CIN I, thus suggesting that these molecules have a contribution towards cervical progression. CONCLUSION: These �ndings suggest that HLA-G and IL-17 expression may be an early marker for assess-ing the progression of cervical lesions.

RESUMOCONTEXTO E OBJETIVO: A de�ciência na imunidade celular localizada parece contribuir para a pato-gênese e progressão das neoplasias intraepiteliais cervicais (NIC), no entanto, ainda não está totalmente esclarecido o mecanismo molecular fundamental nesse processo de progressão. A identi�cação de novos marcadores moleculares de prognóstico e diagnóstico das NIC em estágios precoces pode ajudar a dimi-nuir a quantidade de casos de NIC. Várias novas moléculas com função imunorregulatória foram desco-bertas nos últimos anos, inclusive o antígeno leucocitário humano G (HLA-G), que, através de interação com os receptores, tem importantes funções tolerogênicas. Diversas linhas de evidência sugerem que as células T-ajudantes produtoras de interleucina-17 (IL-17, células Th17), podem desempenhar um papel na imunidade antitumoral. Porém, recentes relatos implicaram as células Th17 e suas citocinas tanto em processos pro- quanto anti-tumorigênicos. O objetivo do estudo foi avaliar o papel do HLA-G e Th17 na imunopatogênese das NIC I.TIPO DE ESTUDO E LOCAL: Estudo transversal analítico com grupo controle em 58 espécimes cervicais dos arquivos de um hospital universitário público com assistência prestada no nível terciário.MÉTODOS: Avaliamos a expressão de HLA-G e IL-17 por imunoistoquímica no microambiente cervical, associando esses achados com as características clínico-patológicas. RESULTADOS: Houve tendência aumentada da expressão de HLA-G e IL-17 em espécimes que apresenta-ram NIC I, sugerindo que essas moléculas têm contribuição na progressão cervical. CONCLUSÃO: Estes resultados sugerem que a expressão do HLA-G e da IL-17 pode ser um marcador precoce para avaliar a progressão das lesões cervicais.

IBSc. Master’s Student, Department of Toxicology and Clinical Analysis, School of Pharmaceutical Sciences, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil.IIBSc. Postgraduate Student, Department of Toxicology and Clinical Analysis, School of Pharmaceutical Sciences, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil.IIIMSc. Pharmacist, Department of Toxicology and Clinical Analysis, School of Pharmaceutical Sciences, Universidade Federal Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil.IVPhD. Associate Professor, Department of Clinical Analysis, School of Pharmaceutical Sciences, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), Araraquara, São Paulo, Brazil. VPhD. Researcher, Department of Clinical Analysis, School of Pharmaceutical Sciences, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp), Araraquara, São Paulo, Brazil.VIPhD. Assistant Professor, Department of Pathology, School of Medicine, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil. VIIPhD. Titular Professor, Division of Clinical Immunology, Faculdade de Medicina de Ribeirão Preto (FMRP), Ribeirão Preto, São Paulo, Brazil.VIIIPhD. Associate Professor, Department of Statistics, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil.IXPhD. Associate Professor, Department of Obstetrics and Gynecology, School of Medicine, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil.XPhD, Associate Professor, Department of Toxicology and Clinical Analysis, School of Pharmaceutical Sciences, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Rio Grande do Norte, Brazil.

KEY WORDS:HLA-G antigens.Interleukin-17.Cervix uteri.Immunohistochemistry.Cervical intraepithelial neoplasia.

PALAVRAS-CHAVE:Antígenos HLA-G.Interleucina-17.Colo do útero.Imunoistoquímica.Neoplasia intraepitelial cervical.

Greater expression of the human leukocyte antigen-G (HLA-G) and interleukin-17 (IL-17) in cervical intraepithelial neoplasia: analytical cross-sectional study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):336-42 337

INTRODUCTIONImpaired local cell immunity contributes towards the pathogen-esis and progression of cervical intraepithelial neoplasia (CIN). �e mechanism of progression from CIN to cancer has not been well explained, but intensive research has been conducted in an attempt to discover which molecules of the immune system are involved in this process, since they are known to have a very important role.1

Human leukocyte antigen G (HLA-G) is a non-classical class I molecule, which can be present both in membrane-bound and in soluble form, and it has been well recognized as a tolero-genic molecule, inhibiting both innate and adaptive immune responses.2 Under physiological conditions, HLA-G expression has limited distribution, occurring particularly in cytotropho-blast cells, where it contributes towards fetal-maternal tolerance.3 However, HLA-G expression may be induced under several path-ological conditions, including malignant lesions, allogra�s and in�ammatory and autoimmune disorders.4

Recently, studies have provided evidence that the tolerogenic protein HLA-G shows aberrant expression in a variety of can-cers, and it has been suggested that this is a mechanism for tumor escape from immunosurveillance. Within the context of cervi-cal cancer, HLA-G expression has been correlated with disease progression in patients with cervical cancer. However, the role of HLA-G in cervical premalignant and malignant lesions has not been de�ned clearly.5

�17 cells have been characterized as interleukin (IL)-17-producing CD4(+) T cells that also produce IL-21, IL-22, and IL-26.6 Greater numbers of IL-17-producing cells have also been found both in peripheral blood and in tumor tissues from can-cer patients at advanced stages.7 Although these data suggest that T-helper 17 (�17) cells potentially have an impact on tumors, the nature and role of �17 cells in the progression of cervical cancer remain unknown.

�e presence of HLA-G in CIN patients has been correlated with a worse prognosis and less chance of survival, but the cer-vical expression of HLA-G and IL-17 has not been evaluated. In the present study, the possible role of HLA-G and IL-17 in the pathogenesis and progression of cervical lesions was investigated. We measured HLA-G and IL-17 expression and correlated their levels in CIN I and chronic cervicitis (CC) patients with the clini-cal and pathological features, by means of immunohistochemistry. �is study may help in understanding the possible roles of coex-pression of HLA-G and IL-17 in the progression of cervical lesions.

OBJECTIVES�e aim of this study was to assess the expression of human

leukocyte antigen-G and interleukin-17 in cervical intraepithe-lial neoplasia.

METHODS

Patients�e study protocol was approved under No. 526/11 by the Ethics Committee of Hospital Universitário Onofre Lopes (HUOL), Universidade Federal do Rio Grande do Norte (UFRN). Cervical biopsies obtained from 58 patients were selected from the archives of the Pathology Department, UFRN School of Medicine, Brazil, during the years 2006-2009. Out of these patients, 35 were con-�rmed as presenting CIN I and 23 had CC. Clinical and patho-logical information about the patients, such as age, histories of smoking and alcohol consumption, contraceptive method, edu-cation level, age at �rst intercourse, ethnicity, number of sexual partners during lifetime, parity and number of abortions, was obtained from the patients’ medical records.

HistologyCervical biopsies are routinely performed in our gynecology unit. Fi�y-eight cervical specimens were obtained. All biopsy material was prepared using hematoxylin and eosin (HE) stain-ing for analysis and was classi�ed by a single pathologist as pre-scribed by Richart for diagnosing CIN.8

�e CIN terminology divides cervical cancer precursors into three groups: CIN I corresponds to lesions previously diag-nosed as mild dysplasia; CIN II corresponds to moderate dyspla-sia; and CIN III to both severe dysplasia and carcinoma in situ, since pathologists could not reproducibly distinguish between the two. At the time of introducing the CIN system, it was thought to de�ne a spectrum of histological abnormalities that shared common etiology, biology and natural history.9 In cases of chronic cervicitis, round cells (including lymphocytes, plasma cells and histiocytes) predominate in the in�ammatory in�ltrate and are associated with varying amounts of granulation tissue and stromal �brosis. �e diagnosis of chronic cervicitis should be reserved for cases in which there is de�nite clinical and histo-logical evidence of a signi�cant chronic in�ammatory process.10

�e 20 cervical biopsies from healthy women were kindly provided by the gynecology department of Faculdade de Medicina de Ribeirão Preto (FMRP).

Immunohistochemistry Sections of thickness 3 µm were cut, placed on organosilane-pretreated slides, and subjected to immunohistochemical assay using two monoclonal antibodies: 5A6G7 (EXBIO, Vestec, Czech Republic) against soluble HLA-G5, diluted at 1:50; and ebio-65DEC17 (Ebioscience, San Diego, California, USA), which reacts with human IL-17A, diluted at 1:100. �e cervical spec-imens were dewaxed in xylene, rehydrated in a graded alcohol series and rinsed in water. For antigen retrieval, the sections were

ORIGINAL ARTICLE | Miranda LN, Reginaldo FPS, Souza DMBO, Soares CP, Silva TGA, Rocha KBF, Jatobá CAN, Donadi EA, Andrade JML, Gonçalves AKS, Crispim JCO

338 Sao Paulo Med J. 2015; 133(4):336-42

immersed in 10 mM sodium citrate bu�er (pH 6.2). Endogenous peroxidase blocking was performed using 3% hydrogen peroxide. Nonspeci�c binding was performed using 3% low-fat dried milk diluted 1:100 in phosphate-bu�ered saline (PBS). �e slides were incubated with the primary monoclonal antibody in a humidi-�ed chamber at 4 ºC overnight. Next, MACH 4 Universal HRP Polymer Detection (Biocare Medical, California, USA) was added and incubated for 30 minutes. Finally, the samples were incu-bated with 3,3-diaminobenzidine (DAB, Gibco; Gaithersburg, Maryland, USA), lightly counterstained with Harris hematox-ylin for 15 seconds, exhaustively rewashed with tap water, air-dried and mounted using Permount mounting medium (Merck, Darmstadt, Germany).

To validate the anti-HLA-G monoclonal antibody (mAb) and the immunohistochemical method, we systematically ana-lyzed para�n-embedded sections of trophoblastic tissue (posi-tive control). To validate the anti-IL-17, we systematically ana-lyzed para�n-embedded sections of laryngeal tissue (positive control). �e baseline expression of these molecules was eval-uated by means of twenty cervical biopsies on healthy patients without cytological abnormalities, which were obtained from the Department of Gynecology, FMRP. �e negative control was pre-pared by omitting the primary antibody.

�e immunohistochemical evaluation of protein expression was done through analysis by a pathologist. �e �ndings were classi�ed according to the quantity of labeled cells and the inten-sity of their expression pattern. An average of 10 �elds at 400 x magni�cation was used for microscopic evaluation of immu-nostaining, on each histological section. For quanti�cation, the expression of the markers used was scored as follows: 0 for no expression; 1 for 1-30% positive cells; 2 for 31-70% positive cells; and 3 for 71-100% positive cells. �is classi�cation system was based on earlier work by Xie et al.11

Statistical analysis�e chi-square test or Fisher’s exact test was used to test for asso-ciations between: 1) qualitative clinical or demographic variables (education level, ethnicity, smoking habit, alcohol use and con-traceptive method used) and expression of HLA-G (present or absent) and IL-17 (present or absent); and 2) histopathological �ndings and expression levels (Tables 1 and 2) relating to HLA-G (0%, 1-30%, 31-70% and 71-100%) and IL-17 (0%,1-30%, 31-70% and 71-100%).

�e means of the quantitative clinical or demographic vari-ables (age, age at �rst intercourse, number of sexual partners during lifetime, parity and number of abortions) were compared between the CC and CIN I groups by means of two-sample t tests.

Logistic regression analysis was performed to assess the e�ect of HLA-G and IL-17 expression (present or absent) on the odds

of presenting CIN I (in comparison with CC), a�er adjustment for relevant clinical and demographic variables. �ese included age, age at �rst intercourse, number of sexual partners during lifetime, parity and oral contraceptive used.

�e statistical analyses were conducted using the GraphPad InStat so�ware (San Diego, California, USA) or R version 2.12.2. Tests yielding P-values < 0.05 were considered signi�cant.

RESULTS

Characteristics of the study population�e clinical and pathological variables of the participants studied are shown according to histological group in Table 3. �e average ages of the CC and CIN I patients were 38.21 years (standard deviation, SD = 14.43) and 33.02 years (SD = 10.61), respectively. In both groups, the majority of the participants were non-Caucasian and had completed high school. �e CC and CIN I patients were comparable regarding their age at �rst sexual intercourse and the number of sexual partners during their lifetimes, but CIN I cases were more likely to have had a higher number of sexual partners during their lifetimes. In rela-tion to cigarette smoking and alcohol use, both groups showed a few users. CC patients were likely to be regular users of con-traceptive methods.

HistologyIn the present study, we used immunohistochemical staining to analyze the expression and cell location of HLA-G and IL-17 in 58 cervical specimens. From the histopathological �ndings, the cervical tissue samples were strati�ed as CIN I patients (n = 35) or CC patients (n = 23).

Table 1. Quantitative distribution of expression of human leukocyte antigen G (HLA-G) in cervical precursor lesions

Low expression High expression0 negative 1 (1-30%) 2 (31-70%) 3 (71-100%)

n (%) n (%) n (%) n (%)CC (n = 23) 8 (34.81) 4 (17.39) 6 (26.06) 5 (21.74)CIN I (n = 35) 6 (17.14) 14 (40.00) 11 (31.43) 4 (11.43)

Chi-square test for independent samples, P = 0.1604. CC = chronic cervicitis; CIN = cervical intraepithelial neoplasia.

Table 2. Quantitative distribution of expression of IL-17 in cervical precursor lesions

Low expression High expression0 negative 1 (1-30%) 2 (31-70%) 3 (71-100%)

n (%) n (%) n (%) n (%)CC (n = 23) 7 (30.43) 14 (60.87) 2 (8.70) 0 (0)CIN I (n = 35) 5 (14.28) 24 (68.57) 6 (17.15) 0 (0)

Chi-square test for independent samples, P = 0.2735. CC = chronic cervicitis; CIN = cervical intraepithelial neoplasia.


Sao Paulo Med J. 2015; 133(4):336-42 339

Expression of HLA-G and IL-17 in cervical precursor lesionsTo explore whether HLA-G and IL-17 might be involved in the CIN cases, we �rst examined whether HLA-G and IL-17 were present in cervical specimens. In the whole group, HLA-G molecules were detected in 44 cases (75.86%). Among speci-mens that presented HLA-G expression, 29 out of 35 (82.86%) exhibited CIN I, and 15 out of 23 (65.22%) exhibited CC. Similarly, IL-17 molecules were detected in 46 cases (79.31%). Considering only the patients who presented IL-17 expres-sion, 30 out of 35 patients (85.71%) exhibited CIN I and 16 out of 23 (69.56%) exhibited CC. Absence of HLA-G and IL-17

Table 3. Clinical and pathological variables observed in patients with cervical lesionsCategory CC CIN I CC + CIN IAge (years) n = 23 n = 35 n = 58

Mean ± SD, range 38.21 ± 14.43 33.02 ± 10.61 35.08 ± 12.41Education level n = 20 (%) n = 28 (%) n = 48 (%)

Illiterate 1 (5) 0 1 (2.08)Elementary 7 (35) 12 (42.85) 19 (39.59)High school 10 (50) 16 (57.15) 26 (54.17)University 2 (10) 0 2 (4.16)

Ethnicity n = 23 (%) n = 34 (%) n = 57 (%)Caucasian 5 (21.7) 8 (23.52) 13 (22.8)Non-Caucasian 18 (78.3) 26 (76.48) 44 (77.2)

Age at �rst intercourse (years)

n = 21 (%) n = 30 (%) n = 51 (%)

Mean ± SD, range 17.85 ± 4.71 17.96 ± 3.61 17.92 ± 4.05Sexual partners during lifetime (n)

n = 19 (%) n = 29 (%) n = 48 (%)

0-1 12 (63.1) 17 (58.62) 29 (60.42)2-3 7 (36.9) 8 (27.58) 15 (31.25)4-5 0 3 (10.34) 3 (6.25)6 + 0 1 (3.44) 1 (2.08)

Smoking habit n = 18 (%) n = 26 (%) n = 44 (%)Yes 3 (16.7) 4 (15.38) 7 (15.9)No 14 (87.50) 20 (86.96) 34 (87.18)

Contraceptive method n = 19 (%) n = 32 (%) n = 51 (%)Oral contraceptives 11 (57.9) 15 (46.87) 26 (50.99)Injectable contraceptives

2 (10.52) 2 (6.25) 4 (7.84)

Intrauterine device 1 (5.28) 1 (3.12) 2 (3.92)Sterilization 2 (10.52) 2 (6.25) 2 (3.92)Condom use 0 2 (6.25) 2 (3.92)No method 3 (15.78) 10 (31.25) 13 (25.49)

Parity n = 22 (%) n = 33 (%) n = 55 (%)0-2 12 (54.55) 18 (54.55) 30 (54.55)3-7 8 (36.35) 11 (33.33) 19 (34.55)> 7 2 (9.10) 4 (12.12) 6 (10.9)

Abortions (n) n = 22 (%) n = 32 (%) n = 54 (%)0-2 21 (95.45) 31 (96.87) 52 (96.29)

3-7 1 (4.55) 1 (3.13) 2 (3.71)> 7 0 0 0

CC = chronic cervicitis; CIN = cervical intraepithelial neoplasia; SD = standard deviation.

Table 4. Association between human leukocyte antigen G (HLA-G) and interleukin-17 (IL-17) status and histopathological �ndingsHistopathological �ndings

HLA-G expressionn (%) Positive Negative

CC 23 15 (65.22) 8 (34.78)CIN I 35 29 (82.86) 6 (17.14)Histopathological �ndings

IL-17 expressionn (%) Positive Negative

CC 23 16 (69.56) 7 (30.44)CIN I 35 30 (85.71) 5 (14.29)

CC = chronic cervicitis; CIN = cervical intraepithelial neoplasia.

expression was observed in the control group, as shown in Figures 1 and 2, and in Table 4.

A�er adjustment for other covariables, the occurrences of HLA-G were signi�cant (P-value = 0.04), with odds ratio (OR) estimated as 6.61 (95% con�dence interval, CI: 1.22-49.55). �is indicated that the odds of having CIN I (compared with CC) was 6.61 times greater (or 661% greater) for women who expressed HLA-G than for those who did not. Age was the only other sig-ni�cant predictor, a�er adjustment for other covariables, with an OR of 0.87 (95% CI: 0.75- 0.96, P-value = 0.02), thus indicating a protective e�ect. In other words, the older the patient was, the smaller the odds of having CIN I also were. None of the other covariables were signi�cant (Table 5).

HLA-G expression was primarily detected in the epithe-lial cells, �broblasts and lymphocytes, and a standard dial-type cytoplasmic membrane was maintained. HLA-G was strongly expressed in trophoblastic slices that were used as positive con-trols, while HLA-G expression was not found in any specimens obtained from healthy controls.

DISCUSSIONCervical squamous intraepithelial lesions are a precancerous stage of cervical cancer.12 �e mechanism that promotes the pro-gression of cervical lesions has not been clearly explained, but the immune response appears to be an important factor.5 �erefore, identi�cation of new molecular markers to improve clinical diag-nosing of early-stage cervical lesions is still necessary and may enable more e�ective evaluation of patients with early-stage lesions, thereby resulting in slower progression of these lesions.

In the cervical context, Guimarães et al. reported that HLA-G expression was low in cervical cancer specimens.13 On the other hand, Zheng et al. reported that HLA-G is abundantly expressed in premalignant and malignant cervical intraepithelial lesions.5

�us, our study found that HLA-G expression was a signi�cant predictor in relation to CIN I and age, such that overall, HLA-G was present in approximately 75.86% of the cases and was pri-marily detected in epithelial cells, �broblasts and lymphocytes. �e presence of HLA-G was not in�uenced by other factors, such


340 Sao Paulo Med J. 2015; 133(4):336-42

as sex, ethnicity, number of partners during lifetime, parity and oral contraceptive use. �is suggests that the HLA-G molecule could be associated with the progression of cervical lesions.

In addition, polymorphic sites of HLA-G genes in cervi-cal lesions and cancer have been studied. In high-grade and

invasive cervicovaginal cancer patients, the 14 base pair (bp) In/In polymorphism seems to be associated with greater development of invasive cervical cancer.14 On the other hand, spontaneous demethylation events in the HLA-G pro-moter do not play a primary role in promoting escape from immunosurveillance, in relation to development of precan-cerous cervical lesions.15

To our knowledge, the present study is the �rst to explore the HLA-G and IL-17 expression pro�le in the cervical micro-environment in CIN I patients, in whom more than half of the biopsies (75.86%) exhibited HLA-G expression. �e presence of HLA-G, which was signi�cantly associated with CIN and age, was not in�uenced by other variables. �us, the data shown here certainly contribute towards shedding some light on the physiopathology of CIN, in which HLA-G expression in cer-vical cells may act in conjunction with other factors, such as immunosuppression induced by HPV infection, thereby result-ing in the more severe cervical disease observed in CIN III and cervical cancer patients.

Since the �rst description of HLA-G expression, its asso-ciation with malignant lesions has been intensively studied. �e data available so far have shown that the vast majority of tumors may express varying degrees of HLA-G isoforms, thus re�ecting a potential immune escape mechanism. It is also worth mentioning that HLA-G expression is highly dependent on tumor microenvironment factors, particular when IL-10 and a hypoxic factor are present.16

�e role of IL-17 in the tumor microenvironment is still controversial. Information about the behavior of cytokines in CIN cases is scarce. Previous studies have shown that patients with uterine cervical cancer (UCC) have a higher proportion of �17 cells. Notably, in UCC patients, increased �17 prevalence has been correlated with clinical stage, lymph node metastases and vasoinvasion.7

Our study found that IL-17 expression was greater in CIN I cases. IL-17 molecules were detected in 46 cases (79.31%) and, when considering only the patients that presented IL-17 expres-sion, 30 out of 35 (85.71%). Recently, in patients with ovarian cancer, Lan et al. showed that the IL-17 levels were signi�cantly greater in ovarian cancer cases than in normal ovarian tissues (P < 0.001).17 Moreover, ovarian tumor antigen-speci�c CD4(+) T cells secrete high levels of IL-17.18 However, the exact role of IL-17 in tumor immunopathogenesis remains unde�ned. It has been reported that expression of interleukin-17 in tumor cells suppresses tumor progression through enhanced antitumor immunity or promotes tumor progression through an increase in in�ammatory angiogenesis.19

Many studies have discussed the role of HLA-G and IL-17 in various types of cancer.16,20 However, this is the �rst study

Figure 1. Human leukocyte antigen G (HLA-G) expression in cervical epithelium was analyzed by means of immunohistochemistry. Labeling was accomplished using anti-HLA-G 5A6G7 mAb (EXBIO, Czech Republic).

A) Absence of expression of human leukocyte antigen G (HLA-G) in normal cervix.B) Slight human leukocyte antigen G (HLA-G) staining in chronic cervicitis (CC).C) Moderate human leukocyte antigen G (HLA-G) staining in chronic cervicitis (CC).D) Strong human leukocyte antigen G (HLA-G) staining in chronic cervicitis (CC).E) Slight human leukocyte antigen G (HLA-G) staining in cervical intraepithelial

neoplasia (CIN) I.F) Moderate human leukocyte antigen G (HLA-G) staining in cervical intraepithelial

neoplasia (CIN) I.G) Strong human leukocyte antigen G (HLA-G) staining in cervical intraepithelial

neoplasia (CIN) I.

A

B

D

F

C

E

G


Sao Paulo Med J. 2015; 133(4):336-42 341

to correlate the expression of two molecules that are impor-tant in the early stages of the cervical lesion. Consistently, our study demonstrated that coexpression of HLA-G and IL-17 was implicated in the pathogenesis and progression of cervical lesions (CC and CIN I), correlating these �ndings with clini-cal and pathological features.

CONCLUSIONTaken together, our data suggest that in CIN I patients, the increased HLA-G levels could be correlated with progression of cervical lesions, and that presence of IL-17 may be a useful indi-cator for representing the severity of tissue injury. �us, the data suggest that �17 cells are mediators during the immunological process of CIN development, thereby indicating that HLA-G and IL-17 potentially have a role in the development and progression of cervical lesions.

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Table 5. Logistic regression analyses on cervical intraepithelial neoplasia (CIN) I status. Model adjusted according to interleukin-17 (IL-17), human leukocyte antigen G (HLA-G), age, age at �rst intercourse, number of partners during lifetime, parity and oral contraceptive useIndependent variable OR 95% CI P-valueIL-17 4.46 0.73-33.07 0.11HLA-G 6.61 1.22-49.55 0.04Age 0.87 0.75-096 0.02Age at �rst intercourse 1.10 0.91-1.35 0.35Number of partners during lifetime 1.25 0.66-3.46 0.58Parity 1.54 0.98-2.72 0.09Oral contraceptive use 0.80 0.18-3.53 0.77

OR = odds ratio; CI = con�dence interval.

Figure 2. Interleukin-17 (IL-17) expression in the cervical epithelium was analyzed by means of immunohistochemistry. Labeling was accomplished using anti-IL-17 (Ebioscience, San Diego, California, USA).

A) Absence of expression of interleukin-17 (IL-17) in normal cervix. B) Slight interleukin-17 (IL-17) staining in chronic cervicitis (CC).C) Moderate interleukin-17 (IL-17) staining in chronic cervicitis (CC). D) Slight interleukin-17 (IL-17) staining in cervical intraepithelial neoplasia (CIN) I.E) Moderate interleukin-17 (IL-17) staining in cervical intraepithelial neoplasia (CIN) I.

A

B

D

C

E


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papilloma virus (HPV). J Histochem Cytochem. 2010;58(5):405-11.

14. Ferguson R, Ramanakumar AV, Koushik A, et al. Human leukocyte

antigen G polymorphism is associated with an increased risk of

invasive cancer of the uterine cervix. Int J Cancer. 2012;131(3):E312-9.

15. Gillio-Tos A, Bicalho Mda G, Fiano V, et al. Case-control study of HLA-G

promoter methylation status, HPV infection and cervical neoplasia in

Curitiba, Brazil: a pilot analysis. BMC Cancer. 2012;12:618.

16. Singer G, Rebmann V, Chen YC, et al. HLA-G is a potential tumor

marker in malignant ascites. Clin Cancer Res. 2003;9(12):4460-4.

17. Lan C, Huang X, Lin S, et al. High density of IL-17-producing cells is

associated with improved prognosis for advanced epithelial ovarian

cancer. Cell Tissue Res. 2013;352(2):351-9.

18. Cannon MJ, Goyne HE, Stone PJ, et al. Modulation of p38 MAPK

signaling enhances dendritic cell activation of human CD4+ Th17

responses to ovarian tumor antigen. Cancer Immunol Immunother.

2013;62(5):839-49.

19. Kryczek I, Banerjee M, Cheng P, et al. Phenotype, distribution,

generation, and functional and clinical relevance of Th17 cells in the

human tumor environments. Blood. 2009;114(6):1141-9.

20. Wägsäter D, Löfgren S, Hugander A, Dimberg J. Expression of

interleukin-17 in human colorectal cancer. Anticancer Res.

2006;26(6B):4213-6.

Acknowledgements: We are grateful to Elizabeth Maia de Oliveira, who

provided technical help, and Francisco Pignataro Lima (departmental

chair of pathology), who provided general support. We want to thank

the National Council for Scienti�c and Technological Development

(Conselho Nacional de Desenvolvimento Cientí�co e Tecnológico, CNPq)

for the grant for this research.



Date of �rst submission: May 14, 2013


Accepted: February 12, 2014


Janaína Cristiana de Oliveira Crispim

Departamento de Análises Clínicas e Toxicológicas

Faculdade de Ciências Farmacêuticas, Universidade Federal do Rio

Grande do Norte

Rua General Cordeiro de Farias, s/no

Petrópolis — Natal (RN) — Brasil

CEP 59012-570

Tel. (+55 84) 3342-9829


Sao Paulo Med J. 2015; 133(4):343-9 343

ORIGINAL ARTICLEDOI: 10.1590/1516-3180.2014.8000815

Semiquantitative fecal calprotectin test in postinfectious and non-postinfectious irritable bowel syndrome: cross-sectional studyTeste calprotectina fecal semiquantitativa na síndrome do intestino irritável pós-infecciosa e não pós-infecciosa: estudo transversalLiliana-Elisabeta DavidI, Teodora Surdea-BlagaII, Dan-Lucian DumitrascuIII

Second Department of Internal Medicine, “Iuliu Hatieganu”, University of Medicine and Pharmacy, Cluj-Napoca, Romania

ABSTRACTCONTEXT AND OBJECTIVE: The presence of a certain degree of in�ammation in the gut wall is now ac-cepted in irritable bowel syndrome (IBS). Fecal calprotectin is considered to be a reliable test for detecting intestinal in�ammation. Our aim was to assess the presence of in�ammation in postinfectious IBS (PI-IBS), compared with non-postinfectious IBS (NPI-IBS). A secondary objective was to determine the usefulness of a rapid fecal calprotectin test in in�ammatory bowel diseases (IBD). DESIGN AND SETTING: This was a cross-sectional study. Patients with IBS and IBD at a single tertiary gastroenterology center were prospectively included in this study. METHODS: 116 patients with Rome III IBS score (76 females; 48 ± 12 years) were investigated; 24 patients (15 females) had PI-IBS. Intestinal in�ammation was assessed using the semiquantitative fecal calprotec-tin test. The results were expressed as T1, T2 or T3 according to the severity of in�ammation (< 15 µg/g; 15-60 µg/g; > 60 µg/g). Using the same test, we evaluated 20 patients with IBD (12 males; 47 ± 13 years). RESULTS: None of the patients with IBS had a T2 or T3 positive test. Among PI-IBS patients, 33% had a T1 positive test. Among NPI-IBS patients, 9.8% had a T1 positive test, which was signi�cantly di�erent to PI-IBS. The calprotectin test was positive in all IBD patients: 80% with T3, 10% with T2 and 10% with T1. CONCLUSIONS: Using a semiquantitative test for fecal calprotectin, positive tests were more frequent in PI-IBS patients than in NPI-IBS patients.

RESUMOCONTEXTO E OBJETIVO: A presença de certo grau de in�amação na parede do intestino é agora aceita na síndrome do intestino irritável (SII). A calprotectina fecal é considerada teste con�ável para detectar in�amação intestinal. Nosso objetivo foi avaliar a presença de in�amação na SII pós-infecciosa (SII-PI), em comparação com a SII não pós-infecciosa (SII-NPI). Um objetivo secundário foi determinar a utilidade de um teste rápido fecal da calprotectina em doenças in�amatórias intestinais (DII).TIPO DE ESTUDO E LOCAL: Este foi um estudo transversal. Pacientes com SII e DII em um único centro terciário de gastroenterologia foram prospectivamente incluídos neste estudo.MÉTODOS: 116 pacientes com escore Roma III de SII (76 mulheres, 48 ± 12 anos) foram investigados; 24 pacientes (15 mulheres) tinham SII-PI. In�amação intestinal foi avaliada pelo teste semi-quantitativo de calprotectina fecal. Os resultados foram expressos como T1, T2 ou T3 de acordo com a gravidade da in�amação (< 15 µg/g; 15-60 mg/g; > 60 mg/g). Usando o mesmo teste, foram avaliados 20 pacientes com DII (12 homens, 47 ± 13 anos).RESULTADOS: Nenhum dos pacientes com SII teve um teste positivo T2 ou T3. Na PI-IBS, 33% tiveram um teste positivo T1. Entre os pacientes SII-NPI, teste T1 positivo estava presente em 9,8%, taxa signi�cativa-mente diferente quando comparada com SII-PI. O teste de calprotectina foi positivo em todos os pacientes com DII: 80% com T3, 10% com T2 e 10% com T1.CONCLUSÕES: Usando teste semi-quantitativo para calprotectina fecal, relatamos positividade em pa-cientes SII-PI com mais frequência que em pacientes SII-NPI.

IBSc. Doctoral Student and Head Nurse, Second Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania.IIMD, MSc. Doctoral Student and Attending Physician, Second Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania.IIIMD, PhD. Head of Department, Second Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania.

KEY WORDS:Leukocyte L1 antigen complex.In�ammation. In�ammatory bowel diseases. Irritable bowel syndrome.Gastroenteritis.

PALAVRAS-CHAVE:Complexo antígeno L1 leucocitário.In�amação. Doenças in�amatórias intestinais. Síndrome do intestino irritável.Gastroenterite.

ORIGINAL ARTICLE | David LE, Surdea-Blaga T, Dumitrascu DL

344 Sao Paulo Med J. 2015; 133(4):343-9

INTRODUCTIONIt is now accepted that a certain degree of in�ammation in the gut wall is present in irritable bowel syndrome.1 Since irritable bowel syndrome is a functional disorder, with a very good prog-nosis in terms of survival, it is preferable to use noninvasive tests in order to evaluate the presence of in�ammation. More than a decade ago, measurement of calprotectin in feces was proposed as a surrogate marker of intestinal in�ammation.2 Calprotectin represents 60% of granulocytic cytosolic proteins, and therefore its concentration re�ects the neutrophil migration in the gastro-intestinal tract. Increased levels of calprotectin indicate intestinal in�ammation, but it is not disease-speci�c.3

Over the last few years, several studies have focused on evaluating the value of fecal calprotectin for detecting muco-sal in�ammation, especially in patients with in�ammatory bowel disease, both in an active phase and in clinical remission. Patients with clinically quiescent in�ammatory bowel disease have some degree of mucosal in�ammation,4 as proved by high levels of fecal calprotectin. For example, Sipponen et al. reported that there were high levels of calprotectin (up to 1000 mcg/g) in 13% of their in�ammatory bowel disease patients who were in clinical remission.5 Fecal calprotectin also has prognostic value, such that the probability of remaining in clinical remis-sion is higher when the fecal calprotectin level is low.5 �ere is also evidence that patients with mucosal healing seen through endoscopy have lower or normal fecal calprotectin levels.6,7 Fecal calprotectin levels also become increased in other organic disorders such as small bowel enteropathy, microscopic colitis, infectious diarrhea, segmental colitis associated with diverticu-losis and colorectal cancer.8

Fecal calprotectin levels are low both in irritable bowel syn-drome patients and in healthy controls.8,9 Several studies have shown that increased fecal calprotectin levels can di�erentiate between organic colonic diseases and nonorganic disease (espe-cially irritable bowel syndrome), in symptomatic patients.8,10 Using a cuto� of 10 mg/l, fecal calprotectin had sensitivity of 89% and speci�city of 79% for organic disease.8

Postinfectious irritable bowel syndrome is a speci�c type of irritable bowel syndrome, acknowledged by the Rome working committees.1 However, there is evidence that postinfectious irri-table bowel syndrome patients di�er from non-postinfectious irritable bowel syndrome patients by having a low level of intesti-nal in�ammation.11 Persistent in�ammation a�er the acute infec-tion may be important in the pathogenesis of postinfectious irri-table bowel syndrome.

We started from the hypothesis that fecal calprotectin would be positive in a higher proportion of patients with postinfectious irritable bowel syndrome, compared with non-postinfec-tious irritable bowel syndrome patients.

OBJECTIVEThe main objective of our study was to find out whether there were any differences in fecal calprotectin levels in patients with postinfectious irritable bowel syndrome, compared with non-postinfectious irritable bowel syndrome patients, using a rapid semiquantitative fecal calprotectin test. A second objec-tive of the study was to investigate the usefulness of a rapid and inexpensive fecal calprotectin test in a group of patients with obvious intestinal inflammation, such as patients with inflammatory bowel diseases.

METHODS

Study design and setting�is was a cross-sectional study carried out in a public hospital for six months in 2012.

Subjects

Irritable bowel syndrome patientsA total of 116 consecutive irritable bowel syndrome patients referred to a single tertiary gastroenterology department were prospectively included in this study a�er they gave their informed consent. �e patients were diagnosed as having irri-table bowel syndrome in accordance with the Rome III criteria, i.e. abdominal pain present on at least three days per month on average, over the last three months, with the onset of symptoms at least six months earlier, in the absence of any structural or bio-chemical cause.1 Among the 116 patients with irritable bowel syndrome, 76 (65.5%) were females, and the mean age was 48 ± 12 years. To our knowledge, there are no data in the literature that have compared the levels of fecal calprotectin in postinfec-tious irritable bowel syndrome and non-postinfectious irritable bowel syndrome patients. �is was a pilot study and we used a convenience sample.

�e patients with irritable bowel syndrome were grouped into postinfectious irritable bowel syndrome and non-postinfectious irritable bowel syndrome. �e diagnosis of postinfectious irrita-ble bowel syndrome was established by asking the patients about their medical history over the year before the onset of irritable bowel syndrome.12 Patients were assigned to the postinfectious irritable bowel syndrome group if they recognized a triggering event consisting of an acute episode of gastroenteritis (nausea, vomiting and diarrhea), during the year before the irritable bowel syndrome symptoms developed. �ey were assigned to the non-postinfectious irritable bowel syndrome group, if they did not recall such an episode in the past. Twenty-four patients (20.6%) presented postinfectious irritable bowel syndrome, of whom 15 were female. �ere were no di�erences regarding age and gender

Semiquantitative fecal calprotectin test in postinfectious and non-postinfectious irritable bowel syndrome: cross-sectional study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):343-9 345

between the postinfectious irritable bowel syndrome group and the non-postinfectious irritable bowel syndrome group.

Patients with coexisting cardiovascular, pulmonary, hepatic, renal or musculoskeletal disease, severe immune de� ciency, malignancy or alcohol abuse, or who were receiving non-ste-roidal anti-in� ammatory drugs, were excluded from the study because these conditions may be associated with intestinal in� ammation.13,14 Patients with menstrual or nasal bleeding dur-ing the � ve days prior to fecal testing were also excluded, since blood in the feces could increase the calprotectin levels.15,16

In� ammatory bowel disease patientsFecal calprotectin levels are high in patients with in� ammatory bowel diseases,5 and vary with the severity of in� ammation. Fecal calprotectin is used in current practice to monitor the evo-lution of patients with in� ammatory bowel diseases, but the costs of ELISA (enzyme-linked immunosorbent assay) tests are quite high. In order to achieve the second objective of this study and to con� rm previously published data,3,5 we applied a rapid and inex-pensive fecal calprotectin test to a small group of patients with in� ammatory bowel diseases.

We selected 20 consecutive patients (eight females) with in� ammatory bowel diseases who had been admitted to our department: 15 with ulcerative colitis, 3 with Crohn’s disease and 2 with unspeci� ed colitis. � e mean age of the in� ammatory bowel disease group was 47 ± 13 years. � e diagnosis of in� am-matory bowel disease was based on the macroscopic appearance of the colonic mucosa during lower gastrointestinal endoscopy, and was con� rmed from histopathological analysis on colonic biopsies. � e patients were seen either at the � rst � are of coli-tis, or during a long remission without treatment. Patients with Crohn’s disease complications (� stulae, abscesses or symptomatic intestinal strictures requiring surgery) were excluded.

Assessment of fecal calprotectin We assessed intestinal in� ammation by means of a rapid, semi-quantitative commercially available test (CalDetect, SOFAR, Trezzano Rosa, Italy), which uses an immunochromatographic method to detect the presence of calprotectin in the feces. � ere are studies showing that rapid tests are useful as a screening test for excluding gastrointestinal in� ammation when the cuto� of 15 mcg/g is used, with a negative predictive value of 94%.17 � e test can be performed on the same day, or within a maximum of one week if the feces are kept at between 2 and 8 °C. Its major advantage is that the result is available a� er 15 minutes. We always used the test within the � rst hour a� er obtaining the sam-ple of feces. � e result can be negative or positive.

According to the producer’s speci� cations, the presence of one red control band (C) alone indicates that calprotectin is not

present in the feces, and we referred to this situation as a clearly negative test. � e presence of two color bands (C and T1) corre-sponds to fecal calprotectin < 15 mcg/g, and was referred to in our study as a T1 positive test. � e presence of three color bands (C, T1 and T2) indicates fecal calprotectin of between 15 and 60 mcg/g and was referred to in our study as a T2 positive test. � e presence of four color bands (C, T1, T2 and T3) indicates fecal calprotectin > 60 mcg/g, and was referred to in our study as a T3 positive test.18

� us, according to this test, the fecal calprotectin assess-ment may give one of the following results: negative or positive. If positive, the test returns one of three values: T1 if fecal cal-protectin < 15 mcg/g (suggesting minimal in� ammation); T2 if fecal calprotectin = 15-60 mcg/g (moderate in� ammation); T3 if fecal calprotectin > 60 mcg/g (severe in� ammation)18 (Figures 1 and 2).

All patients, both those with irritable bowel syndrome and those with in� ammatory bowel disease, were evaluated using this fecal calprotectin test, but no comparison between the two groups was made.

Statistical analysisDescriptive statistics (mean ± standard deviation) were used for parametric data. To compare the proportions of positive tests in cases of postinfectious irritable bowel syndrome versus cases of non-postinfectious irritable bowel syndrome, we used the Z test

Figure 2. Plaque showing a T3 positive calprotectin test. Four color bands are visible, C corresponds to the control band (C).

Figure 1. Plaque showing a negative fecal calprotectin test. Only the control band is visible.


346 Sao Paulo Med J. 2015; 133(4):343-9

for proportions. An error probability of P < 0.05 was considered statistically signi�cant.

Ethical issues�is study was conducted in accordance with the Declaration of Helsinki regarding human studies. All patients gave their informed consent and the study received approval from our insti-tution’s Ethics Committee.

RESULTS

Fecal calprotectin in irritable bowel syndrome patientsEight patients (33%) out of 24 with postinfectious irrita-ble bowel syndrome and nine patients (9.8%) out of 92 with non-postinfectious irritable bowel syndrome had a T1 posi-tive calprotectin test (Figure 3). None of the patients had a T2 or a T3 positive fecal calprotectin test, and therefore none of the irritable bowel syndrome patients had moderate or severe in�ammation. All the other patients with irritable bowel syn-drome, i.e. both with postinfectious and non-postinfectious irri-table bowel syndrome, had a negative fecal calprotectin test (T0). �e proportion of patients with a mild positive fecal calpro-tectin test (T1) was signi�cantly higher (Z = 2.9; P < 0.001) in the postinfectious irritable bowel syndrome group than in the non-postinfectious irritable bowel syndrome group (Figure 3).

�e post-hoc power analysis on this test indicated a power of 0.65.

Fecal calprotectin in in�ammatory bowel disease patientsOut of the 20 patients with in�ammatory bowel disease, none had a negative fecal calprotectin test. �e majority of the in�am-matory bowel disease patients (16/20) had a T3 positive fecal cal-protectin test, thus suggesting severe in�ammation. �e results are summarized in Figure 4.

DISCUSSION�e usefulness of calprotectin for detecting intestinal in�am-mation is accepted worldwide. Our study performed both on irritable bowel syndrome patients and on in�ammatory bowel disease patients showed that even a simpler method such as a semiquantitative test for fecal calprotectin is useful for detect-ing intestinal in�ammation. In addition, using this semiquan-titative method, our study is one of the �rst to demonstrate that patients with postinfectious irritable bowel syndrome have a higher degree of in�ammation than do patients with non-postinfectious irritable bowel syndrome. A limited number of studies have used this immunochromatographic method for detecting colonic in�ammation.3,19 �e semiquantitative test had sensitivity and speci�city comparable to ELISA-based fecal calprotectin tests for detecting in�ammation in patients with ulcerative colitis and Crohn’s disease.3

In our study, 20% of the patients were classi�ed as presenting postinfectious irritable bowel syndrome. Our result was similar to other observations regarding the incidence of postinfectious irritable bowel syndrome following infectious gastroenteritis (in the 12th month a�er the acute episode), which have ranged

33%

67%

9.8%

91.2%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PI-IBS NPI-IBS

Calprotectin-positive T1

Calprotectin-negative T0

Figure 3. Proportions of patients with a mild T1 positive fecal calprotectin test and a T0 negative fecal calprotectin test in cases of postinfectious irritable bowel syndrome (PI-IBS) and non-postinfectious irritable bowel syndrome (NPI-IBS).

Figure 4. Results from fecal calprotectin testing among patients with irritable bowel diseases. T1, mild in�ammation; T2, moderate in�ammation; and T3, severe in�ammation. The results are expressed as the number of patients; and the rate from 20 patients with in�ammatory bowel diseases.

2 ; 10% 2 ; 10%

16 ; 80%

0

2

4

6

8

10

12

14

16

T1 T2 T3


Sao Paulo Med J. 2015; 133(4):343-9 347

from 13% to 31%.12,20 In our irritable bowel syndrome group, 14.6% of the patients had a positive fecal calprotectin test (T1 positive), thus suggesting mild in�ammation. Half of them had postinfectious irritable bowel syndrome. Another study that used this semiquantitative method among irritable bowel syndrome patients reported that there was no increase in fecal calprotec-tin levels in irritable bowel syndrome in relation to healthy con-trols.21 Our study showed that a higher proportion of patients with postinfectious irritable bowel syndrome had a positive cal-protectin test, compared with patients with non-postinfectious irritable bowel syndrome. �is suggests that a�er an acute epi-sode of enterocolitis, there is a degree of persistent in�ammation.

Other studies have also reported mild in�ammation in cases of irritable bowel syndrome. Tibble et al. evaluated fecal cal-protectin (using the ELISA method for quanti�cation) in 602 patients with gastrointestinal complaints, of whom 339 were clas-si�ed as presenting nonorganic disease (all of them had irritable bowel syndrome symptoms), and 263 as presenting organic dis-ease. Fecal calprotectin < 10 mg/l was considered normal. In the nonorganic group, the median fecal calprotectin level was 4 mg/l, with a range of 1-50 mg/l.8 �us, several irritable bowel syndrome patients had fecal calprotectin > 10 mg/l, but < 50 mg/l, which suggested that there was some degree of in�ammation in these irritable bowel syndrome cases. �ese authors did not provide further information regarding the postinfectious status of these patients.8 Similar results were reported in another study. �e range of fecal calprotectin detected using ELISA was 0-24 mcg/g, with a median value of 6 mcg/g. �e highest sensitivity and spec-i�city of fecal calprotectin for di�erentiating organic from func-tional disorders was observed using a cuto� value of 24.3 mcg⁄g.22

In our study, we used a semiquantitative test to detect fecal calprotectin, with positive tests expressed in mcg/g. �us, we cannot directly compare our results with those obtained using the ELISA method (values expressed in mg/l). However, we can say that, in the same way as shown in Tibble et al. study,8 fecal cal-protectin was positive in some of our irritable bowel syndrome patients, although only low levels were detected.

Both in the postinfectious irritable bowel syndrome and in the non-postinfectious irritable bowel syndrome, there is evi-dence of some degree of in�ammation. Some studies have reported increased numbers of intraepithelial T lymphocytes and enterochroma�n cells in rectal biopsy specimens, 12 weeks a�er acute gastroenteritis, compared with the cell counts in control subjects.23-25 In another study, the number of enterochroma�n cells was signi�cantly higher in a group with postinfectious irri-table bowel syndrome than in a group with non-postinfectious irritable bowel syndrome, but the number of T lymphocytes was similar.26 Our study showed that a higher proportion of patients with postinfectious irritable bowel syndrome had a positive

calprotectin test, compared with patients with non-postinfec-tious irritable bowel syndrome (33% versus 10%). �is suggests that the degree of intestinal in�ammation is higher in patients with postinfectious irritable bowel syndrome than in those with non-postinfectious irritable bowel syndrome.

�e usefulness of fecal calprotectin testing in cases of in�am-matory bowel disease has already been proven. We also tested this semiquantitative method on in�ammatory bowel disease patients. Out of 20 patients with in�ammatory bowel disease, 80% had a T3 positive test, i.e. fecal calprotectin > 60 mcg/g. Using ELISA testing on fecal calprotectin, a high cuto� value set at 100 mcg/g had better accuracy than the usual cuto� limit of 50 mcg/g.27 Our cuto� value for moderate to severe in�am-mation (as seen in in�ammatory bowel disease) was 60 mcg/g. Only 20% of our in�ammatory bowel disease patients had fecal calprotectin < 60 mcg/g. Our results from in�ammatory bowel disease patients were similar to those reported in other stud-ies, in which the calprotectin levels were rarely below 60 mcg/g, and varied widely between 54 and 6032 mcg/g.28 A large study (including 823 patients) that used CalDetect, reported that only 7% of patients with active Crohn’s disease had a calprotectin level < 15 ng/ml, while among patients with inactive Crohn’s disease, 89% had a calprotectin level < 15 ng/ml. �ese results were very close to those observed using ELISA methods, thus resulting in very good performance for this rapid test.3

In cases of irritable bowel syndrome, many patients are still concerned with abdominal pain or diarrhea, and some of them undergo repeated colonoscopies. Patients with in�ammatory bowel disease o�en need repeated colonoscopies for follow-up and evaluation of treatment e�cacy. It is obvious that in these cases, fecal calprotectin testing is preferable, since it is inex-pensive, noninvasive, rapid, sensitive and speci�c for intestinal in�ammation.

On the other hand, fecal calprotectin testing has some dis-advantages. False positive results may occur. �us, use of non-steroidal anti-in�ammatory drugs can increase fecal calpro-tectin levels.29,30 Age is also thought to in�uence calprotectin levels.15 �e presence of blood in stools (at least 100 ml/day) increases fecal calprotectin levels, and therefore testing should be avoided in patients with menstrual or nasal bleeding.15,16 It is worth mentioning that several authors have showed that there is considerable variability of calprotectin levels in the same fecal sample, or in di�erent samples on consecutive days, from the same patients.31 �is disadvantage can be overcome by repeat-ing this inexpensive and rapid test several times.

�is study shows the usefulness of a simple and inexpen-sive semiquantitative fecal test for assessing the degree of intes-tinal in�ammation in di�erent pathological bowel diseases. It is consistent with previous data that showed that in irritable bowel


348 Sao Paulo Med J. 2015; 133(4):343-9

syndrome, in�ammation may be present to a lower degree.32 We showed that postinfectious irritable bowel syndrome more frequently presented positive fecal calprotectin than did non-postinfectious irritable bowel syndrome, i.e. in cases of postin-fectious irritable bowel syndrome, intestinal in�ammation may be more frequently encountered than in cases of non-postinfec-tious irritable bowel syndrome.

Our study has several limitations. Since there are no other data in the literature regarding use of this rapid test among patients with irritable bowel syndrome, we used a convenience sample. For objectivity, we determined the post-hoc power of the test, which was quite low, even if the di�erences observed between the postinfectious and non-postinfectious irritable bowel syndrome groups were statistically signi�cant. We are aware that it would have been ideal to have had higher power and, implicitly, a larger sample size. �is pilot study shows that in order to obtain a power greater than 0.8, larger sample popu-lations of irritable bowel syndrome patients are needed. In addi-tion, we did not compare the results from the rapid fecal calpro-tectin test with a more precise determination of fecal calprotectin, such as an ELISA quantitative test. However, patients with irrita-ble bowel syndrome had fecal calprotectin < 15 mcg/g, similar to data reported in the literature. One advantage of the test that we used was that the cuto� values could di�erentiate between low levels of fecal calprotectin. Our results con�rmed previously reported data regarding fecal calprotectin in in�ammatory bowel disease, and showed that this rapid and inexpensive test can be used even among these patients.

�e semiquantitative test for fecal calprotectin is useful and a�ordable within general practice and therefore it can be used to di�erentiate functional from organic diseases. Among irri-table bowel syndrome patients, calprotectin is more frequently present in cases of postinfectious irritable bowel syndrome than in cases of non-postinfectious irritable bowel syndrome. Future directions evolving from this study will involve using rapid qualitative tests to investigate the di�erences in fecal calprotec-tin levels between postinfectious irritable bowel syndrome and non-postinfectious irritable bowel syndrome. Whether identify-ing patients with irritable bowel syndrome with mild in�amma-tion would change their management remains to be determined.

CONCLUSIONSA simple, rapid and inexpensive test such as the semiquantitative fecal calprotectin assay is able to di�erentiate non-postinfectious irritable bowel syndrome, with absence or low levels of in�am-mation, from postinfectious irritable bowel syndrome patients, whose calprotectin levels are higher. �e test can also be used for identifying patients with severe intestinal in�ammation, such as patients with in�ammatory bowel diseases.

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24. Chaudhary NA, Truelove SC. The irritable colon syndrome. A study of

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27. von Roon AC, Karamountzos L, Purkayastha S, et al. Diagnostic

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29. Meling TR, Aabakken L, Røseth A, Osnes M. Faecal calprotectin

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Last received: May 20, 2014



Teodora Surdea-Blaga

Dan Lucian Dumitrascu

Clinica Medicala 2,

Str. Clinicilor 2-4, 400 003 Cluj-Napoca, Romania

Phone 40 264 593355


350 Sao Paulo Med J. 2015; 133(4):350-7


Development of psychiatric risk evaluation checklist and routine for nurses in a general hospital: ethnographic qualitative study Desenvolvimento de check-list e rotina de avaliação de risco psiquiátrico para enfermeiras num hospital geral: pesquisa qualitativa etnográ�caAna Luiza Lourenço Simões CamargoI, Alfredo Maluf NetoII, Fátima Tahira ColmanIII, Vanessa de Albuquerque CiteroIV

Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: There is high prevalence of mental and behavioral disorders in general hos-pitals, thus triggering psychiatric risk situations. This study aimed to develop a psychiatric risk assessment checklist and routine for nurses, the Psychiatric Risk Evaluation Check-List (PRE-CL), as an alternative model for early identi�cation and management of these situations in general hospitals. DESIGN AND SETTING: Ethnographic qualitative study in a tertiary-level private hospital. METHOD: Three hundred general-unit nurses participated in the study. Reports were gathered through open groups conducted by a trained nurse, at shift changes for two months. The questions used were: “Would you consider it helpful to discuss daily practice situations with a psychiatrist? Which situations?” The data were qualitatively analyzed through an ethnographic approach. RESULTS: The nurses considered it useful to discuss daily practice situations relating to mental and be-havioral disorders with a psychiatrist. Their reports were used to develop PRE-CL, within the patient overall risk assessment routine for all inpatients within 24 hours after admission and every 48 hours thereafter. Whenever one item was present, the psychosomatic medicine team was noti�ed. They went to the unit, gathered data from the nurses, patient �les and, if necessary, attending doctors, and decided on the risk management: guidance, safety measures or mental health consultation. CONCLUSION: It is possible to develop a model for detecting and intervening in psychiatric and behav-ioral disorders at general hospitals based on nursing team observations, through a checklist that takes these observations into account and a routine inserted into daily practice.

RESUMOCONTEXTO E OBJETIVO: Existe alta prevalência de transtornos mentais e comportamentais em hospitais gerais, propiciando situações de risco psiquiátrico. Este estudo objetivou desenvolver uma rotina e um check-list para enfermeiras, a Avaliação de Risco Psiquiátrico (ARP-CL), como modelo alternativo de identi-�cação e manejo precoce destas situações no hospital geral. TIPO DE ESTUDO E LOCAL: Pesquisa qualitativa etnográ�ca, em hospital particular terciário.MÉTODO: Trezentas enfermeiras de unidades gerais participaram do estudo. Os relatos foram coletados em grupos abertos, conduzidos por enfermeira treinada, durante passagens de plantão, por dois meses, através das questões: “Você consideraria útil discutir com um psiquiatra situações da sua prática diária? Quais situações?” Os dados foram analisados qualitativamente através do método etnográ�co. RESULTADOS: Enfermeiras consideraram útil poder discutir rotineiramente com um psiquiatra situações relacionadas a transtornos mentais e de comportamento da sua prática diária. Seus relatos foram utili-zados no desenvolvimento da ARP-CL, na rotina da avaliação de risco global do paciente, para todos os internados nas primeiras 24 horas e posteriormente a cada 48 horas. Quando um item era presente, a equipe de medicina psicossomática era noti�cada, indo à ala e coletando dados com a enfermagem, no prontuário do paciente, ou com o médico assistente, se necessário, decidindo conduta no risco: orienta-ção, medidas de segurança ou consulta em saúde mental. CONCLUSÃO: É possível desenvolver um modelo de detecção e intervenção precoces para transtornos psiquiátricos e de comportamento num hospital geral baseado na observação de enfermeiras, através de check-list que leve em conta essas observações e de uma rotina inserida na prática diária.

IMD, MSc. Doctoral Student, Department of Psychiatry, Escola Paulista de Medicina — Universidade Federal de São Paulo (EPM-Unifesp), and Medical Coordinator of the Department of Psychosomatic Medicine and Psychiatry, Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil.IIMD. Psychiatrist, Department of Psychosomatic Medicine and Psychiatry, Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil.IIIRN. Manager, Inpatient Department, Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil. IVMD, PhD. A�liated Professor, Department of Psychiatry, Escola Paulista de Medicina — Universidade Federal de Sao Paulo (EPM-Unifesp), São Paulo, Brazil.

KEY WORDS:Psychosomatic medicine. Nurses. Psychiatry. Hospitals, general. Risk assessment.

PALAVRAS-CHAVE:Medicina psicossomática. Enfermeiras. Psiquiatria. Hospitais gerais. Medição de risco.

Development of psychiatric risk evaluation checklist and routine for nurses in a general hospital: ethnographic qualitative study | ORIGINAL ARTICLE

Sao Paulo Med J. 2015; 133(4):350-7 351

INTRODUCTION�ere is high prevalence of mental and behavioral disorders in general hospitals.1-4 Psychiatric consultation-liaison services pro-vide the classic model for detection, management and care in these settings,5 potentially enhancing the quality of care, safety measures and teaching opportunities concerning mental health.5,6 Nevertheless, they require economic investments that are not always attractive, given that there is no proof that they contribute towards hospitals’ �nancial earnings.7

In Brazil, there are few structured consultation-liaison ser-vices in private, non-governmental general hospitals. �is reality implies that, in these settings, patients in need of psychiatric care depend on their private doctors to identify emotional distress and trigger psychiatric consultations, which are usually conducted by private-practice psychiatrists and depend either on the patient’s own means or on their health insurance coverage. Furthermore, such services sometimes do not provide enough information for healthcare teams regarding how to manage behavioral and/or emotional situations that occur among patients in general wards.

Surprisingly, even in the presence of structured consulta-tion-liaison services, only 1% to 13% of patients admitted to general hospitals are referred to specialists.1,4 �is small num-ber of referrals may be associated with low rates of detection of psychiatric disorders by physicians and nurses,8 either due to lack of knowledge or due to di�culty in di�erentiating these symptoms from those of clinical and surgical diseases.3,9 Patients with behavioral disorders who are not referred to spe-cialists are o�en subject to insu�cient attention and care, in addition to inadequate psychiatric treatment,1,10 thereby leading to psychiatric risk situations.

�e epidemiological concept of “risk” implies that events with unfavorable outcomes may occur.11 �ere are clinical, social and economic risks involved in psychiatric events,12 such as psy-chological distress and psychiatric disorders relating to worse prognosis for clinical diseases;4,13-17 behavioral changes with an impact on clinical treatment during hospital stay;2 low detection, by the healthcare team, of mental disorders and self-harming behavior or suicidal ideation;1,18,19 non-accurate psychiatric diag-noses;1,20 inappropriate treatment or undertreatment of mental disorders;21,22 and admission of patients with psychiatric disor-ders to clinical-surgical units without proper support.23

OBJECTIVEUsing the concept of risk as a possible screener for psychiatric and behavioral disorders or mental distress, the present study aimed to describe the development of a psychiatric risk assess-ment tool, the Psychiatric Risk Evaluation Checklist (PRE-CL), and a model for a psychiatric risk assessment routine, in order to provide a di�erent model for early identi�cation and appropriate

management of psychiatric risk in general hospitals, taking into account institutional safety and quality-of-care goals.

METHODS�e PRE-CL was developed in an ethnographic study that was conducted in 2004. �e setting was a 512-bed private general-care non-pro�t hospital, located in São Paulo, Brazil, with medi-cal care delivered not only by the hospital’s medical sta� (emer-gency department, intensive care and step-down unit and coronary, obstetrics, nursery, dialysis and rehabilitation units), but also by private-practice doctors who admit their patients to the hospital and decide on their treatment. At that time, the hos-pital did not have a speci�c unit for mental disorders, and it was an institutional policy not to admit patients in need of exclusively psychiatric treatment.

However, the hospital’s medical practice division became highly concerned about events relating to patients who had been admitted for clinical-surgical treatment and who pre-sented either psychiatric or severe behavioral disorders during their stay: patients leaving hospital without medical consent; attempting to use narcotic substances in the hospital’s facilities; presenting suicidal thoughts without psychiatric evaluation; or exhibiting disruptive behavior inside the hospital. Moreover, there were frequent occurrences of inappropriate medical pre-scriptions of narcotics and admissions of patients with exogenous intoxications into the clinical-surgical units without psychiatric monitoring.

�ese high-risk events, whenever they happened and no matter how frequent they were, compromised quality of care and patient safety (as well as family, visitor and sta� safety), and required mobilization of a great quantity of resources from the institution as a whole. With the aim of developing a care model that would allow the healthcare sta� to promptly identify risk situations relating to inpatients’ psychiatric or severe behavioral disorders, thereby providing early and adequate interventions, Hospital Israelita Albert Einstein (HIAE) created a Department of Psychosomatic Medicine composed of two doctors: a con-sultation-liaison psychiatrist and an addiction specialist. It was decided that the new system should work using the risk concept applied to psychiatric issues and should be included in the nurse’s overall risk assessment,18 which is a tool used by the nursing team to evaluate di�erent types of risk during hospitalization (nutri-tional risk, social risk, need for physiotherapeutic care, psycho-logical risk, risk of falls, need for occupational therapeutic care, phlebitis and pain).

Registered nurses are healthcare professionals who are pres-ent in all clinical and surgical units 24 hours a day. Hence, they have an important role in potentially identifying risk situations that should be reassessed continuously. On the other hand, such

ORIGINAL ARTICLE | Camargo ALLS, Maluf Neto A, Colman FT, Citero VA

352 Sao Paulo Med J. 2015; 133(4):350-7

�ndings should be systematically discussed with the psychiatric team. Since it had been decided that nurses would be the ones to use the risk identi�cation tool, it became essential that this tool should be user-friendly and coherent with nurses’ beliefs about psychiatric risks, dissonant behavior and the help that discussion of cases with a psychiatrist would provide in their daily routine, so that they would be able to adhere to the future routine.

For situations to be identi�ed as presenting risks, they have to be regarded as such by the individuals involved in their recogni-tion.24 �erefore, a qualitative ethnographic survey of the hospi-tal’s nursing population was carried out, a�er obtaining approval from the hospital’s Ethics Committee.

�e methodology chosen allowed the researchers to learn about the impressions of this population based on its speci�c cul-tural context24-26 and, later on, to prepare the checklist. �is sur-vey aimed to understand the following questions: • Did the hospital’s nurses think that it would be useful to have

a psychiatrist in their units? • In which situations did nurses �nd a psychiatrist useful? • Did these situations agree with the proposal for psychiatric

inter-consulting and support in the general hospital?

It would also be important to observe the terminology used by the nursing sta� in describing these situations, with the aim of designing an assessment tool for the psychiatric risks to be reported by this nursing population.

�e participants in the survey included the 300 registered nurses who were on duty in clinical units (cardiology, gastroen-terology, neurology, pneumology and internal medicine), as well as in surgery, geriatrics, pediatrics, oncology, the maternity ward, intensive care units, step-down units, gynecology and obstet-rics and the day clinic. Over a two-month period (April and May 2004), reports were gathered through open groups, conducted by a trained nurse at shi� changes (three times per 24 hours: morn-ing, a�ernoon and night), with participation of three to four reg-istered nurses per group and with two groups in each unit. �ese were repeated at least twice in all inpatient units, in each shi�.

�e nurses were invited to brie�y interrupt their shi� change discussions and talk to the trained nurse, and no refusals to par-ticipate were observed. �e reports were manually recorded so that situations in which the participants might feel intimidated by a tape recorder could be avoided. To initially approach the group, two questions were asked: 1. “Would you consider it help-ful to be able to discuss daily practice situations with a psychia-trist?” 2. “In which situations?”

�e knowledge that there was a sense of need for a psychiatric approach to situations that were present in the nurses’ daily practice was very important, since we believed that their adherence to the protocol would only be possible if it had a correspondence to their

needs. Nevertheless, it would be important for the reported situa-tions to be congruent with the scope of the patients’ intervention checklist and not to represent other interests, such as personal needs.

�e reports were qualitatively analyzed using an ethno-graphic approach, with recurrent themes grouped into cate-gories that represented the cultural point of view of the study population.25

RESULTS“...what is simple becomes a problem ...” (report from a nurse).

We observed that the nurses’ reports acknowledged the use-fulness of having discussions with a psychiatrist about situations relating to mental and behavioral disorders that they identi�ed in their clinical practice, as shown below:- Psychiatric diagnosis — histories of mental disorders without

specialized monitoring during hospital stay, strange behav-iors without diagnosis, symptoms observed during stay and admission of psychiatric cases uncovered by alleged medical conditions.

- Psychiatric treatment — absence of treatment for patients with behavioral changes and multi-medication without diag-nosis or opinion from specialist.

- Behavioral changes a�ecting medical treatment — apathy, aggressiveness and fear.

- Risks to the sta� and patient — agitation and aggressiveness involving both self-harm and aggressive behavior towards other people.

�eir reports re�ected situations that have consistently been related to demands for psychiatric monitoring, both in the scien-ti�c literature and in our hospital’s psychiatric consultation-liai-son experience. Nevertheless, although the reports showed that the nursing sta� perceived altered mental and behavioral func-tioning in patients, the terms that they used to describe what they saw (“depressed,” “confused”, etc.) were not attempts to make a psychiatric diagnosis but, rather, attempts to name a behavioral alteration that they had identi�ed. Table 1 shows the nurses’ reports, the categories developed based on these reports and the risk items developed according to the categories.

�rough these observations, it was understood that the tool should take into account these professionals’ perceptions of the situations present in their daily practice and their own way of expressing the mental and behavioral phenomena that they observed, together with general hospital needs relating to mental health, as supported by the scienti�c literature on consultation-liaison. For instance, suicidal behavior is a recognized risk in general hospitals, and it was represented in our tool by the expression “self-harm”, since this was more representative of nurses’ way of describing this behavior. Some of the items,


Sao Paulo Med J. 2015; 133(4):350-7 353

Table 1. Examples of nurses’ reports, categories developed based on these reports and risk items developed according to the categories Reports Categories Risk items developed

Psyc

hiat

ric

diag

nose

s

“substance dependency... withdrawal syndrome... exogenous intoxication.”

History of mental disorder with no specialized follow-up during admission

- History of alcohol and/or drug abuse- History of exogenous intoxication and/or self-harming

behavior - Presence of psychiatric diagnosis and/or psychiatric

medication

“... apathetic, depressed behavior...” Symptoms present upon admission - Abrupt and/or marked alteration or change in behavior posing risk to the patient and/or healthcare team

- Hypoactivity, withdrawal or sadness interfering in treatment or posing risk to patient

“... admission under other diagnosis” Admission of psychiatric cases under clinical diagnosis

- Follow-up by a psychiatrist

Psyc

hiat

ric

trea

tmen

t

“patient with history (and behavior) of panic disorder reporting that it has been treated and he is ok...”

Absence of treatment of patients with behavior alterations

- Presence of psychiatric diagnosis and/or psychiatric medication

“patient uses medications (psychotropic agents) in large amounts with no follow-up”

Polypharmacy with no diagnosis or report by the specialist

- Abrupt discontinuation of psychotropic medication

“... sudden change in behavior...” Behavior alterations with or without re�ection in the clinical treatment

- Abrupt and/or marked alteration or change in behavior posing risk to the patient and/or healthcare team

“...apathetic behavior...” Apathy - Hypoactivity, withdrawal or sadness interfering in treatment or posing risk to patient

“high anxiety of patient and relatives” Anxiety and agitation - Anxiety, agitation or aggressiveness with risk to patient and/or healthcare team

“...just been transplanted, intense fear...” Fear - Abrupt and/or marked alteration or change in behavior posing risk to the patient and/or healthcare team

Risk

to h

ealth

care

te

am a

nd p

atie

nt “...patient out of control, agitated, screaming...” “...patient’s persecution belief...”“verbal aggressiveness, hostility”

Agitation and aggressiveness - Anxiety, agitation or aggressiveness with risk to patient and/or healthcare team

- Abrupt and/or marked alteration or change in behavior posing risk to the patient and/or healthcare team

“suicide attempt” Suicidal behavior or ideation - History of exogenous intoxication and/or self-harming behavior

especially those representing behavioral conditions, received the description “posing risk to patient and/or health team”, in an attempt to give nurses a subjective clue about which patients they could deal with and which patients presented behavioral problems of a magnitude that at least showed a need for discussion with the consultation-liaison psychiatrist.

�e psychiatric risk instrument that was developed is dis-played in Chart 1. �e �rst three items (1 to 3) correspond to behavioral change risks identi�ed on a daily basis by the nurs-ing sta�, according to the results from the survey. Items 5 to 9 correspond to active observation of medical situations that have been described in the literature relating to psychiatric risk and disruptive behavior in general hospitals. Items 5, 10 and 11 were included later on, in order to encompass tobacco users (who had not been recognized by the nurses as having histories of drug use and therefore were not included in item 6), family behavioral risk situations and noti�cation of risk whenever they subjectively felt that something was wrong but could not include their impres-sions in any other item.

A psychiatric risk evaluation routine was developed before o�cially including the PRE-CL as a part of the patient overall risk assessment, through a pilot study that was conducted in the neurology unit for two months in 2005. �e aim of this was to evaluate the ease of use of the routine and the nursing team’s compliance with it. �is procedure showed that the routine did not require any modi�cations.

In July 2005, all the hospital’s nurses were trained through 15-minute explanations with audiovisual material, during shi� changes, in all units of the hospital. Simultaneously, the medical sta� was informed about the new routine by means of discussion forums and specialty meetings. In August 2005, the PRE-CL was de�nitively included in the patient overall risk assessment rou-tine, therefore implying that nurses would apply the tool to every inpatient within the �rst 24 hours a�er admission and would repeat the application every 48 hours during the hospital stay, or at any time when a risk situation might occur.

When at least one risk item was identi�ed as present, the psychiatric risk was noti�ed to the team of the Department of


354 Sao Paulo Med J. 2015; 133(4):350-7

Psychosomatic Medicine and Psychiatry through e-mail, and this team would make a risk assessment within 24 hours. If the nurses felt that a situation might evolve to an event within a short period of time, they could also call the specialist team at any time to dis-cuss the case and start the risk management. Once a risk had been noti�ed, the psychiatrist went to the unit and gathered data from the nursing team about the patient and the risk situation observed, analyzed the patient record (documents, initial assessment of the patient, admission, nursing progression notes, medical progres-sion notes and medical prescription) and, if necessary, the attend-ing medical team was contacted for further information. �e risk assessment did not add any extra costs for the payers, since it did not include a clinical evaluation of the patient.

Based on this analysis, the psychiatrist decided on the risk man-agement, gave guidance to the nurses and, if required, the medi-cal team as well, and this procedure was recorded in the patient’s �les. �e psychiatrist’s evaluation of the risk situation was �led in a database. If the evaluating psychiatrist considered a psychiatric consultation with the patient to be necessary, this suggestion would be made to the attending physician, who would be in charge of addressing the patient or the family, in order to make a referral to a psychiatrist. Once the risk had been identi�ed and con�rmed by the psychiatric team, they would monitor the situation until the risk situation ceased to exist or the patient was discharged from hospital. �e psychiatrist’s risk evaluation interventions, grouped in catego-ries and examples, are shown in Table 2.

DISCUSSIONPatients with behavioral and/or psychiatric disorders are expected to be a part of the daily routine in clinical-surgical wards. In order to deliver proper psychiatric care in general private hospitals, streamlined models of consultation-liaison services should be implemented.27 Nevertheless, there are problems to be considered. Psychiatric consultations usually depend on the health team’s recognition that something is going wrong and that it should at least be discussed with a specialist. Unfortunately, the cases referred for consultation are not always those in need, and patients that would require specialized care are o�en not identi�ed.28

�e liaison model of intervention has the potential to deal with the mental health denominator, although requiring a large number of professionals present in the wards and participating in health team discussions, and thus resulting in quite an expensive and almost prohibitive way of delivering psychiatric care.2 Hence, having a tool that potentially triggers discussions with the spe-cialist and an institutional work �ow that detects, evaluates and manages situations that are considered to present psychiatric risk may represent a way of preserving mental health, quality of care, teaching and safety in clinical-surgical wards, with a small num-ber of specialists and therefore at lower cost.

�e existence of a psychiatric risk evaluation routine inserted into nurses’ daily activities may lead to discussions and interventions even in cases that would not normally be referred for psychiatric consultation. �rough this routine, the health-care team can be supported by the specialist, and their obser-vations about behavioral phenomena can be taken in account. When something feels wrong, despite knowing exactly what is happening, nurses can still use the routine to trigger a risk evaluation, so that they are able to discuss situations in which otherwise fear of the appearance of impropriety could have inhibited further discussion or intervention. In this sense, it is possible that the risk evaluation routine can contribute towards changing the healthcare team’s attitudes and paradigms relating to mental diseases, thus providing a positive and illuminating experience through information and support.5,29

Interestingly, emergency situations are sometimes brought by phone to the psychosomatic medicine team even before the risk is noti�ed. �is is a pattern that we observe frequently in the liaison model, with the feeling that the psychiatrist is part of the health team and will be there to help when needed. �e fact that it is nurses’ daily obligation to assess psychiatric risk among other clinical risks, may bring some seriousness into this matter: potentially, mental health becomes a subject to be taken in account when it comes to quality of care and patients’ secu-rity, just like any other clinical condition. Moreover, perhaps through providing systemization of what to pay attention to, the

Chart 1. Psychiatric risk evaluation checklist1. Anxiety, agitation or aggressiveness posing risk to patient and/or

healthcare team Yes ( ) No ( )2. Abrupt and/or marked alteration or change in behavior posing risk to the

patient and/or healthcare team Yes ( ) No ( )3. Hypoactivity, withdrawal or sadness interfering in treatment or posing risk

to patient Yes ( ) No ( )4. Abrupt discontinuation of psychotropic medication Yes ( ) No ( )5. Tobacco user Yes ( ) No ( )6. History of alcohol and/or drug abuse Yes ( ) No ( )7. History of exogenous intoxication and/or self-harming behavior Yes ( ) No ( )8. Follow-up by a psychiatrist Yes ( ) No ( )9. Presence of psychiatric diagnosis and/or psychiatric medication Yes ( ) No ( )10. Nurse very concerned about patient behavior Yes ( ) No ( )11. Nurse very concerned about patient’s family’s behavior Yes ( ) No ( )


Sao Paulo Med J. 2015; 133(4):350-7 355

PRE-CL can enhance the idea that mental issues do exist and need to be addressed. Nurses are usually the healthcare team members that are always near the patients, and they centralize the clinical information and care routines.

�rough this study, we observed that nurses seem to be aware of behavioral risk situations. It is possible that having a psychiatric risk evaluation routine that is not only part of their daily obligations but also supported by the hospital board can reinforce their belief in what they see and enhance their adher-ence to this routine.

It is also possible that none of this would happen if the PRE-CL was not user-friendly or meaningful to the nursing sta�.24 �at is why we considered it important to proceed with an ethnographic study in order to provide information about how nurses saw mental health features.

It is a peculiarity of our hospital that consulting psychia-trists are o�en private-practice doctors, who are not always familiar with hospital routines and security actions and not used to providing the nursing team with proper information on the patient’s mental health care needs in clinical-surgical wards. Also, sometimes, even if the patient is being followed up at home or within primary care by a psychiatrist, he/she o�en does not agree to attend this patient during the hospital stay for clinical or surgical reasons.

�erefore, clinicians and surgeons o�en take charge of treating their patients’ comorbid psychiatric disorders. In this regard, the evaluation routine allows discussion and support for situations that can be dealt with by general doctors with the aid of the specialist, or triggers mental health consultations in

extreme cases. Further studies are necessary in order to assess whether there are any risk situations that are not detected by the nursing team and whether lack of detection, if pres-ent, re�ects a failure in our tool. One important factor is that the tool can always be renewed, so as to take into account the population that �lls out the data form and the peculiarities of the hospital population, in addition to structural changes in the institution. �rough the PRE-CL, we also have the possi-bility of becoming acquainted with what the institution’s needs are and how they might change through time. One example of this is that we observed that some risks started to be noti�ed based on the behavior of family members. �is showed that there was a need to work with this population, and we were subsequently able to include a speci�c item in the PRE-CL to address behavioral features observed in family members. �is was not surprising, because the presence of relatives during hospital admissions is a strong feature in Brazil,30 but it shows how cultural di�erences should be taken into consideration when building such a tool and routine.

Once again, the information provided by the protocol itself showed the way in which it should be dynamically and con-stantly adjusted to the institutional needs. One interesting fact to bear in mind is that one of the PRE-CL items focuses on sui-cidal behavior, which is a major risk that should be addressed systematically among inpatients in general hospitals, since sui-cide in hospital settings and a�er discharge are major issues in mental health and safety.1,18,19

It is possible that development of a care model for psychosomatic medicine, based precisely on the concept of risk, which is

Table 2. Categories and examples of risk evaluation interventionsCategories of interventions Examples of interventions

Triggering of safety measures during hospital stay

Keep patient accompanied by family or caregiver during hospitalization period Guidance about preparing the room for patients at risk, for instance keeping windows lockedGuidance about how the patient should be taken care of when leaving the room for recreational activities, examinations or rehabilitationAsk nursing team to remove medications or psychoactive substances from the room

Suicide preventionTriggering of mental health care during hospitalizationTriggering of mental health follow-up after dischargeTriggering of safety measures at admission for patients at risk

Prevention relating to medications

Abstinence and prevention of relapses by encouraging nursing team to ask about psychiatric diagnoses and medications during admission Prevention of self-medicationOptimization of psychiatric medications through discussion and guidance for nursing team and medical sta�

Triggering of mental health specialized care Mental health care during hospitalizationMental health care upon dischargeTransfer to a psychiatric clinic

Case management and care guidance (behavioral and/or pharmacological)

By the nurseBy the attending physicianOf institutional nature

Presumptive diagnosis Suggestion of presumptive diagnosis


356 Sao Paulo Med J. 2015; 133(4):350-7

usually a major concern in private general hospitals, may call for a deeper look at mental health demands, thereby fostering long-needed actions, such as: • Development of further research on new models for care

relating to general hospital psychiatry.• Development of institutional routines to deal with behavioral

and psychiatric disorders in clinical-surgical inpatient units. • Provision of proper information on mental health disorders

for healthcare teams. • Training for healthcare teams with regard to early detection

and management of behavioral disorders. • Changes to mental health paradigms in general hospitals.

Concerning further research on PRE-CL and its routines, validation and reliability are important issues that need to be addressed. Studies are already being developed in order to iden-tify at-risk populations and understand how nurses identify the severity of the risks, and how risk interventions may interfere with care during the hospital stay.

Clinical implications We observed that the psychiatric risk evaluation routine led to several changes to the paradigms regarding psychiatric care for clinical and surgical patients at our service. De Albuquerque Citero et al.30 suggested that this could be a parameter for the importance of psychiatric actions at general hospitals. For exam-ple: in the beginning, it was observed that physicians did not want to have a specialist discussing their patients with the nurs-ing team, or even reading the patients’ �les. Implementation of the psychiatric risk assessment gradually changed this approach and, today, physicians themselves o�en ask the nursing sta� to evaluate and notify the psychiatric risk in order to receive guid-ance on how to manage the case. �e routine has also provided the Department of Psychosomatic Medicine with the opportu-nity to map out the pro�le of the institution’s patients according to mental health issues and therefore to propose more appropri-ate interventions with optimization of economic resources, on the basis of documented facts. By acknowledging the needs relating to quality and safety, it was possible to discuss them at the insti-tutional level and develop care protocols for agitated and aggres-sive patients and safety routines for admissions, as well as an inpa-tient unit based on the concept of psychosomatic medicine. In this unit, the clinical nursing sta�, which has been trained on management of behavioral disorders through the psychiatric risk evaluation routine, gives support to clinical and surgical patients with behavioral disorders who demand specialized care, as well as to patients with psychiatric disorders who are voluntarily hos-pitalized. A�er a request from the nursing sta�, the use of the PRE-CL was expanded to the chemotherapy, radiotherapy and

rehabilitation outpatient clinics. We were able to apply the rou-tine in these settings with very few changes, which, once again, showed us the versatility of this care model.

CONCLUSIONIt is possible to develop a model for detecting and intervening in psychiatric and behavioral disorders at general hospitals based on observations made by the nursing team, by means of a check-list that takes into account the way in which these professionals describe and/or report these behaviors, and by means of a rou-tine inserted into their daily practice. �is instrument probably made it easier for the nurses to organize what they saw and to call the specialist without having to justify this option with a clini-cal diagnosis.

It is important that the instrument and the protocol should be �exible in relation to the changes in paradigms and contexts that occur at general hospitals over time, taking into consider-ation the healthcare team’s daily experiences and impressions about their practice.

REFERENCES1. Lipowski ZJ. Current trends in consultation-liaison psychiatry. Can J

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2. Smaira SI, Kerr-Correa F, Contel JO. Psychiatric disorders and

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[Transtornos psiquiátricos e solicitações de interconsulta psiquiátrica

em hospital geral: um estudo de caso controle]. Rev Bras Psiquiatr.

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3. Steinberg H, Torem M, Saravay SM. An analysis of physician resistance

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and demographic pro�le of cancer patients in a consultation-liaison

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5. Kornfeld DS. Consultation-liaison psychiatry: contributions to

medical practice. Am J Psychiatry. 2002;159(12):1964-72.

6. Shaw RJ, Wamboldt M, Bursch B, Stuber M. Practice patterns

in pediatric consultation-liaison psychiatry: a national survey.

Psychosomatics. 2006;47(1):43-9.

7. Andreoli PBA, Citero Vde A, Mari Jde J. A systematic review of

studies of the cost-effectiveness of mental health consultation-

liaison interventions of general hospitals. Psychosomatics.

2003;44(6):499-507.

8. Martucci M, Balestrieri M, Biso� G, et al. Evaluating psychiatric

morbidity in a general hospital: a two-phase epidemiological survey.

Psychol Med. 1999;29(4):823-32.

9. Verhaak PF, Schellevis FG, Nuijen J, Volkers AC. Patients with a

psychiatric disorder in general practice: determinants of general

practitioners’ psychological diagnosis. Gen Hosp Psychiatry.

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10. van Zyl LT, Davidson PR. Delirium in hospital: an underreported event

at discharge. Can J Psychiatry. 2003;48(8):555-60.

11. Last JM. A dictionary of epidemiology. New York: Oxford University

Press; 1983.

12. Levinson CM, Druss BG. Health beliefs and depression in a group

of elderly high utilizers of medical services. Gen Hosp Psychiatry.

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13. Frasure-Smith N, Lespérance F, Talajic M. Depression following

myocardial infarction. Impact of 6-month survival. JAMA.

1993;270(15):1819-25.

14. Furlanetto LM, von Ammon Cavanaugh S, Bueno JR, Creech SD,

Powell LH. Association between depressive symptoms and mortality

in medical inpatients. Psychosomatics. 2000;41(5):426-32.

15. Lustman PJ, Clouse RE. Depression in diabetic patients: the

relationship between mood and glycemic control. J Diabetes

Complications. 2005;19(2):113-22.

16. Prieto JM, Atala J, Blanch J, et al. Role of depression as a predictor

of mortality among cancer patients after stem-cell transplantation. J

Clin Oncol. 2005;23(25):6063-71.

17. Rivard AL, Hellmich C, Sampson B, et al. Preoperative predictors for

postoperative problems in heart transplantation: psychiatric and

psychosocial considerations. Prog Transplant. 2005;15(3):276-82.

18. Joint Commission on Accreditation of Healthcare Organizations. Joint

Commission International Accreditation Standards for Hospitals.

Illinois: Joint Commission Resources; 2002.

19. Royal Australian and New Zealand College of Psychiatrists Clinical

Practice guidelines Team for Deliberate Self-harm. Australian and New

Zealand clinical practice guidelines on the management of adult

deliberate self-harm. Aust N Z J Psychiatry. 2004;38(11-12):868-84.

20. Yan ZY, Gu MJ, Zhong BL, et al. Prevalence, risk factors and recognition

rates of depressive disorders among inpatients of tertiary general

hospitals in Shanghai, China. J Psychosom Res. 2013;75(1):65-71.

21. Cigognini MA, Furlanetto LM. Diagnóstico e tratamento dos

transtornos depressivos em hospital geral [Diagnosis and

pharmacological treatment of depressive disorders in a general

hospital]. Rev Bras Psiquiatr. 2006;28(2):97-103.

22. Kessler RC, Demler O, Frank RG, et al. Prevalence and treatment of

mental disorders, 1990 to 2003. N Engl J Med. 2005;352(24):2515-23.

23. Hickling FW, Abel W, Garner P, Rathbone J. Open general medical

wards versus specialist psychiatric units for acute psychoses.

Cochrane Database Syst Rev. 2007;17(4):CD003290.

24. Douglas M. Risk and blame: essays in cultural theory. London:

Routledge; 1992.

25. Patton MQ. Enhancing the quality and credibility of qualitative

analysis. In: Pattin MQ. Qualitative evaluation and research methods.

2nd ed. California: Sage Publications; 1990.

26. Camargo ALLS. A experiência de ter câncer de mama: do diagnóstico

à reorganização da vida após a mastectomia [thesis]. São Paulo: Escola

Paulista de Medicina da Universidade Federal de São Paulo; 2002.

27. Goldberg RJ. Financial management challenges for general hospital

psychiatry 2001. Gen Hosp Psychiatry. 2001;23(2):67-72.

28. Vaz FJ, Salcedo MS. A model for evaluating the impact of consultation-

liaison psychiatry activities on referral patterns. Psychosomatics.

1996;37(3):289-98.

29. Horner D, Asher K. General practitioners and mental health sta� sharing

patient care: working model. Australas Psychiatry. 2005;13(2):176-80.

30. de Albuquerque Citero V, de Araújo Andreoli PB, Nogueira-Martins

LA, Andreoli SB. New potential clinical indicators of consultation-

liaison psychiatry’s e�ectiveness in Brazilian general hospitals.

Psychosomatics. 2008;49(1):29-38.

Acknowledgements: To Miguel Cendoroglo Neto, Medical Director and

Superintendent at Hospital Israelita Albert Einstein (HIAE), São Paulo,

Brazil; to all HIAE nurses, in particular the Neurology nursing team; and

to Kelly Aparecida de Souza Pereira



Date of �rst submission: December 15, 2013

Last received: June 27, 2014

Accepted: July 11, 2014


Ana Luiza Lourenço Simões Camargo

Rua Barão de Santa Eulália, 170 — apto 21

Real Parque — São Paulo (SP) — Brasil

CEP 05685-090

Tel. (+55 11) 2151-9205

Cel. (+55 11) 99912-3714


358 Sao Paulo Med J. 2015; 133(4):358-366

SHORT COMMUNICATION DOI: 10.1590/1516-3180.2014.00180501

Cross-cultural adaptation of the Social and Emotional Questionnaire on Dementia for the Brazilian population Adaptação transcultural do Questionário Social e Emocional na Demência para a população brasileiraTatiana BelfortI, Jessica BramhamII, José Pedro Simões NetoIII, Maria Fernanda Barroso de SousaIV, Raquel Luiza dos SantosIV, Marcela Moreira Lima NogueiraI, Bianca TorresV, Rachel Dias Lopes da RosaV, Marcia Cristina Nascimento DouradoVI

Center for Alzheimer’s Disease and Related Disorders, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (CDA/IPUB/UFRJ), Rio de Janeiro, Brazil

ABSTRACTCONTEXT AND OBJECTIVE: Impairments in social and emotional functioning may affect the commu-nication skills and interpersonal relationships of people with dementia and their caregivers. This study had the aim of presenting the steps involved in the cross-cultural adaptation of the Social and Emotional Questionnaire (SEQ) for the Brazilian population.DESIGN AND SETTING: Cross-cultural adaptation study, conducted at the Center for Alzheimer’s Disease and Related Disorders in a public university. METHODS: The process adopted in this study required six consecutive steps: initial translation, translation syn-thesis, back translation, committee of judges, pretesting of final version and submission to the original author. RESULTS: In general, the items had semantic, idiomatic, conceptual and experiential equivalence. During the first pretest, people with dementia and their caregivers had difficulties in understanding some items relat-ing to social skills, which were interpreted ambiguously. New changes were made to allow better adjustment to the target population and, following this, a new pretest was performed. This pre-test showed that the changes were relevant and gave rise to the final version of the instrument. There was no correlation between education level and performance in the questionnaire, among people with dementia (P = 0.951).CONCLUSION: The Brazilian Portuguese version of the Social and Emotional Questionnaire was well under-stood and, despite the cultural and linguistic differences, the constructs of the original version were maintained.

RESUMOCONTEXTO E OBJETIVO: O comprometimento do funcionamento social e emocional pode afetar as ha-bilidades de comunicação e relações interpessoais das pessoas com demência e de seus cuidadores. Este estudo tem como objetivo apresentar as etapas envolvidas na adaptação transcultural do Questionário Social e Emocional (SEQ) para a população brasileira. TIPO DE ESTUDO E LOCAL: Estudo de adaptação transcultural, realizado no Centro de Doença de Alzhei-mer e Transtornos Relacionados de uma universidade pública. MÉTODOS: O processo adotado neste estudo exige seis etapas consecutivas: tradução inicial, síntese de tradução, “retrotradução”, comitê de julgadores, pré-teste da versão final e a submissão ao autor original. RESULTADOS: Em geral, os itens apresentaram equivalência semântica, idiomática, conceitual e viven-cial. Durante o primeiro pré-teste, pessoas com demência e seus cuidadores apresentaram dificuldades de compreensão de expressões nos itens referentes à sociabilidade, que foram interpretadas com duplo sentido. Novas alterações foram feitas para maior adequação à população-alvo, sendo em seguida reali-zado um novo pré-teste, que demonstrou a pertinência das adequações, originando então a versão final do instrumento. Não foi encontrada correlação entre o desempenho no questionário pelas pessoas com demência e a escolaridade (P = 0.951). CONCLUSÃO: A versão em português brasileiro do Social Emotional Questionnaire foi bem compreen-dida e, apesar das diferenças culturais e linguísticas, os constructos da versão original foram mantidos.

IBSc. Master’s Student, Center for Alzheimer’s Disease and Related Disorders, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.IIPhD. Senior Lecturer, Clinical Neuropsychology, School of Psychology, University College Dublin, Dublin, Ireland.IIIPhD. Professor, Department of Sociology and Political Science, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil.IVMSc. Doctoral Student, Center for Alzheimer’s Disease and Related Disorders, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.VBSc. Psychologist and Specialist in Aging Studies, Center for Alzheimer’s Disease and Related Disorders, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.VIPhD. Collaborating Professor, Center for Alzheimer’s Disease and Related Disorders, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.

KEY WORDS: Awareness. Cross-cultural comparison. Questionnaires. Dementia. Emotions.

PALAVRAS-CHAVE: Conscientização. Comparação transcultural. Questionários. Demência. Emoções.

Cross-cultural adaptation of the Social and Emotional Questionnaire in Dementia for the Brazilian population | SHORT COMMUNICATION

Sao Paulo Med J. 2015; 133(4):358-366 359

INTRODUCTIONAwareness of deficits has been defined as the capacity to rec-ognize changes caused by impairments relating to the disease process.1,2 It may be expressed at different levels, including the ability to monitor immediate performance, make evaluative judgments about functioning in a given domain and reflect on the nature and impact of a diagnosis or health condition.3 Unawareness of deficits has been commonly reported as a clini-cal feature of neurodegenerative disorders, but there are con-flicting results regarding the frequency and its relationship with disease severity.4,5 Impaired awareness of deficits may be pres-ent in the early stages, ranging from very mild to very severe.6

Awareness of social and emotional functioning relates to essential aspects of social interactions, such as the capac-ity to understand other people and oneself, and the capacity to comprehend interpersonal relationships.7 Under different patho-logical conditions, the level of impaired awareness of social and emotional functioning is related to the various degenerative pat-terns.8 In Alzheimer’s disease, there are common alterations, such as apathy, disinhibition and reduced mental flexibility. However, recognition of emotions may be preserved in Alzheimer’s disease, in comparison with vascular dementia.8,9 Under frontotemporal dementia, individuals might present behavior that is incompat-ible with rules and social norms, along with difficulty in under-standing emotions.10

Impairment of social and emotional functioning may damage communication skills and interpersonal relationships, thereby directly influencing the activities of daily living and the quality of life of people with dementia and their caregivers.11 The instru-ments for assessing dementia mainly focus on the cognitive and functional domains.12 There is a lack of availability of appropriate specific instruments for measuring social and emotional func-tioning.7 Therefore, a cross-cultural adaptation process needs to be undertaken in order to improve the knowledge about recogni-tion of social and emotional functioning among Brazilian people with dementia.13

The Social and Emotional Questionnaire (SEQ) was originally developed in English by Bramham et al.11 to evaluate social and emotional functioning. The questionnaire was used to assess behav-ioral reports relating to specific acquired social difficulties follow-ing prefrontal cortex damage in adults, and it particularly focused on recognition of emotion and empathic reactions. It has been val-idated for other populations such as older adults with dementia, young adolescents and people with anorexia nervosa.9,14,15

OBJECTIVEThis study had the aim of presenting the cross-cultural adapta-tion process of the Social and Emotional Questionnaire (SEQ) for people with dementia in the Brazilian population.

METHODSThe SEQ comprises 30 items distributed into five factors: emo-tion recognition, empathy, social conformity, antisocial behav-ior and sociability.11 The emotion recognition subscale includes items that assess the perceived ability to recognize basic emotions in others (happiness, anger, sadness, fear and disgust).11

The ratings are scored on a five-point Likert scale, from “strongly disagree” (1) to “strongly agree” (5). The “people with dementia” and “caregivers” versions are essentially identical.11,14 People with dementia rate their socioemotional functioning with regard to their ability to recognize emotions, the extent of their empathetic reactions and their behavior in social situa-tions. Caregivers also complete the SEQ, in relation to the current functioning of people with dementia.7 The score is based on the degree of discrepancy between results from people with demen-tia and from their caregivers.7,11

The first description of psychometric properties was made in relation to brain injury patients.11 The items that loaded most highly in each factor were used to form five subscales: emotion recognition (5, 8, 12, 18, 23); empathy (3, 9, 15, 20, 30); social conformity (11, 14, 25); antisocial behavior (1, 6, 13, 24); and sociability (4, 16, 17, 19, 21, 27, 29). The total score for the patient version of the SEQ had good correlation with the patients’ total score on the Patient Competency Rating Scale (PCRS) (P = 0.01) and the total score for the proxy version had strong correlation with the proxy-version total score of PCRS (P < 0.01). Based on these results, the SEQ was considered to be a valid instrument for assessing the recognition of social and emotional functioning among brain injury patients.11

Nelis et al.7 conducted the first validation study on the SEQ among people with dementia. Varimax rotation yielded three interpretable solutions: the 11-item emotional recognition and empathy (ERE) domain (3, 5, 8, 9, 11, 12, 15, 18, 20, 23, 30), the 7-item social relationship (SR) domain (16, 17, 19, 25, 26, 28, 29) and the 6-item prosocial behavior (PB) domain (2, 4, 6, 10, 13, 22). There were small but significant differences between self-ratings and caregivers’ ratings for all the domains: ERE: F(1, 96) = 17.98, P < 0.001; SR: F(1, 96) = 4.65, P < 0.03; and PB: F(1, 96) = 4.10, P < 0.04. According to these data, people with mild dementia have reduced awareness of social functioning, especially with regard to emotional recognition and empathy.7

Cross-cultural adaptationThe cross-cultural adaptation process was based on the pro-tocol proposed by Beaton et al.,16 after obtaining permission from the original author of the scale. The following consec-utive steps were implemented: initial translation, translation synthesis, back translation, committee of judges, pretesting of the final version and submission to the author of the original

SHORT COMMUNICATION | Belfort T, Bramham J, Simões Neto JP, Sousa MFB, Santos RL, Nogueira MML, Torres B, Rosa RDL, Dourado MCN

360 Sao Paulo Med J. 2015; 133(4):358-366

instrument.16 The study was approved by the Research Ethics Committee of the Institute of Psychiatry (IPUB) of the Universidade Federal do Rio de Janeiro (UFRJ). All the partic-ipants with dementia and their caregivers signed the informed consent statement.

Initial translationThe initial translation of the original English version of the instrument into Brazilian Portuguese was performed by three independent translators who were fluent in both English and Portuguese (T1, T2 and T3). Translators T1 and T2 were pro-fessionals who did not have any knowledge of the content, in order to try to reduce the possible influence of academic words.16 The third translator (T3) was a psychologist with experience in the field, who was capable of identifying the constructs of the items of the instrument.16,17 This step maintained operational equivalence, thus keeping the characteristics of using the SEQ, such as the vehicle and formatting of questions and instructions, along with the way of applying the instrument.16,18

Translation synthesisFor the second stage, the three translations were analyzed by two psychologists (doctoral students) who had not partici-pated in the previous step, but had mastered the constructs of the instrument.13 The synthesis was based on the results from the translations.16

First back translationThe third stage was back translation, which formed a quality control on the translation that been produced. The back trans-lation was performed on the translated synthesis by a bilingual psychologist, who was a doctoral student in the field of deficit awareness, but had no knowledge of the original scale.16,19 The objective was to check for any type of inconsistency or concep-tual error in the translations.16

Committee of judgesFor the fourth stage, a committee of judges was organized to evaluate the equivalence between the original version and the Brazilian version of the instrument.16 The committee was com-posed of eight healthcare professionals: one neurologist, two psychiatrists, three physiotherapists and two psychologists. The committee evaluated the semantic, idiomatic, conceptual and experiential equivalence.16 These different forms of equivalence related to the following: the essence of the content with regard to literal translation of the words (semantic equivalence); col-loquialisms and linguistic expressions (idiomatic equivalence); the concept of the phenomenon assessed (conceptual equiva-lence); and the culture experienced (experiential equivalence).20

After the committee had expressed its views, a new synthesis in Portuguese was put forward, in which the changes suggested by the judges were added.16,21

Pretesting of the final versionFor the fifth stage, a pretest with the new translated synthesis was applied in order to ascertain the degree of comprehension of the instrument among the target population.16,21 The sample comprised 30 participants, i.e. 15 people with dementia and their caregivers. The participants had been diagnosed with possible or probable Alzheimer’s disease in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR).22 Only individuals with mild and moderate Alzheimer’s disease, corresponding to Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE) scores of 12-26 were included in the study.23,24

The pretesting was performed at the Center for Alzheimer’s Disease and Related Disorders (CDA) of IPUB/UFRJ, between September 2013 and March 2014. The assessment method was different for caregivers and people with dementia. This distinc-tion was made in an attempt to minimize the impact of the cog-nitive deficits among people with mild and moderate dementia with regard to comprehending the items. The caregivers pro-vided responses to the SEQ in a self-applied manner, while the people with dementia were assessed through face-to-face inter-views. The people with dementia and their caregivers answered the questionnaire on the same day, which took approximately seven minutes to do.

Some comprehension difficulties were observed from the pretesting process. The final version was then resubmitted to a new committee of judges, composed of five specialist psycholo-gists who were fluent speakers of Portuguese and English, with the objective of achieving better equivalence between the orig-inal items and the adapted version.16 After further adaptations, the final version was built and a new pretest was conducted. The new sample was composed of 20 participants, i.e. 10 people with dementia and their caregivers, with the same inclusion and exclusion criteria as in the first sample. All the participants were able to understand and answer the final version.

Second back translationThe second back translation was performed by a different pro-fessional, who had full knowledge of the subject and full skills in Portuguese and English.

Submission to the author of the original instrumentAfter the pretesting adjustments had been made, the final Brazilian Portuguese version was sent to the author of the orig-inal instrument.16 Particularly with regard to evaluating the


Sao Paulo Med J. 2015; 133(4):358-366 361

second back translation, the participation by the author of the original instrument helped to ensure that the adapted version was compatible with the original.16,19

Statistical analysisSimple statistics were included to analyze the effect of education on comprehension of the SEQ items. The statistical analyses were performed using the SPSS software for Windows, release 21.0. We used Spearman’s correlation to investigate the relationships between education level and dementia in both pretests of the translated SEQ.

RESULTSThe sociodemographic characteristics of the samples are pre-sented in Table 1.

The original questions of the SEQ and the results from the initial translation, translation synthesis, back translation and sub-mission to the author of the original instrument are presented in Table 2. The results from the evaluation by committee of judges and from the pretesting of the final version are described within the text, below.

During the development of the first translated synthesis, we tried to achieve a consensus with regard to identifying the best translation. The psychologists responsible for the transla-tion synthesis noticed that the translation performed by T1 was more formal than the others, which would possibly affect the comprehension of the instrument. Therefore, T2 and T3 were

prioritized because the language that they used was more similar to the words used in Brazilian daily life. The back translation had good equivalence regarding the reference framework and general meaning, in comparison with the original instrument.

The committee of judges analyzed all the stages: the transla-tions, the translation synthesis and the back translation. The items had semantic, idiomatic, conceptual and experiential equiva-lence. Operational adjustments were proposed in an attempt to aid in applying and correcting the instrument. In items 6, 7, 10, 16 and 25, we included the female gender in brackets to help in identifying the participant in each sentence. We added an area for counting the results from each individual column, at end of the questionnaire, in the versions applied to both the people with dementia and their caregivers. Furthermore, we decided to include an area for the total score (sum of the columns). In order to improve the comprehension of the total scores, we also added an area for the scores relating to the people with dementia and their caregivers, and for the formula for calculating the discrep-ancy between people with dementia and their caregivers, along with the cutoff points.

In the pretests, the participants were divided according to the severity of their disease, as assessed using the Clinical Dementia Rating.23 During the first pretest, the people with dementia and their caregivers had difficulty in understanding items 7, 17 and 27. In item 7, “Eu sou engraçado”, the word “engraçado” was replaced by the synonym “divertido”, since the first word was under-stood by people with dementia in a pejorative way, i.e. someone

First pretest Second pretestSociodemographic characteristics CDR 1 (n = 11) CDR 2 (n = 4) CDR 1 (n = 9) CDR 2 (n = 1)PwD

DiagnosisMD = 9.09% (n = 1) MD = 25% (n = 1) MD = 11.11% (n = 1) MD = 0VD = 9.09% (n = 1) VD = 25% (n = 1) VD = 22.22% (n = 2) VD = 0

AD = 81.81% (n = 9) AD = 50% (n = 2) AD = 66.66% (n = 6) AD = 100% (n = 1)Age 74.6 ± 8.11 79.2 ± 2.62 77.33 ± 7.31 82

GenderMale = 18.18% (n = 2) Male = 50% (n = 2) Male = 55.55% (n = 5) Male = 100% (n = 1)

Female = 81.81% (n = 9) Female = 50% (n = 2) Female = 44.44% (n = 4) Female = 0MMSE 20.8 ± 3.6 17.75 ± 5.67 20.66 ± 3.24 16

CaregiversAge 54.7 ± 13.69 61.5 ± 13.32 66.77 ± 13.37 67Years of education 12.2 ± 2.37 12.7 ± 4.03 11 ± 3.42 15

GenderMale = 36.36% (n = 4) Male = 50% (n = 2) Male = 0 Male = 0

Female = 63.63% (n = 7) Female = 50% (n = 2) Female = 100% (n = 9) Female = 100% (n = 1)MMSE 29 ± 1.0 29.7 ± 0.5 28.88 ± 1.16 29

Relationship to the patient

Wife = 9.09% (n = 1) Husband = 25% (n = 1) Wife = 55.55% (n = 5) Wife = 100% (n=1)Husband = 18.18% (n = 2) Son = 25% (n = 1) Son = 11.11% (n = 1)

Son = 18.18% (n = 2) Daughter = 50% (n = 2) Daughter = 11.11% (n = 1)Daughter = 45.45% (n = 5) Niece = 11.11% (n = 1)Caregiver = 9.09% (n = 1) Friend = 11.11% (n = 1)

CDR = Clinical Dementia Rating; 1 = Mild impairment; 2 = Moderate impairment; PwD = People with Dementia; MD = Mixed dementia; VD = Vascular dementia; AD = Alzheimer’s dementia; MMSE = Mini Mental State Examination.

Table 1. Sociodemographic characteristics of pretest samples


362 Sao Paulo Med J. 2015; 133(4):358-366

Original version Translations (T1, T2 and T3)Translated

synthesis (TS)Back translation (B1)

Final translated synthesis (FTS)

1. I express my feelings appropriately in public

T1. Eu expresso adequadamente os meus sentimentos em público Eu expresso

adequadamente os meus sentimentos em público

I express my feelings in public adequately

Eu expresso adequadamente os meus sentimentos em público

T2. Eu expresso os meus sentimentos apropriadamente em público

T3. Eu expresso meus sentimentos de forma apropriada em publico

2. I avoid arguments

T1. Eu evito discussões

Eu evito discussões I avoid arguments Eu evito discussõesT2. Eu evito argumentar

T3. Eu evito discussões

3. When others are afraid, I reassure them

T1. Quando outra pessoa está assustada, eu a tranquilizo Quando outras pessoas têm medo, eu as acalmo

When other people feel scared, I calm them down

Quando outras pessoas têm medo, eu as acalmo

T2. Quando as pessoas temem, eu as apoio

T3. Quando outras pessoas têm medo, eu as tranquilizo

4. I speak my mind

T1. Eu falo o que penso

Eu falo o que penso I say what I think Eu falo o que pensoT2. Eu falo o que penso

T3. Eu falo o que penso

5. I notice when other people are happy

T1. Eu reparo quando a outra pessoa está felizEu percebo quando as pessoas estão felizes

I realize when other people are happy

Eu percebo quando as pessoas estão felizes

T2. Eu noto quando as pessoas estão felizes

T3. Eu reparo quando outras pessoas estão felizes

6. I am critical of others

T1. Eu sou critico com as outras pessoasEu sou crítico com as outras pessoas

I am critical of othersEu sou crítico(a) com as outras pessoas

T2. Eu crítico as pessoas

T3. Eu sou crítico com as outras pessoas

7. I am amusing

T1. Eu sou uma pessoa engraçada

Eu sou engraçado I am funny Eu sou divertido(a)T2. Eu sou engraçado

T3. Eu sou divertido

8. I notice when other people are frightened

T1. Eu reparo quando outra pessoa está com medo Eu percebo quando as pessoas estão com medo

I realize when other people are scared

Eu percebo quando as pessoas estão com medo

T2. Eu noto quando as pessoas estão com medo

T3. Eu reparo quando outras pessoas estão assustadas

9. When others are happy, I am pleased for them

T1. Quando outra pessoa está feliz, eu fico contente por ela Quando as pessoas estão felizes, fico contente por elas

When other people are happy, I feel happy for them

Quando as pessoas estão felizes, fico contente por elas

T2. Quando as pessoas estão felizes, fico contente por elas

T3. Quando outras pessoas estão felizes, eu me alegro por elas

10. I am not aggressive

T1. Eu não sou agressivo

Eu não sou agressivo I am not aggressiveEu não sou agressivo(a)



11. I co-operate with others

T1. Eu coopero com os outrosEu ajudo as outras pessoas

I am helpfulEu ajudo as outras pessoas

T2. Eu coopero com as pessoas

T3. Eu coopero com os outros

12. I notice when other people are disgusted

T1. Eu noto quando outra pessoa esta revoltada Eu percebo quando as outras pessoas estão chateadas

I realize when other people are upset

Eu percebo quando as outras pessoas estão enojadas

T2. Eu noto quando as pessoas se aborrecem

T3. Eu reparo quando os outros estão chateado

13. I am impatient with other people

T1. Eu sou impaciente com os outrosEu sou impaciente com as outras pessoas

I am impatient with others

Eu sou impaciente com as outras pessoas

T2. Eu sou impaciente com as pessoas

T3. Eu sou impaciente com as outras pessoas

14. I am apologetic

T1. Eu me desculpo quando faço algo errado

Eu sei pedir desculpasI am able to apologize

Eu sei pedir desculpasT2. Eu estou sempre me desculpando com as pessoas

T3. Eu peço desculpas

15. When others are angry, I calm them down

T1. Quando outra pessoa está zangada, eu a acalmo Quando as pessoas estão com raiva, eu as acalmo

When other people are angry, I calm them down

Quando as pessoas estão com raiva, eu as acalmo

T2. Quando as pessoas estão com raiva, eu as acalmo

T3. Quando os outros estão com raiva, eu os tranquilizo

16. I am confident meeting new people

T1. Eu me sinto confiante ao ter um encontro com uma pessoa desconhecida Eu me sinto seguro

conhecendo novas pessoas

I feel safe when I meet new people

Eu me sinto seguro(a) conhecendo novas pessoas

T2. Eu sou confiante ao conhecer novas pessoas

T3. Eu me sinto confiante conhecendo novas pessoas

Table 2. Steps of the cross-cultural adaptation process


Sao Paulo Med J. 2015; 133(4):358-366 363

Table 2. Steps of the cross-cultural adaptation process

Original version Translations (T1, T2 and T3)Translated

synthesis (TS)Back translation (B1)

Final translated synthesis (FTS)

17. I have difficulties making and keeping close relationships

T1. Eu tenho dificuldades em criar e manter relacionamentos íntimos Eu sinto dificuldades

em fazer e manter relações afetivas

I feel trouble in making and keeping personal relationships

Eu sinto dificuldades em fazer e manter amizades

T2. Eu tenho dificuldades em fazer e manter relações duradouras

T3. Eu sinto dificuldades em fazer e manter relações afetivas

18. I notice when other people are sad

T1. Eu reparo quando outra pessoa está triste Eu percebo quando outras pessoas estão tristes

I realize when other people are sad

Eu percebo quando outras pessoas estão tristes

T2. Eu noto quando outras pessoas estão tristes

T3. Eu reparo quando outras pessoas estão tristes

19. I am sociable

T1. Eu sou sociável

Eu sou sociável I am sociable Eu sou sociávelT2. Eu sou amigável

T3. Eu sou sociável

20. When others are disgusted, I am appalled for them

T1. Quando outra pessoa está revoltada, eu fico chocado por ela Quando os outros estão chateados, eu me preocupo com eles

When other people are upset, I worry about them

Quando os outros estão enojados, eu me preocupo com eles

T2. Quando as pessoas estão aborrecidas, me solidarizo a elas

T3. Quando os outros estão chateados, eu me preocupo com eles

21. I take a long time to make decisions

T1. Eu levo muito tempo para tomar decisões Eu preciso de muito tempo para tomar decisões

I need much time to make decisions

Eu preciso de muito tempo para tomar decisões

T2. Eu levo um bom tempo para tomar decisões

T3. Eu preciso de muito tempo para tomar decisões

22. I do what I want to and do not care what others think

T1. Eu faço o que quero e não me incomodo com o que os outros pensam Eu faço o que quero e

não me preocupo com que as outras pessoas pensam

I do what I want and I do not worry about what other people think

Eu faço o que quero e não me preocupo com que as outras pessoas pensam

T2. Eu faço o que quero fazer e não me importo com o que as pessoas pensam

T3. Eu faço o que eu quero e não me preocupo com o que os outros vão pensam

23. I notice when other people are angry

T1. Eu reparo quando outra pessoa está zangada Eu percebo quando as outras pessoas estão com raiva

I realize when other people are angry

Eu percebo quando as outras pessoas estão com raiva

T2. Eu noto quando as outras pessoas estão com raiva

T3. Eu reparo quando outras pessoas estão com raiva

24. I do things without thinking

T1. Eu faço as coisas sem pensarEu faço coisas sem pensar

I make things without thinking

Eu faço coisas sem pensar

T2. Eu faço coisas sem pensar

T3. Eu faço coisas sem pensar

25. I have good manners

T1. Eu tenho boas maneiras

Eu sou educado I am polite Eu sou educado(a)T2. Eu sou educado

T3. Eu sou bem educado

26. I am close to my family

T1. Eu sou ligado à minha famíliaEu sou próximo da minha família

I am close to my family members

Eu sou próximo da minha família

T2. Eu sou próximo da minha família

T3. Eu sou próximo da família

27. I let someone know if I find them attractive

T1. Eu deixo outra pessoa saber se a acho atraente Eu deixo outra pessoa saber se a acho atraente

I let someone know if I think the person is attractive

Eu demonstro quando acho outra pessoa atraente

T2. Eu deixo as pessoas perceberem se eu as acho atraentes

T3. Eu permito que alguém saiba se o acho atraente

28. I keep in touch with old friends

T1. Eu mantenho contato com os velhos amigosEu mantenho contato com velhos amigos

I keep touch with old friends

Eu mantenho contato com velhos amigos

T2. Eu mantenho contato com amigos de longa data

T3. Eu mantenho contato com velhos amigos

29. I prefer being alone than with others

T1. Eu prefiro ficar sozinho do que com os outros Eu prefiro estar sozinho do que com outras pessoas

I would rather staying alone than with other people

Eu prefiro estar sozinho do que com outras pessoas

T2. Eu prefiro estar sozinho a estar com pessoas ao meu redor

T3. Eu prefiro ficar sozinho do que com outras pessoas

30. When others are sad, I comfort them

T1. Quando outra pessoa está triste, eu a conforto Quando as pessoas estão tristes, eu as conforto

When other people are sad, I comfort them

Quando as pessoas estão tristes, eu as conforto

T2. Quando as pessoas estão tristes eu as conforto

T3. Quando os outros estão tristes eu os conforto

T1, T2 and T3 = Translation 1, Translation 2 and Translation 3; TS = Translated synthesis; B1 = Back translation; FTS = Final translated synthesis.


364 Sao Paulo Med J. 2015; 133(4):358-366

who makes jokes inappropriately. In item 17: “Eu sinto dificul-dades em fazer e manter relações afetivas”, 80% of the people with dementia (81% CDR1; 75% CDR2) and 46.6% of the care-givers (54.5% CDR1; 25% CDR2) interpreted this sentence as relating to sexual intercourse. Since this is an item of sociability, the expression “affective relationships” was replaced by “fazer e manter amizades”. In item 27, “Eu deixo outra pessoa saber se a acho atraente”, 46.6% of the people with dementia (45.5% CDR1; 50% CDR2) and 33.33% of the caregivers (36.3% CDR1; 25% CDR2) had difficulty in understanding the meaning of the sen-tence. Therefore, the sentence was modified to “Eu demonstro quando acho outra pessoa atraente ou interessante”. After analy-sis by a new committee of judges, changes were made in order to adapt the inappropriate words to the target population. A new version of the instrument was built and a second pretest was performed. In this new version of the SEQ, all the items were correctly understood both by the people with dementia and by their caregivers.

There was no correlation between education level and dementia, either in the first pretest (r = - 0.343, P = 0.210) or in the second pretest (r = 0.023, P = 0.951) of the translated SEQ.

The Brazilian version was sent to the author of the original instrument, who made some observations about the translations of items 1, 12 and 20. In item 1, the word “appropriately” was translated as “adequadamente” (adequately). The author consid-ered that there was a slight difference between the two words, but she believed that the sense was still maintained. In items 12 and 20, the word “disgusted” had been translated as “chateado” (upset), but the author explained that those items relate to emo-tional recognition and are based on the five basic emotions (hap-piness, sadness, anger, fear and disgust). Therefore, the word “disgusted” was changed to “enojado”. Although this is not a com-mon word in the Brazilian context, we decided to keep the main characteristics of the instrument. The modifications suggested by the author of the original instrument were made and the final version of SEQ was thus concluded (Table 2).

DISCUSSION Unawareness of social and emotional functioning among peo-ple with dementia may have implications such as understanding other people and themselves, comprehension of interpersonal relationships and the ability to respond empathically to the emo-tions of other people.7,15 More broadly, unawareness of social and emotional functioning is associated with poor treatment out-come and high burdens on caregivers.15 The SEQ is an instru-ment that has been shown to be sensitive to social and emotional unawareness in relation to some diseases, including dementia.15

The objective of this study was to culturally adapt the SEQ for the Brazilian population, while maintaining the original concept

of the instrument and taking the distinct aspects of cultural and language into consideration.19 Cross-cultural adaptation of a research instrument is an important step in scientific investiga-tions. Errors at this stage may misrepresent the original inten-tion of the instrument, thereby compromising the validity and reliability of the study.17 The language differences and, especially, the cultural specificities of each country show why adaptation of an instrument is much more complex than merely translating it. This process needs to be a combination of literal translation of the words and sentences with rigorous consideration of the cul-tural context and lifestyle of the target population.18

The cross-cultural adaptation of the SEQ to Brazilian Portuguese had semantic, idiomatic, conceptual and experi-ential equivalence and it seems that the translated words and expressions kept their original characteristics.19 During the pre-tests, we observed that people with dementia had difficulty in understanding some items relating to social skills and emo-tional recognition and empathy. These items were interpreted ambiguously and a new committee of judges was necessary in order to discuss the equivalence of words. The statistical anal-ysis showed that there was no correlation between education level and dementia in the translated questionnaire. Thus, we can suggest that the difficulties with some items may have been due to cognitive impairment or the presence of unawareness of any deficit caused by the disease. Nelis et al.7 indicated that peo-ple with early-stage dementia show reduced awareness of their social functioning, particularly with regard to emotion recogni-tion and empathy, but also in their social relationship skills and prosocial behavior.7

This study had some limitations. The sample selection did not highlight any proportional distribution of the different lev-els of severity of the disease, which hindered the comparison between groups. If the distribution had been more homoge-neous, better distinction of the capacity to comprehend the instrument among the people with mild and moderate demen-tia would have been possible. We also only ran simple statisti-cal tests, given that the objective of this study was to present the first steps of the process of validation of the instrument (trans-lation, adaptation and semantic equivalence) for the Brazilian population.25 The subsequent steps, aimed towards investigating the psychometric properties, are being processed and will be pre-sented in future studies.26

CONCLUSIONThe cross-cultural adaptation process of the Social and Emotional Questionnaire demonstrated that this instrument was well understood by the Brazilian population. Regardless of the cul-tural and linguistic differences, the main constructs of the origi-nal version were maintained.


Sao Paulo Med J. 2015; 133(4):358-366 365

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26. Kachani AT, Barbosa ALR, Brasiliano S, et al. Tradução, adaptação

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Sources of funding: Fundação de Amparo à Pesquisa do Estado do Rio

de Janeiro, E-26/102.256/2010

Conflict of interest: None

Date of first submission: October 29, 2014


Accepted: January 5, 2015


Tatiana Teresa Belfort Almeida dos Santos

Av. Lúcio Costa 3300, bloco 05 apto 401

Barra da Tijuca — Rio de Janeiro (RJ) — Brasil

CEP 22630-010

Tel. (+55 21) 99153-8078


Sao Paulo Med J. 2015; 133(4):367-70 367

SHORT COMMUNICATIONDOI: 10.1590/1516-3180.2014.9490902

Main reasons for medical consultations in family healthcare units in the city of Recife, Brazil: a cross-sectional study Principais motivos de consultas médicas em unidades de saúde da família na cidade do Recife, Brasil: um estudo transversalRinailda de Cascia Santos TorresI, Karine Sobral MarquesI, Kamila de Nazaré Ribas LealI, Pedro Augusto Sampaio Rocha-FilhoII

Universidade de Pernambuco (UPE) and Universidade Federal de Pernambuco (UFPE)

ABSTRACTCONTEXT AND OBJECTIVE: Only a few studies have focused on the main reasons for consultations at primary healthcare units within the Family Health Program. The aim here was to describe the reasons that led patients to seek assistance at four primary healthcare units in the city of Recife, Brazil.DESIGN AND SETTING: Cross-sectional study at primary healthcare units in the city of Recife.METHODS: Among adult patients who were consecutively attended at four primary healthcare units in the city of Recife, their two main reasons for going there were recorded by medical students. The students did not interfere in the consultation dynamics. The data were gathered between September 2010 and March 2011 and between November 2012 and August 2013. The reasons for the consultations were grouped into broader categories in accordance with the International Classi�cation of Primary Care (ICPC-2).RESULTS: 478 patients were included. Their mean age was 45.9 years (± 16 years) and 71% were female. Pain was the main reason for seeking medical attention (34%), followed by evaluation of tests, prescription renewal and medical certi�cates (17.6%). The most frequent types of pain were musculoskeletal pain (15.7%), headache (10.4%) and abdominal pain (8%). The main reasons for consultation according to ICPC-2 were in the general and nonspeci�c, musculoskeletal, nervous system-related and digestive tract categories.CONCLUSION: Pain was the most frequent reason for seeking medical attendance at these primary healthcare units.

RESUMOCONTEXTO E OBJETIVO: Existem poucos estudos sobre quais as principais causas de atendimento nas unidades básicas de saúde do Programa de Saúde da Família. O objetivo foi descrever quais as razões que levam os pacientes a procurar quatro Unidades Básicas de Saúde da cidade do Recife, Brasil. TIPO DE ESTUDO E LOCAL: Estudo transversal em unidades básicas de saúde na cidade do Recife.MÉTODOS: Pacientes adultos consecutivamente atendidos em quatro unidades básicas de saúde na cidade do Recife tiveram as duas principais razões para o atendimento registradas por estudantes de medicina. Os estudantes não interferiram na dinâmica da consulta. A coleta de dados ocorreu entre setembro de 2010 e março de 2011 e entre novembro de 2012 e agosto de 2013. As razões para as consultas foram agrupadas em categorias mais amplas de acordo com a Classi�cação Internacional da Atenção Primária (ICPC-2).RESULTADOS: 478 pacientes foram incluídos, a idade média foi de 45,9 anos (± 16 anos), 71% eram do sexo feminino. A dor foi a principal razão para procura de atendimento médico (34%), seguida por avalia-ção de exames, renovação de receitas ou atestados médicos (17,6%). A dor musculoesquelética foi a mais frequente (15,7%), seguida por cefaleia (10,4%) e dor abdominal (8%). As principais causas de atendimen-to foram gerais e não especí�cas, musculoesqueléticas, relacionadas ao sistema nervoso e ao aparelho digestivo (ICPC-2).CONCLUSÃO: A dor foi o motivo mais frequente para procurar atendimento médico nas unidades básicas de saúde.

IMedical Student, Universidade de Pernambuco (UPE), Recife, Pernambuco, Brazil.IIMD, PhD. Adjunct Professor, Department of Neuropsychiatry, Universidade Federal de Pernambuco (UFPE), and Neurologist, Universidade de Pernambuco (UPE), Recife, Pernambuco, Brazil.

KEY WORDS: Health services. Primary health care. Community health centers. Epidemiology. Pain.

PALAVRAS-CHAVE: Serviços de saúde. Atenção primária à saúde. Centros comunitários de saúde. Epidemiologia. Dor.

SHORT COMMUNICATION | Torres RCS, Marques KS, Leal KNR, Rocha-Filho PAS

368 Sao Paulo Med J. 2015; 133(4):367-70

INTRODUCTION�e Family Health Program (Programa de Saúde da Família, PSF) is put into practice through multiprofessional teams that are based at primary care facilities. Recife is the capital of the state of Pernambuco, in the northeastern region of Brazil. PSF was the strategy used by Recife’s Public Health Department to reorga-nize its primary care provision. Recife is divided in six health-care districts. District I has nine family health teams; district II, 17 teams; district III, 22 teams; district IV, 32 teams; district V, 15 teams; and district VI, 31 teams. According to data from the Primary Care Information System (SIAB), more than 200,000 families had been registered for attendance through the PSF in Recife up to August 2013.1

Only a few studies have focused on the main reasons for seeking consultations at primary care units. �e main reasons have been found to relate to general and unspeci�ed, respiratory, digestive and musculoskeletal symptoms.2-4

Knowing what kind of illnesses are treated by PSF teams is extremely important for training the teams and planning pri-mary care, thereby making it possible to create a list of priorities and alternatives for solving these problems.

OBJECTIVE�e purpose of this article was to describe the most frequent rea-sons for seeking consultations at four primary care facilities in the city of Recife, Brazil.

METHODS�is study was carried out from September 2010 to March 2011 and from November 2012 to August 2013 in four primary care facilities in the city of Recife (Santo Amaro, in healthcare district I; Chié, in district II; Alto do Maracanã, in district III; and Sinos, in district IV). �ese units are linked to Pernambuco University and to the “Professor Fernando Figueira” Integral Medicine Institute, and they were chosen because of their availability of structural conditions for receiving undergraduates.

Patients over the age of 18 who were consecutively attended dur-ing the study periods, at medical consultations that had previously been scheduled at the four primary care facilities, were included.

�e data were recorded by medical undergraduates who did not interfere in the consultation dynamics and did not ask the patients any questions. �e patients’ two main reasons for seeking the consul-tation were logged through an open questionnaire during the medi-cal consultation, based on what was said to the doctor. �e students were trained for three months before the beginning of the study.

All the patients gave their informed consent for their inclu-sion in the study. �e study was approved by the Research Ethics Committees of the “Professor Fernando Figueira” Integral Medicine Institute and of the Oswaldo Cruz University Hospital.

�e reasons for seeking medical consultations were grouped into broader categories in accordance with the 17 chapters of the second edition of the International Classi�cation of Primary Care (ICPC-2).5

�e statistical analysis was carried out using Epi-Info 7.1.3.10 for Windows. All the variables were analyzed descriptively. Means and standard deviations were calculated for quantitative variables. Absolute and relative frequencies were calculated for qualitative variables. Categorical variables were compared across groups using the chi-square test.

RESULTS�e total number of patients seen at the primary care units over the study period was 481. �ree patients refused to participate in the study. �us, 478 patients were included in the study, of whom 338 (71%) were female. �e patients’ mean age was 45.9 years (± 16 years).

Table 1 shows the reasons for seeking consultations at the primary care units. Pain was the most commonly reported com-plaint at all the primary care facilities.

�e kinds of pain reported by patients were as follows, in fre-quency order: musculoskeletal pain (15.7%; 75/478); headache (10.4%; 50/478); abdominal pain (8%; 38/478); and chest pain

Table 1. Patients’ most frequent reasons for seeking medical consultations at primary care units

Main complaint (reason for appointment)

n (%)Second

complaint n (%)

Pain 163 (34.1) 54 (36)Test evaluations/prescription renewal/medical certi�cates

84 (17.6) 24 (16)

Hypertension 25 (5.2) 9 (6)Airway symptoms (coughing; sneezing/nasal congestion; shortness of breath/dyspnea; throat symptom)

25 (5.2) 4 (2.7)

Skin complaints 15 (3.1) 4 (2.7)Anxiety/depression 11 (2.3) 6 (4)Vomiting/diarrhea 10 (2) 3 (2)Palpable tumor 10 (2) 0Paresthesia 9 (1.8) 4 (2.7)Asthenia 9 (1.9) 3 (2)Dizziness 8 (1.6) 0Gynecological complaints 7 (1.4) 0Edema 7 (1.4) 3 (2)Fever 6 (1.3) 1 (0.7%)Urinary tract infection 6 (1.3) 3 (2)Allergy 6 (1.3) 1 (0.01)Trauma 5 (1) 0Pregnancy suspicion 5 (1) 0Ophthalmological complaints 4 (0.8) 0Others 63 (13.2) 31 (21)Total 478 (100) 150 (100)

Main reasons for medical consultations in family healthcare units in the city of Recife, Brazil: a cross-sectional study | SHORT COMMUNICATION

Sao Paulo Med J. 2015; 133(4):367-70 369

Table 3. All reasons for seeking medical consultations grouped according to the 17 chapters of the International Classi�cation of Primary Care (ICPC-2)

ICPC chapters n (%)General and unspeci�ed 153 (32)Musculoskeletal 95 (19.9)Neurological 89 (18.6)Digestive 59 (12.3)Cardiovascular 51 (10.7)Respiratory 30 (0.06)Psychological 26 (0.05)Female genital 23 (0.05)Skin 22 (0.05)Endocrine/metabolic and nutritional 14 (0.03)Urological 14 (0.03)Pregnancy, childbearing, family planning 10 (0.02)Ear 10 (0.02)Eye 7 (0.02)Male genital 5 (0.01)Blood, blood-forming organs and immune mechanism 3 (0.01)Social problems 0Total 478 (100)

*Chi-square test.

Pain (main reason)

P value*Test evaluations/prescription renewal/

medical certi�cates (main reason)P value*

More than one reason for the medical appointment

P value*

Age (years)18-39 (n = 175) 68 (38.9%)

0.0420 (11.4%)

0.0245 (25.7%)

0.1440-59 (n = 203) 71 (35%) 40 (19.7%) 71 (35%)> 59 (n = 100) 24 (24%) 24 (24%) 34 (34%)

SexMale (n = 139) 35 (25.2%)

0.0121 (15.1%)

0.3826 (18.7%)

< 0.01Female (n =339) 128 (37.8%) 63 (18.6%) 124 (36.6%)

Primary care unitSanto Amaro (n = 47) 22 (46.8%)

0.09

4 (8.5%)

0.13

12 (25.5%)

0.06Chié (n = 62) 19 (30.7%) 10 (16.1%) 17 (27.4%)Alto do Maracanã (n = 322) 111 (34.5%) 65 (20.2%) 113 (35.1%)Sinos (n = 47) 11 (23.4%) 5 (10.6%) 8 (17%)

Table 2. Association of patients’ characteristics and primary care unit with the reasons for seeking the medical consultation

(1.1%; 5/478). �e most frequent types of musculoskeletal pain were back pain (33%) and joint pain (33%).

Table 2 shows the associations between the sociodemo-graphic variables, primary care facilities and reasons for seek-ing consultations. Older individuals had signi�cantly less pain and asked for more evaluations of tests, prescription renewals and medical certi�cates. Women had signi�cantly more pain and more reasons for seeking consultations.

Table 3 shows the reasons for seeking consultations, grouped according to ICPC chapters. �e most common reasons were in the categories of the “general and unspeci�c”, “musculoskeletal”, “neurological” and “digestive” chapters.

DISCUSSIONPain was the most frequent reason for seeking consultations at primary care units, according to our study. Other authors have also found that pain is an important reason for seeking consul-tations at primary care units.2,4 Magnago et al. found a di�er-ent result, but they used a structured questionnaire that did not include pain among its options.6

Although pain is a frequent reason why patients seek medical consultations, it is not being properly evaluated and treated.4 If pri-mary care teams are trained to diagnose the causes of pain and to provide treatment for this symptom, the demand among patients for healthcare at levels dealing with cases of higher complexity, as well as overloading of emergency services, can be avoided.

A signi�cant number of patients went to the primary care unit to request prescription renewals and have tests evaluated. �is was concordant with what was found in other studies.4,6,7

Even though hypertension had previously been found to be one of the most frequent reasons for consultations, its fre-quency in our study was lower than what we had expected. With the aim of providing attendance for hypertension and

diabetes mellitus patients, a reorganized attendance plan for these diseases, known as HIPERDIA, was created in 2002. �is made it possible to register and attend to these patients through primary care.8 Attendance for hypertension and diabe-tes patients at these units follows the program’s enrollment �ow, with participation in weekly meetings with multidisciplinary teams. At these meetings, the doctor renews and modi�es pre-scriptions, talks about healthy habits and lifestyles in order to improve clinical control over these illnesses and answers ques-tions. Patients are enrolled in the program a�er the diagnosis of diabetes or hypertension has been con�rmed through an earlier appointment. �rough this procedure, patients attended within

SHORT COMMUNICATION | Torres RCS, Marques KS, Leal KNR, Rocha-Filho PAS

370 Sao Paulo Med J. 2015; 133(4):367-70

HIPERDIA only seek medical consultations in cases of compli-cations relating to these diseases.

Women presented signi�cantly more reasons for seeking medical consultations in our study. As far as we know, only one previous study evaluated what is related to the number of rea-sons for medical consultations within primary care in Brazil. �at study also found that women presented more reasons than men did, and that the number of reasons increased with advancing age.4

We found that the most common reasons for seeking medical consultation, as categorized in the chapters of the ICPC related to the “general and unspeci�c”, “musculoskeletal”, “neurological” and “digestive” chapters. �ese were among the most frequent reasons in another two studies,3,4 and the “general and unspeci�c” category was the �rst reason in one of them.4

Our study has some limitations. �e primary care facilities were selected using convenience criteria and not randomly from among all the units in the city. �e units selected are teaching units that regularly receive medicine undergraduates and may not be representative of the city’s primary care. Nevertheless, we tried to include primary care facilities from four of the city’s six healthcare districts. Sixty-seven percent of the patients were interviewed at a single primary care unit. However, it should be highlighted that we did not �nd any signi�cant di�erences among the primary care facilities.

CONCLUSIONSPain was the most frequent reason for seeking medical attention at all the primary care facilities, followed by requests for test eval-uation, prescription renewal and medical certi�cates. �e most frequent type of pain was musculoskeletal pain, followed by headache and abdominal pain. �e most common reasons for seeking medical consultations, according to the ICPC categories related to the general and unspeci�c, musculoskeletal, neurologi-cal and digestive chapters.

REFERENCES1. Brasil. Ministério da Saúde. DATASUS. Sistema de Informação de

Atenção Básica - Cadastramento Familiar – Pernambuco. Available from:

http://tabnet.datasus.gov.br/cgi/deftohtm.exe?siab/cnv/SIABFPE.def.

Accessed in 2015 (Mar 19).

2. Pimentel IR, Coelho BC, Lima JC, et al. Caracterização da demanda

em uma Unidade de Saúde da Família [Description of demand in

a Family Health Unit]. Revista Brasileira de Medicina de Família e

Comunidade. 2011;6(20):175-81. Available from: http://www.rbmfc.

org.br/rbmfc/article/view/95/364. Accessed in 2015 (Feb 20).

3. Colombo D, Santa Helena ET, Agostinho ACMG, Didjurgeit JSMA.

Padrão de prescrição de medicamentos nas unidades de programa

de saúde da família de Blumenau [Prescribed drugs in attendance

sampling at basic health service in Blumenau]. Rev Bras Cienc Farm.

2004;40(4):549-58.

4. Landsberg GAP, Savassi LCM, Sousa AB, et al. Análise da demanda em

Medicina de Família no Brasil utilizando a Classi�cação Internacional

de Atenção Primária [Analysis of demand for family medical care in

Brazil using the International Classi�cation of Primary Care]. Ciênc

Saúde Coletiva. 2012;17(11):3025-36.

5. World Organization of National Colleges, Academies, and Academic

Associations of General Practitioners/Family Physicians. Classi�cação

Internacional de Atenção Primária (CIAP 2) - Comitê Internacional

de Classi�cação da WONCA. Florianópolis: Sociedade Brasileira de

Medicina de Família e Comunidade; 2009. Available from: http://

www.sbmfc.org.br/media/�le/CIAP%202/CIAP%20Brasil_atualizado.

pdf. Accessed in 2015 (Feb 20).

6. Magnago RF, Moreira DS, Cunha L, Sakae TM. Per�l dos usuários do

posto de saúde da família do bairro Humaitá, Tubarão – SC [Pro�le of

users of users of the Humaitá Family care station in Tubarão, Santa

Catarina]. ACM Arq Catarin Med. 2009;38(2):7-15.

7. Radaelle SM, Takeda SMP, Gimeno LID, et al. Demanda de serviço de

saúde comunitária na periferia de área metropolitana. [The demand

for community health services in the metropolitan periphery area].

Rev. Saúde Pública. 1990;24(3):232-40.

8. Brasil. Ministério da Saúde. Secretaria de Políticas de Saúde. Departamento

de Ações Programáticas Estratégicas. Plano de reorganização da atenção

à hipertensão arterial e ao diabetes melittus. Brasília: Ministério da Saúde;

2001. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/

miolo2002.pdf. Accessed in 2015 (Feb 20).

Acknowledgements: Scienti�c Initiation Fellowship Institutional

Program grants (CNPq) to Rinailda de Cascia Santos Torres and Kamila

de Nazaré Ribas Leal



Date of �rst submission: August 19, 2014

Last received: January 24, 2015

Accepted: February 9, 2015


Pedro Augusto Sampaio Rocha Filho

Rua General Joaquim Inácio, 830 — Sala 1.412 — Edifício The Plaza

Business Center

Recife (PE) — Brasil

CEP 50070-270

Tel. (+55 81) 3129-8897


Sao Paulo Med J. 2015; 133(4):371-6 371

CASE REPORTDOI: 10.1590/1516-3180.2013.7550003

Nimesulide-induced fatal acute liver failure in an elderly woman with metastatic biliary adenocarcinoma. A case reportInsu�ciência hepática aguda fatal induzida por nimesulida em uma mulher idosa com adenocarcinoma biliar metastático. Um relato de casoSara Santos BernardesI, André Souza-NogueiraII, Estefânia Gastaldello MoreiraIII, Marina Okuyama KishimaIV, Alda Fiorina Maria Losi GuembarovskiIV, Tercilio Luiz TuriniIV, Conceição Aparecida TuriniV

University Hospital, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil

ABSTRACTCONTEXT: Nimesulide is a selective inhibitor of the enzyme cyclooxygenase 2. Although considered to be a safe drug, cases of acute hepatitis and fulminant liver failure have been reported in Europe, the United States and South America, especially among elderly female patients. Until now, there had not been any reports in the literature relating to Brazilian subjects. CASE REPORT: An 81-year old female who had been using nimesulide therapy for six days presented hematemesis and epistaxis two days before hospitalization. Clinical examination showed an extensive coagulation disorder, di�use hematomas, hypotension and tachypnea. Laboratory tests revealed abnor-malities in coagulation tests; leukocytosis; reduced platelet, hemoglobin and red blood cell counts; and elevated direct bilirubin, serum aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase and renal function biomarkers. Hepatitis B and C tests were not reactive. Carcino-embryonic antigen (CEA), CA-19-9 and CA-125 levels were increased by, respectively, 1,000, 10,000 and 13 fold, whereas the alpha-fetoprotein level was normal, thus indicating a malignant tumor in the bile duct that did not originate from the liver. Thirty-six hours after hospitalization, the patient’s condition worsened, leading to death. The necropsy �ndings included acute hepatitis with hepatocellular collapse, as well as metastasis of a carcinoma, probably from the bile duct. CONCLUSION: Despite the carcinoma presented by the patient, nimesulide use may have contributed towards the fatal acute liver failure. Until this issue has been clari�ed, caution is required in prescribing nimesulide for liver disease patients.

RESUMOCONTEXTO: A nimesulida é um inibidor seletivo da enzima ciclo-oxigenase 2. Apesar de ela ser conside-rada fármaco seguro, casos de hepatite aguda e falência hepática fulminante foram descritos na Europa, Estados Unidos e América do Sul, principalmente em idosos do sexo feminino. Até o momento não há relatos na literatura em indivíduos brasileiros.RELATO DE CASO: Mulher de 81 anos, em uso terapêutico de nimesulida por seis dias, apresentou he-matêmese e epistaxe dois dias antes da hospitalização. O exame clínico mostrou importante distúrbio de coagulação, hematomas difusos, hipotensão e taquipneia. Os exames laboratoriais mostravam altera-ção das provas de coagulação, leucocitose, redução do número de plaquetas, hemoglobina e hemácias, aumento de bilirrubina direta, elevação dos valores de aspartato aminotransferase (AST), gama glutamil transpeptidase (GGT), fosfatase alcalina e marcadores de função renal. Exames para hepatite B e C apre-sentaram-se não reagentes. Elevados níveis dos marcadores antígeno carcinoembriônico (CEA), CA-19-9 e CA-125 foram encontrados (1.000, 10.000 e 13 vezes, respectivamente), enquanto a alfa-fetoproteína estava normal, indicando um tumor maligno no ducto biliar, não oriundo do fígado. Trinta e seis horas após a hospitalização, a paciente evoluiu a óbito. Os achados necroscópicos incluíram hepatite aguda com colapso hepatocelular, bem como metástase de carcinoma, provavelmente do ducto biliar.CONCLUSÃO: Apesar do carcinoma apresentado pela paciente, o uso de nimesulida pode ter contribuído para o dano hepático. Até que esta questão seja esclarecida, a prescrição de nimesulida deve ser cuidado-sa para pacientes com doenças hepáticas.

IMSc. Assistant Professor, Department of General Pathology, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil. IIMSc. Universidade Estadual de Londrina (UEL), and Poison Information Center, University Hospital, Universidade Estadual de Londrina, Londrina, Paraná, Brazil. IIIPhD. Adjunct Professor, Department of Physiological Sciences, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil. IVMD. Adjunct Professor, Department of Clinical Medicine, University Hospital, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil.VMD. Adjunct Professor, Department of Pathology, Clinical and Toxicology Analysis, Universidade Estadual de Londrina (UEL), and Poison Information Center, University Hospital, Universidade Estadual de Londrina (UEL), Londrina, Paraná, Brazil.

KEY WORDS:Anti-in�ammatory agents, non-steroidal.Liver failure, acute.Drug-induced liver injury.Cholestasis.Drug toxicity.

PALAVRAS-CHAVE:Anti-in�amatórios não esteroides.Falência hepática aguda.Doença hepática induzida por drogas.Colestase.Toxicidade de drogas.

CASE REPORT | Bernardes SS, Souza-Nogueira A, Moreira EG, Kishima MO, Guembarovski AFML, Turini TL, Turini CA

372 Sao Paulo Med J. 2015; 133(4):371-6

INTRODUCTIONNimesulide (NIM) has analgesic, anti-in�ammatory and anti-pyretic activity due to its potent inhibitory e�ects on the enzyme cyclooxygenase 2 (COX-2), while causing relatively low occurrence of gastrointestinal injury.1 Despite being widely prescribed and considered quite safe, nimesulide has been linked to cases of severe liver injury, especially when prescribed to susceptible patients.2-7 �e hepatic events that have been reported during treatment with nimesulide include asymptomatic and reversible elevation of liver enzymes,8,9 acute hepatitis associated with hepatocellular necrosis, cholestasis and some isolated cases of fatal acute liver failure.10,11

Nimesulide-induced fatal hepatotoxicity is uncommon (one case in one million patients), even though nimesulide is one of the non-steroidal anti-in�ammatory drugs (NSAIDs) that more frequently induce acute hepatitis.4,12 It is relatively insensitive to accumulated dose and is patient-speci�c, and it is considered to have idiosyncratic toxicity.7 In a analyses on 32 cases of liver failure of unknown cause a�er transplantation, six were corre-lated with therapeutic nimesulide ingestion within six months.3 In a retrospective study on drug-induced liver injury, Licata et al.13 found that nimesulide corresponded to 70% of all NSAID-related cases. Moreover, it has been reported that NIM-induced hepato-toxicity seems to be more common in middle-age females.3,14-16 Interestingly, in a case report on six cases of NIM-induced hepa-totoxicity, Van Steenbergen et al.10 reported hepatocellular necro-sis in all four female patients, whereas they demonstrated bland cholestasis in the remaining two male patients.

Experimental evidence shows that, besides hepatotoxic-ity, nimesulide promotes hyperplasia of the bile ducts and for-mation of reactive metabolites that covalently modify proteins, and it induces oxidative stress and mitochondrial injury.17,18 In NIM-induced cell damage, reduced glutathione consump-tion has been observed, with consequent oxidative stress and damage to the macromolecular infrastructure, thereby leading to mitochondrial uncoupling, decreased phosphorylation index (ADP/O2 ratio), and mitochondrial membrane permeability transition, followed by cell death.11,17-20

�e individual risk factors that can predispose a patient to increased risk of developing nimesulide-associated hepatic adverse reactions, such as speci�c gene abnormalities, altera-tions to speci�c gene expression or epigenetic factors, are cur-rently unknown.7 We report on the case of an elderly female with hepatic adenocarcinoma metastasis from the biliary duct, with early onset of hematological disorders a�er ingestion of nimesulide at therapeutic doses.

CASE REPORTA 81-year-old female with no hepatitis, no medical history of adverse drug reactions and adequate renal and hepatic func-tion developed hematemesis and epistaxis two days before

hospitalization in a university hospital in southern Brazil. She had taken NIM, once a day, for six days. Three weeks ear-lier, she had taken diclofenac for seven days, which was sus-pended four days before the beginning of nimesulide therapy.

On medical admission, large amounts of di�use hematomas, bilateral epistaxis and melena were observed. �e patient pre-sented hypotension (80 x 40 mmHg), heart rate of 70 beats per minute, respiratory frequency of 26 breaths per minute, sponta-neous ventilation and sudoresis. �e laboratory tests on admis-sion showed metabolic acidosis compensated with respiratory alkalosis, and increased lactate. Prothrombin time (PT), partial thromboplastin time (PTT), �brinogen level and platelet count were low and therefore fresh-frozen plasma and platelet trans-fusion was conducted. �e hematological pro�le comprised diminished red blood cell, hemoglobin and hematocrit levels, with leukocytosis. �e renal pro�le on admission was charac-terized by increased urea and creatinine levels. Serum aspartate transaminase (AST), an indicator of deep hepatic lesions, was ten times above the normal level, while serum alanine transam-inase (ALT) levels were normal. Total and direct bilirubin lev-els were increased but indirect bilirubin was normal. C-reactive protein, an in�ammatory biomarker, was 30 times above the normal level. To rule out the suspicion of upper gastrointesti-nal bleeding, upper gastrointestinal endoscopy was conducted. During this examination, the patient su�ered respiratory arrest and evolved to a decreased consciousness level, needing orotra-cheal intubation.

Eighteen hours a�er admission, the renal and hepatic dam-age advanced, as demonstrated by higher levels of urea, creat-inine, AST, ALT and bilirubins (including the indirect form). At this time, gamma-glutamyl transferase (GGT) and alkaline phosphatase were determined and their levels were highly ele-vated. �e hematological pro�le continued to worsen and, 36 hours a�er hospitalization, a red blood cell, fresh-frozen plasma and cryoprecipitate transfusion was conducted. On the same day, the hospital’s poison information center was noti�ed in order to investigate the possibility of intoxication.

All the laboratory test results are presented in Table 1. Testing for hepatitis C and B produced negative results. Carcinoembryonic antigen (CEA) and CA-19-9 levels were increased, respectively, by 1,000 and 10,000-fold. CA-125 was slightly increased (13-fold) and alpha-fetoprotein (AFP) levels were normal (Table 2). Soon a�er the blood component trans-fusion, the patient’s general state continued to worsen and she su�ered a 12-minute cardiorespiratory arrest which evolved to asystole and death.

�e necropsy �ndings included liver acute hepatitis with in�ammatory in�ltrate, coagulative necrosis and hepatocellular collapse (Figure 1). Moreover, there was metastasis of moderately di�erentiated carcinoma, probably from the bile duct (Figure 2).

Nimesulide-induced fatal acute liver failure in an elderly woman with metastatic biliary adenocarcinoma. A case report | CASE REPORT

Sao Paulo Med J. 2015; 133(4):371-6 373

DISCUSSIONTo the best of our knowledge, this is the � rst case report on NIM-induced hepatotoxicity in a liver cancer patient, and in a Brazilian subject. Cancer is a major public health problem and is responsible for 27% of deaths worldwide, surpassed only by car-diovascular diseases. Its prevalence is increasing in developing countries as a result of population aging.21 Females over 50 years of age seem to be highly susceptible to NIM-induced liver

Table 1. Laboratory tests on admission (0 hour) and 18 hours after hospitalization

Reference value Admission 18 hoursHematological pro� le

Red blood cells 3.9-5.0 x 106 cells/µl 2.3 3.0Hemoglobin 12-15.5 g/dl 9.0 10.8Hematocrit 35-45% 26.7 31.4White blood cells 4,000-10,000/µl 19,700 16,500Platelets 150,000-400,000/µl 96,000 51,000

Blood coagulation pro� lePT 70-100% 35.6 36.9PTT 26-37 seconds 37.0 39.0INR 0.8-1.2 2.10 2.04Fibrinogen 150-500 mg/dl 64 95

Blood gasometrypH 7.350-7.450 7.22 7.27pO2 80-110 mm/Hg 49.5 91.8pCO2 35-45 mm/Hg 31.6 30.0HCO3 23-26 mEq/l 12.4 13.3Base excess -2 to 2 -14.0 -12.2Total CO2 22-28 mmol/l 13.3 14.3

Renal pro� leUrea 15-38 mg/dl 75 88Creatinine 0.6-1.3 mg/dl 1.32 1.59

Hepatological pro� leAST 10-31 U/l 300 1,159ALT 30-65 U/l 60 166Total bilirubin 0-1 mg/dl 3.96 5.24Direct bilirubin 0-0.3 mg/dl 3.57 3.70Indirect bilirubin < 0.7 mg/dl 0.39 1.54GGT 5-55 U/l - 537AP 50-136 U/l - 260

OthersLactate 0.4-2 mmol/l 7.86 5.76C-reactive protein < 3 mg/l 92.3 93.1

Hematological, blood coagulation, renal and hepatological pro� les and blood gasometry, lactate and C-reactive protein in an 81-year-old woman with acute hepatitis induced by nimesulide therapy. PT = prothrombin time; PTT = partial thromboplastin time activity; INR = international normalization ratio; AST = aspartate transaminase; ALT = alanine transaminase; GGT = gamma-glutamyl transferase, AP = alkaline phosphatase.

Table 2. Hepatitis and cancer biomarker testsReference value Values

Hepatitis C NR NRHepatitis B (HBsAg) NR NRCEA < 3 ng/ml 1,224.35CA-19-9 < 37 U/ml 10,079.97CA-125 < 35 U/ml 476.4AFP < 8 ng/ml 7.49

Hepatitis C and B tests and CEA, CA-19-9, CA-125 and AFP cancer biomarkers in an 81-year-old woman with acute hepatitis induced by nimesulide therapy. Increased CEA together with increased CA-19-9 and CA-125 indicates a malignant tumor originating from the bile duct. Normal AFP levels rule out malignant tumors originating from the liver. CEA = carcinoembryonic antigen. AFP = alpha-fetoprotein. NR = non-reactive.

Figure 1. Histopathological features of the liver, focusing on acute liver failure: acute hepatitis with hepatocellular collapse in the patient’s liver. The arrows show extensive areas of coagulative necrosis and in� ammatory in� ltrate (hematoxylin and eosin stain; original magni� cation X 20).

Figure 2. Histopathological features of the liver, focusing on adenocarcinoma metastasis: adenocarcinoma metastasis, probably originating from the bile duct, in the patient’s liver. The arrows show the neoplastic cells (hematoxylin and eosin stain; original magni� cation X 40).


374 Sao Paulo Med J. 2015; 133(4):371-6

damage, which generally presents rapid worsening, despite ces-sation of drug therapy.3,13,14,16

We conducted a systematic search in PubMed (Medline), Scopus, Cochrane Library, Lilacs and SciELO, to �nd papers that reported human hepatic injury due to NSAIDs (Table 3). Nimesulide is one of the NSAIDs that more frequently induce hepatic injury, and the majority of cases were correlated with therapeutic drug use. Furthermore, nimesulide-induced hep-atotoxicity seems to be more common in middle-age females. �e hepatic events reported during treatment with nimesulide include from asymptomatic and reversible elevation of liver enzymes to fatal acute liver failure. Although the patient had taken diclofenac three weeks before developing the clini-cal symptoms, we believe that nimesulide played a major role in her liver injury: �rst, because the patient was within the at-risk group; and second, because nimesulide was the current NSAID therapy. Several case reports have described occur-rences of acute hepatitis with in�ammatory in�ltrate and hepa-tocellular collapse in cases of NIM-induced toxicity.4,10,14,16 In this case report, this condition was con�rmed biochemically (increased AST, ALT, GGT and bilirubin levels) and histopatho-logically. Although the patient did not present jaundice, total bili-rubin was higher than 3 mg/dl, with predominance of the direct form. When associated with increased alkaline phosphatase, the increase in direct bilirubin indicates post-hepatic hyperbilirubi-nemia, which can occur due to bile duct obstruction or biliary tract tumors.22,23 In NIM-induced liver failure, cholestatic liver injury is also reported, and this could explain the predominance of direct bilirubin and the increased alkaline phosphatase lev-els.4,10 �e extensive liver damage observed explains the coag-ulation disorders, which are a common feature in nimesulide

toxicity,6,16 as well as the metabolic acidosis due to increased lac-tate.23 It is known that solid tumors and metastasis can induce disseminated intravascular coagulation (DIC),24,25 but no labora-tory tests that could indicate this diagnosis were performed.

Even though kidney failure was not observed at the nec-ropsy, the patient presented some degree of renal damage, as suggested by the increased serum urea and creatinine levels. Schattner et al.6 described kidney failure in a 70-year-old woman who therapeutically ingested nimesulide for �ve days, two weeks before symptoms. Apostolou et al.26 reported on the case of a 68-year-old female who took one tablet of 100 mg of nimesulide and developed acute renal failure with di�use ischemic lesions and lymphocyte in�ltration into the kidney, similar to what has been described in cases of nephritis due to NSAIDs.

Cancer biomarkers are widely used for diagnosis, progno-sis and patient follow-up.27 Approximately 99% of malignant gallbladder tumors originate from the epithelium, and 95% are adenocarcinomas.28 Increased CEA together with increased CA-19-9 is widely used as a gallbladder bile tumor marker.29,30 Simultaneous CEA, CA-19-9 and CA-125 elevation indicates primary malignancy from the bile ducts.30,31 Normal alpha-fetoprotein levels rule out cancer originating from the liver.30,31

Furthermore, following acute liver injury with extensive necro-sis, an increase in AFP is interpreted as a sign of dedi�erentiated hepatic regeneration.32-34 At the necropsy on the liver, the pres-ence of both acute hepatitis and adenocarcinoma was con�rmed, and the characteristics were those of a bile duct cancer metastasis. It is known that cancer can a�ect the function of the tissue in which it is hosted. Although the patient was in the group at risk of NIM-induced hepatotoxicity, the liver cancer metastasis prob-ably also contributed towards the fatal acute liver failure.

Table 3. Literature review using MeSH (Medical Subject Headings) terms relating to human hepatic injury and use of non-steroidal anti-in�ammatory agents, performed on September 18, 2013

Electronic database Search strategyResults

Found Related

PubMed (Medline) “Non steroidal anti-in�ammatory agents” AND “Acute liver failure” 5 reports2 case reports

1 review

Scopus “Non steroidal anti-in�ammatory agents” AND “Acute liver failure” 30 reports3 case reports

3 reviews2 original articles

Embase “Non steroidal anti-in�ammatory agents” AND “drug-induced liver injury” 1 report 1 case report

Lilacs “Non steroidal anti-in�ammatory agents” AND “drug-induced liver injury” 5 reports3 case reports

1 letterSciELO “Drug induced liver injury” 4 reports --

CONCLUSIONSBased on the literature and the present case, until this issue has been clarified, caution is required in prescribing nime-sulide for patients within the at-risk group, including liver disease patients.

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Pharmacokinet. 1998;35(4):247-74.

2. Merlani G, Fox M, Oehen HP, et al. Fatal hepatotoxicity secondary to

nimesulide. Eur J Clin Pharmacol. 2001;57(4):321-6.

Nimesulide-induced fatal acute liver failure in an elderly woman with metastatic biliary adenocarcinoma. A case report | CASE REPORT

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3. Walker SL, Kennedy F, Niamh N, McCormick PA. Nimesulide

associated fulminant hepatic failure. Pharmacoepidemiol Drug Saf.

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acetaminophen‐induced liver injury. Hepatology. 2005;41(1):26-31.



Date of �rst submission: August 18, 2013

Last received: February 10, 2014

Accepted: March 7, 2014


Conceição Aparecida Turini

Hospital Universitário

Universidade Estadual de Londrina

Avenida Robert Koch, 60

Londrina (PR) — Brasil

CEP 86038-350

Tel./Fax. (+55 43) 3371-2422


Sao Paulo Med J. 2015; 133(4):377-80 377

CASE REPORTDOI: 10.1590/1516-3180.2013.7930003

Microcephaly-chorioretinopathy syndrome, autosomal recessive form. A case reportSíndrome de microcefalia-coriorretinopatia, forma autossômica recessiva. Um relato de casoRafael Fabiano Machado RosaI, Flávia EnkII, Korine CamargoII, Giovanni Marco TraviIII, André FreitasIII, Rosana Cardoso Manique RosaIV, Carla GraziadioV, Vinicius Freitas de MattosVI, Paulo Ricardo Gazzola ZenVII

Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.

ABSTRACTCONTEXT: The autosomal recessive form of microcephaly-chorioretinopathy syndrome is a rare genetic condition that is considered to be an important di�erential diagnosis with congenital toxoplasmosis.CASE REPORT: Our patient was a seven-year-old white boy who was initially diagnosed with congeni-tal toxoplasmosis. However, his serological tests for congenital infections, including toxoplasmosis, were negative. He was the �rst child of young, healthy and consanguineous parents (fourth-degree relatives). The parents had normal head circumferences and intelligence. The patient presented microcephaly and speci�c abnormalities of the retina, with multiple di�use oval areas of pigmentation and patches of cho-rioretinal atrophy associated with di�use pigmentation of the fundus. Ophthalmological evaluations on the parents were normal. A computed tomography scan of the child’s head showed slight dilation of lateral ventricles and basal cisterns without evidence of calci�cations. We did not �nd any lymphedema in his hands and feet. He had postnatal growth retardation, severe mental retardation and cerebral palsy. CONCLUSIONS: The �nding of chorioretinal lesions in a child with microcephaly should raise suspicions of the autosomal recessive form of microcephaly-chorioretinopathy syndrome, especially in cases with an atypical pattern of eye fundus and consanguinity. A speci�c diagnosis is essential for an appropriate clini-cal evaluation and for genetic counseling for the patients and their families.

RESUMOCONTEXTO: A forma autossômica recessiva da síndrome de microcefalia-coriorretinopatia é condição genética rara, considerada um importante diagnóstico diferencial com toxoplasmose congênita.RELATO DO CASO: O paciente era um menino branco de sete anos de idade, inicialmente diagnosti-cado com toxoplasmose congênita. No entanto, suas sorologias para infecções congênitas, incluindo a toxoplasmose, eram negativas. Ele foi o primeiro �lho de pais jovens, hígidos e consanguíneos (parentes de quarto grau). Os pais apresentavam perímetro cefálico e inteligência normais. O paciente apresentava microcefalia e anormalidades especí�cas da retina com áreas ovais de pigmentação múltiplas e difusas, além de manchas de atro�a coriorretiniana associadas à pigmentação difusa do fundo de olho. A avaliação oftalmológica dos pais foi normal. A tomogra�a computadorizada de crânio da criança mostrou discreta dilatação dos ventrículos laterais e cisternas basais, sem evidência de calci�cações. Nós não veri�camos a presença de linfedema em suas mãos e pés. Ele possuía retardo do crescimento pós-natal, de�ciência mental grave e paralisia cerebral.CONCLUSÃO: O achado de lesões coriorretinianas em uma criança com microcefalia deve aumentar a suspeita da forma autossômica recessiva da síndrome de microcefalia-coriorretinopatia, principalmente em casos com padrão atípico de fundo de olho e consanguinidade. O diagnóstico preciso é essencial para correta avaliação clínica e aconselhamento genético dos pacientes e suas famílias.

IPhD. Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.IIUndergraduate Medical Student, Universidade Luterana do Brasil (ULBRA), Canoas, Rio Grande do Sul, Brazil.IIIMD. Ophthalmologist, Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.IVMD. Pediatrician, Grupo Hospitalar Conceição (GHC), Porto Alegre, Rio Grande do Sul, Brazil.VMD. Assistant Professor of Clinical Genetics and Student in the Postgraduate Program on Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), and Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.VIMD. Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.VIIPhD. Adjunct Professor of Clinical Genetics and of the Postgraduate Program on Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), and Clinical Geneticist, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, Rio Grande do Sul, Brazil.

KEY WORDS:Microcephaly.Retina.Intellectual disability.Consanguinity.Toxoplasmosis.

PALAVRAS-CHAVE:Microcefalia.Retina.De�ciência intelectual.Consanguinidade.Toxoplasmose.

CASE REPORT | Rosa RFM, Enk F, Camargo K, Travi GM, Freitas A, Rosa RCM, Graziadio C, Mattos VF, Zen PRG

378 Sao Paulo Med J. 2015; 133(4):377-80

INTRODUCTION�e �ndings of microcephaly and chorioretinopathy in a new-born usually lead to the hypothesis of congenital infection, espe-cially in countries where some of these diseases, like toxoplasmo-sis, are prevalent.1 However, these features have been described in families presenting both autosomal dominant and recessive pat-terns of inheritance.2-4

�e aim of our report was to describe a boy who presented microcephaly-chorioretinopathy syndrome that was compatible with an autosomal recessive form. �is is a rare condition that is considered to be an important di�erential diagnosis with con-genital toxoplasmosis.

CASE REPORTOur patient was a seven-year-old white boy who was initially diagnosed with congenital toxoplasmosis. He was the �rst child of young, healthy and consanguineous parents (fourth-degree rela-tives), and had a healthy sister of three years of age (Figure 1).

�e mother had a history of one previous loss of pregnancy. She said that she had not smoked, consumed alcohol or made use of illicit drugs during the pregnancy. �e family history was negative for similar cases. �e parents had normal head circum-ferences and intelligence. �e child was born from an uneventful pregnancy, by means of cesarean delivery, at eight months of ges-tational age, weighing 2,740 g (i.e. within the range of the 50-90th percentiles), measuring 47 cm (50-98th percentiles), with head circumference of 32 cm (10-50th percentiles) and Apgar score of 9 at �ve minutes. Serological tests for congenital infections (toxo-plasmosis, rubella, cytomegalovirus, herpes simplex and syphi-lis) were negative. No lymphedema was observed in his hands and feet and the patient also did not present anemia, petechiae, maculopapular rash or jaundice.

He was hospitalized due to pneumonia on four occa-sions, the first at four months of age. At four years and seven months, his weight was 11 kg (< 3rd percentile), length 101 cm (< 3rd percentile), head circumference 42 cm (< 2nd percen-tile) and ear length 6.5 cm (> 97th percentile). He had a high arched palate, prominent large ears, pointed chin, spasticity and atrophy of the upper and lower limbs, right-side cryptor-chid testis and bilateral overlapping of the second and fourth toes over the third toes (Figure 2). In the neurological evalua-tion, he was hypertonic, presented little social interaction and had significant neuropsychomotor delay. He was not capable of supporting his head or speaking words, but he did not have seizures. A computed tomography scan of the head showed slight dilation of lateral ventricles and basal cisterns without evidence of calcifications. Electroencephalographic evalu-ation showed a cerebral pattern with little organization and subcortical paroxysms.

In an eye examination, he did not �x on or follow objects and he was unable to perform the Snellen visual acuity test. He did not have any relative a�erent pupillary defect, ocular misalignment or abnormalities in the slit-lamp examination. Signi�cant blepharitis was observed in both eyes. His pupils were isochoric and, in an eye fundus examination, peripapil-lary retinal atrophy was observed. �ere was abnormality of the peripheral retinal pigment epithelium, typical of chorioreti-nopathy, with poorly de�ned borders and little perilesional pig-mentation, along with a minor juxtapapillary lesion occupying the macula and multiple clumps of pigment spread across the retina (Figure 3). Ophthalmological assessments on his parents and sister were normal.

The radiological investigation showed microcephaly and bilateral hip dislocation. High resolution GTG-banded karyo-typing was normal (46,XY). He developed chickenpox and died as a result of complications at 11 years of age, and no elec-troretinography could be performed at that time. No autopsy was performed.

Figure 1. Pedigree of the family showing the consanguinity observed between the patient’s parents.

I

II

III

IV

V

VI

1

1

1

1

1 2

2 3

1* 2 3

4

2

2

2

*Abortion.

Microcephaly-chorioretinopathy syndrome, autosomal recessive form. A case report | CASE REPORT

Sao Paulo Med J. 2015; 133(4):377-80 379

DISCUSSIONOur patient presented microcephaly and speci� c abnormalities of the retina with multiple di� use oval areas of pigmentation and patches of chorioretinal atrophy associated with di� use pig-mentation of the fundus, and a family history of consanguinity between the parents. � e ophthalmological evaluations on these � rst-degree relatives were normal. Our patient, similar to those described by Schmidt et al.3 and Abdel-Salam et al.,5 also pre-sented postnatal growth retardation, severe mental retardation and cerebral palsy. � ese � ndings are consistent with the auto-somal recessive form of microcephaly-chorioretinopathy syn-drome (OMIM #251270).6 Lymphedema, a feature not seen in our patient, has also been described only in association with fam-ilies presenting dominant inheritance.7

In our review of the literature, using the descriptors “Microcephaly” AND “Chorioretinopathy” AND “(Autosomal Recessive)”, we found only two related articles (one case report and one original article) (Table 1).4,8 � e case report was made by Cantú et al.4 � e authors described two sisters and their brother who presented microcephaly, microphthalmia, chorio-retinal degeneration and optic atrophy. Similar to our patient, they also had delayed growth and development.4 Consanguinity, a feature seen in our family, was also suspected by Cantú et al.,4 because the parents were born in the same village and two of their grandparents had the same unusual last name. Nonetheless, the distribution of the a� ected individuals (two sisters and their brother, with una� ected parents) suggests an autosomal recessive pattern of inheritance. � e recessive form of microcephaly-chorioretinopathy syndrome is considered to be a very rare condition and has been correlated with homozygous mutations in the TUBGCP6 gene on chromosome 22q.8

� e � nding of retinal lesions in a child with microcephaly suggests the diagnosis of congenital toxoplasmosis, especially in endemic areas such as Brazil, as observed with our patient.1 If a pregnant woman acquires primary infection, Toxoplasma gondii may be transmitted to the fetus and cause in� amma-tory lesions that may lead to permanent neurological damage, including microcephaly and chorioretinopathy.1 � e chorio-retinopathy of microcephaly-chorioretinopathy syndrome is reminiscent of that associated with congenital toxoplasmosis. Because of the similarity of the � ndings, some authors have suggested the designation “pseudotoxoplasmosis” for this syn-drome.9 However, the chorioretinopathy of toxoplasmosis is more con� ned to the perimacular region and is more associated with other eye abnormalities such as microphthalmia and cata-racts, as well as intracranial calci� cations and seizures.10 � us, the chorioretinal changes present in patients with microceph-aly-chorioretinopathy syndrome di� er from the scars of toxo-plasmic chorioretinopathy because of their multiplicity and widespread localization, as observed in our patient. � e � nding

A D

B E

C F

RE LE

Figure 3. Images of the eye fundus examination showing peripapillary retinal atrophy; abnormality of the peripheral retinal pigment epithelium, typical of chorioretinopathy, with poorly de� ned borders and little perilesional pigmentation; and a minor juxtapapillary lesion occupying the macula and multiple clumps of pigment spread across the retina in the right eye (RE: right eye; LE: left eye).

Figure 2. Appearance of the patient at � ve years of age showing microcephaly, prominent large ears, pointed chin (A and B), and spasticity of upper limbs (A).

A B

in our patient of absence of immunoglobulin M (IgM)-speci� c antibodies for toxoplasmosis also help to rule out the possibility of diagnosing this congenital infection.

CASE REPORT | Rosa RFM, Enk F, Camargo K, Travi GM, Freitas A, Rosa RCM, Graziadio C, Mattos VF, Zen PRG

380 Sao Paulo Med J. 2015; 133(4):377-80

Table 1. Results obtained from each database using the descriptor of the diagnosis presented by the patient. The search in these databases was conducted on November 29, 2013

Database Search strategyResults

Found RelatedMedline (Medical Literature Analysis and Retrieval System Online; (via PubMed)

Microcephaly AND Chorioretinopathy AND (Autosomal Recessive)

3 1 case report4

Embase (via Portal da Saúde)Microcephaly AND Chorioretinopathy AND (Autosomal Recessive)

141 case report4

1 original article8

Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde; via Biblioteca Virtual em Saúde)

Microcephaly AND Chorioretinopathy AND (Autosomal Recessive)

0 0

SciELO (Scienti�c Electronic Library Online)Microcephaly AND Chorioretinopathy AND (Autosomal Recessive)

0 0

CONCLUSIONS�us, the �nding of chorioretinal lesions in a child with micro-cephaly should also raise suspicions of the autosomal recessive form of microcephaly-chorioretinopathy syndrome, especially in cases with an atypical pattern of eye fundus and family history of consanguinity. �is is essential for an appropriate clinical evalua-tion and for genetic counseling for the patients and their families.

REFERENCES1. Petersen E. Toxoplasmosis. Semin Fetal Neonatal Med. 2007;

12(3):214-23.

2. McKusick VA, Stau�er M, Knox L, Clark DB. Chorioretinopathy with

hereditary microcephaly. Arch Ophthalmol. 1966;75(5):597-600.

3. Schmidt B, Jaeger W, Neubauer H. Ein Mikrozephalie-Syndrom mit

atypischer tapetoretinaler degeneration bei 3 Geschwistern [A

microcephalic syndrome with atypical tapetoretinal degeneration in

3 siblings]. Klin Monbl Augenheilkd. 1967;150(2):188-96.

4. Cantú JM, Rojas JA, García-Cruz D, et al. Autosomal recessive

microcephaly associated with chorioretinopathy. Hum Genet.

1977;36(2):243-7.

5. Abdel-Salam GM, Czeizel AE, Vogt G, Imre L. Microcephaly with

chorioretinal dysplasia: characteristic facial features. Am J Med Genet.

2000;95(5):513-5.

6. Microcephaly and chorioretinopathy with or without mental

retardation, autosomal recessive. OMIM®. Online Mendelian

Inheritance in Man®. Available from: http://www.omim.org/

entry/251270?search=microcephaly%20chorioretinopathy%20

recessive&highlight=microcephaly%20chorioretinopathy%20

recessive. Accessed in 2014 (May 15).

7. Casteels I, Devriendt K, Van Cleynenbreugel H, et al. Autosomal

dominant microcephaly--lymphoedema-chorioretinal dysplasia

syndrome. Br J Ophthalmol. 2001;85(4):499-500.

8. Pu�enberger EG, Jinks RN, Sougnez C, et al. Genetic mapping and

exome sequencing identify variants associated with �ve novel

diseases. PLoS One. 2012;7(1):e28936.

9. McKusick VA. Mendelian Inheritance in Man. 11th ed. Baltimore: Johns

Hopkins University Press; 1994.

10. Kodjikian L, Wallon M, Fleury J, et al. Ocular manifestations in

congenital toxoplasmosis. Graefes Arch Clin Exp Ophthalmol.

2006;244(1):14-21.





Accepted: June 3, 2014


Rafael Fabiano Machado Rosa

Genética Clínica — Universidade Federal de Ciências da Saúde de Porto

Alegre (UFCSPA)

Rua Sarmento Leite, 245/403

Centro — Porto Alegre (RS) — Brasil

CEP 90050-170

Tel. (+55 51) 3303-8771

Fax. (+55 51) 3303-8810


Sao Paulo Med J. 2015; 133(4):381-2 381

LETTER TO THE EDITORDOI: 10.1590/1516-3180.2015.00301103

Possible implication of vagal nerve stimulation for treating refractory psoriasisPossível implicação da estimulação do nervo vagal para o tratamento da psoríase refratáriaNima DerakhshanI, Mahboubeh KazemiII

Shiraz University of Medical Sciences, Shiraz, Iran

Psoriasis is a chronic, relapsing, immune-based skin disease that a�ects an estimated 1-3% of the world’s population.1 �ere is no consensus regarding the exact etiology of psoriasis; among several postulated pathophysiological causes, excessive activity of T cell-mediated immune response, and T-helper (�) in particular, is the most accepted theory. �is is supported by increased levels of pro-in�ammatory cytokines, especially tumor necrosis factor (TNF-α) in the serum, skin lesions and joints of these patients.2,3

Although inhibitors of tumor necrosis factor (TNF-α) have been shown to be e�ective for treating refractory psoriasis,3,4 there are no therapies providing long-lasting remission for these patients.

Since Tracey5 proposed the so-called in�ammatory re�ex, the data now emerging has been elucidating and supporting the existence of a neural circuit that modulates immune response. �is cholinergic anti-in�ammatory pathway originates from e�erent vagal �bers. It seems that inhibition of TNF-α production in the spleen following vagal nerve stimulation occurs through acetylcholine signaling via the α7 nicotinic acetylcholine receptor that is expressed on cytokine-producing macrophages.5,6 �is signal is relayed through an acetylcholine-producing, memory phenotype T cell population that has been identi�ed in mice, which is necessary for inhibition of cytokine production through vagus nerve stimulation.7

Immunomodulation via vagal nerve stimulation has been implicated in the treatment of other immune disorders involving the TNF-α pathway, such as in�ammatory bowel disease.8 In this regard, we support the hypothesis that vagal nerve stimulation may prove useful for treating refractory psoriasis and psoriatic arthritis through its cholinergic anti-in�ammatory e�ects, by means of modulating TNF-α production.9

�is novel idea encourages interest in conducting a double-blind case-control study to inves-tigate the possible role of vagal nerve stimulation in treating psoriasis and psoriatic arthritis.

IMD. Resident in Neurosurgery, Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.IIMD. Obstetrician and Gynecologist, Department of Gynecology and Obstetrics, Shiraz University of Medical Sciences, Shiraz, Iran.

LETTER TO THE EDITOR | Derakhshan N, Kazemi M

382 Sao Paulo Med J. 2015; 133(4):381-2

REFERENCES1. Derakhshan N. NFκB inhibitors as a potential novel hypothesized

treatment for psoriasis. Sao Paulo Med J. 2011;129(6):433-4.

2. Zaba LC, Cardinale I, Gilleaudeau P, et al. Amelioration of epidermal

hyperplasia by TNF inhibition is associated with reduced Th17

responses. J Exp Med. 2007;204(13):3183-94.

3. Tobin AM, Kirby B. TNF alpha inhibitors in the treatment of psoriasis

and psoriatic arthritis. BioDrugs. 2005;19(1):47-57.

4. Kircik LH, Del Rosso JQ. Anti-TNF agents for the treatment of psoriasis.

J Drugs Dermatol. 2009;8(6):546-59.

5. Tracey KJ. Re�ex control of immunity. Nat Rev Immunol. 2009;9(6):418-28.

6. Pavlov VA, Tracey KJ. The cholinergic anti-in�ammatory pathway.

Brain Behav Immun. 2005;19(6):493-9.

7. Rosas-Ballina M, Olofsson PS, Ochani M, et al. Acetylcholine-

synthesizing T cells relay neural signals in a vagus nerve circuit.

Science. 2011;334(6052):98-101.

8. Meregnani J, Clarençon D, Vivier M, et al. Anti-in�ammatory e�ect

of vagus nerve stimulation in a rat model of in�ammatory bowel

disease. Auton Neurosci. 2011;160(1-2):82-9.

9. Das UN. Can vagus nerve stimulation halt or ameliorate rheumatoid

arthritis and lupus? Lipids Health Dis. 2011;10:19.





Accepted: March 11, 2015


Nima Derakhshan, M.D

Resident of Neurosurgery

Neuroscience Research Center, Department of Neurosurgery,

Shiraz University of Medical Sciences

Chamran Hospital — Chamran Avenue — Shiraz — Iran

Postal Code: 7194815644

Tel/Fax. + 98-711-6234508

Cellphone. +98-917-7161290


Sao Paulo Med J. 2015; 133(4):383 383

COCHRANE HIGHLIGHTSDOI: 10.1590/1516-3180.20151334T1

Antiviral treatment for Bell’s palsy (idiopathic facial paralysis)

This is the abstract of a Cochrane Systematic Review published in Cochrane Database of Systematic Reviews 2015, issue 5. Art. No.: CD001869. DOI: 10.1002/14651858.CD001869.pub5. For full text and details about authors, see reference 1.

Ildiko Gagyor, Vishnu B. Madhok, Fergus Daly, Dhruvashree Somasundara, Michael Sullivan, Fiona Gammie, Frank Sullivan

The independent commentary was written by Osvaldo Massaiti Takayanagui

ABSTRACTBACKGROUND: Corticosteroids are widely used in the treatment of id-iopathic facial paralysis (Bell’s palsy), but the e�ectiveness of additional treatment with an antiviral agent is uncertain. Signi�cant morbidity can be associated with severe cases of Bell’s palsy.OBJECTIVES: To assess the e�ects of antiviral treatments alone or in combination with any other therapy for Bell’s palsy.METHODS:Search methods: On 7 October 2014 we searched the Cochrane Neu-romuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, DARE, NHS EED, and HTA. We also reviewed the bibli-ographies of the identi�ed trials and contacted trial authors and known experts in the �eld and relevant drug companies to identify additional published or unpublished data. We searched clinical trials registries for ongoing studies.Selection criteria: We considered randomised controlled trials or quasi-randomised controlled trials of antivirals with and without cor-ticosteroids versus control therapies for the treatment of Bell’s palsy. We excluded trials that had a high risk of bias in several domains.Data collection and analysis: Pairs of authors independently assessed tri-als for relevance, eligibility, and risk of bias, using standard Cochrane procedures.MAIN RESULTS: Eleven trials, including 2883 participants, met the inclu-sion criteria and are included in the �nal analysis. We added four studies to the previous review for this update. Some of the trials were small, and a number were at high or unclear risk of bias. Other trials did not meet current best standards in allocation concealment and blinding.Incomplete recovery: We found no signi�cant bene�t from adding an-tivirals to corticosteroids in comparison with corticosteroids alone for people with Bell’s palsy (risk ratio (RR) 0.69, 95% con�dence interval (CI) 0.47 to 1.02, n = 1715). For people with severe Bell’s palsy (House Brack-mann scores of 5 and 6 or the equivalent in other scales), we found a reduction in the rate of incomplete recovery at month six when antivi-rals plus corticosteroids were used (RR 0.64, 95% CI 0.41 to 0.99, n = 478). The outcome for the participants receiving corticosteroids alone was signi�cantly better than for those receiving antivirals alone (RR 2.09, 95% CI 1.36 to 3.20, n = 1169). The treatment e�ect of placebo was sig-ni�cantly lower than that of antivirals plus corticosteroids (RR 0.56, 95% CI 0.41 to 0.76, n = 658). Antivirals alone had a non-signi�cant detrimen-tal e�ect on the outcome compared with placebo (RR 1.10, 95% CI 0.87 to 1.40, n = 658).

Motor synkinesis or crocodile tears: In three trials comparing antivirals and corticosteroids with corticosteroids and placebo that assessed this out-come, we found a signi�cant di�erence in long-term sequelae in favour or antivirals plus corticosteroids (RR 0.73, 95% CI 0.54 to 0.99, n = 869). Three trials comparing antivirals alone with corticosteroids alone in-vestigating this outcome showed fewer sequelae with corticosteroids (RR 1.44, 95% CI 1.11 to 1.85, n = 873). We found no data on long-term sequelae for other comparisons.Adverse events: Adverse event data were available in three studies giving comparison data on 1528 participants. None of the four comparisons (antivirals plus corticosteroids versus corticosteroids plus placebo or no treatment; antivirals versus corticosteroids; antivirals plus corticosteroids versus placebo; antivirals versus placebo) showed signi�cant di�erences in adverse events between treatment and control arms. We could �nd no correlation with speci�c treatment within these results.AUTHORS’ CONCLUSIONS: Moderate-quality evidence from ran-domised controlled trials showed no additional bene�t from the combination of antivirals with corticosteroids compared to cortico-steroids alone or with placebo, and no bene�t from antivirals alone compared to placebo, for the treatment of Bell’s palsy. Moderate-quali-ty evidence showed a small but just signi�cant bene�t of combination therapy compared with corticosteroids alone in severe Bell’s palsy. We found no signi�cant increase in adverse events from the use of anti-virals compared with either placebo or corticosteroids.

The full text of this review is available free of charge from: http://onlineli-brary.wiley.com/doi/10.1002/14651858.CD001869.pub5/pdf/abstract.

REFERENCE1. Gagyor I, Madhok VB, Daly F, et al. Antiviral treatment for Bell’s

palsy (idiopathic facial paralysis). Cochrane Database Syst Rev.

2015;CD001869.

COMMENTS Con�icting results with regard to the bene�t of antiviral therapy combined with steroids for medical treatment of Bell’s palsy have been obtained. This meta-analysis showed that there was no bene�t from combining antivirals with corticosteroids, in comparison with cor-ticosteroids alone or with placebo, and no bene�t from antivirals alone compared with placebo. Therefore, this study does not support routine addition of antivirals to steroids for treating Bell’s palsy.

Osvaldo Massaiti Takayanagui. Titular Professor, Department of Neu-roscience and Behavioral Science, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), São Paulo, Brazil.

384 Sao Paulo Med J. 2015; 133(4):384

COCHRANE HIGHLIGHTS DOI: 10.1590/1516-3180.20151334T2

In�uenza vaccines for preventing cardiovascular disease

This is the abstract of a Cochrane Systematic Review published in Cochrane Database of Systematic Reviews (CDSR) 2015, issue 5. Art. No.: CD005050. DOI: 10.1002/14651858.CD005050.pub3. For full cita-tion and authors’ details, see reference 1.

Christine Clar, Zainab Oseni, Nadine Flowers, Maryam Keshtkar-Jahromi, Karen Rees

The independent commentary was written by Juvencio José Duailibe Furtado

ABSTRACTBACKGROUND: This is an update of the original review published in 2008. The risk of adverse cardiovascular outcomes is increased with in�uenza-like infection, and vaccination against in�uenza may improve cardiovascular outcomes.OBJECTIVES: To assess the potential bene�ts of in�uenza vaccination for primary and secondary prevention of cardiovascular disease.METHODS:Search methods: We searched the following electronic databases on 18 October 2013: The Cochrane Library (including Cochrane Central Reg-ister of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of E�ects (DARE), Economic Evaluation Database (EED) and Health Tech-nology Assessment database (HTA)), MEDLINE, EMBASE, Science Cita-tion Index Expanded, Conference Proceedings Citation Index – Science and ongoing trials registers (www.controlled-trials.com/ and www.clini-caltrials.gov). We examined reference lists of relevant primary studies and systematic reviews. We performed a limited PubMed search on 20 February 2015, just before publication.Selection criteria: Randomised controlled trials (RCTs) of in�uenza vac-cination compared with placebo or no treatment in participants with or without cardiovascular disease, assessing cardiovascular death or non-fatal cardiovascular events.Data collection and analysis: We used standard methodological pro-cedures as expected by The Cochrane Collaboration. We carried out meta-analyses only for cardiovascular death, as other outcomes were reported too infrequently. We expressed e�ect sizes as risk ratios (RRs), and we used random-e�ects models.MAIN RESULTS: We included eight trials of in�uenza vaccination com-pared with placebo or no vaccination, with 12,029 participants receiv-ing at least one vaccination or control treatment. We included six new studies (n = 11,251), in addition to the two included in the previous version of the review. Four of these trials (n = 10,347) focused on pre-vention of in�uenza in the general or elderly population and reported cardiovascular outcomes among their safety analyses; four trials (n = 1682) focused on prevention of cardiovascular events in patients with established coronary heart disease. These populations were analysed separately. Follow-up continued between 42 days and one year. Five RCTs showed de�cits in at least three of the risk of bias criteria assessed. When reported (seven studies), vaccination provided adequate immu-nogenicity or protection against in�uenza. Cardiovascular mortality was reported by four secondary prevention trials and was signi�cantly reduced by in�uenza vaccination overall (risk ratio (RR) 0.45, 95% con�-dence interval (CI) 0.26 to 0.76; P value 0.003) with no signi�cant hetero-

geneity between studies, and by three trials reporting cardiovascular mortality as part of their safety analyses when the numbers of events were too small to permit conclusions. In studies of patients with coro-nary heart disease, composite outcomes of cardiovascular events tend-ed to be decreased with in�uenza vaccination compared with placebo. Generally no signi�cant di�erence was found between comparison groups regarding individual outcomes such as myocardial infarction.AUTHORS’ CONCLUSIONS: In patients with cardiovascular disease, in-�uenza vaccination may reduce cardiovascular mortality and combined cardiovascular events. However, studies had some risk of bias, and re-sults were not always consistent, so additional higher-quality evidence is necessary to con�rm these �ndings. Not enough evidence was avail-able to establish whether in�uenza vaccination has a role to play in the primary prevention of cardiovascular disease.

This abstract is available free of charge from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005050.pub3/abstract.

REFERENCE1. Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M, Rees K. In�uenza

vaccines for preventing cardiovascular disease. Cochrane Database

Syst. 2015;5:CD005050.

COMMENTSVaccination against the in�uenza virus is known to signi�cantly protect populations that receive it. The inclusion of this type of immunization in the Brazilian calendar had the primary objective of reducing the com-plications inherent to the disease caused by this virus. Thus, it is under-stood that individuals with chronic diseases or associated comorbidi-ties, and even pregnant women, would bene�t signi�cantly, thereby reducing complications and often death. One of the groups that would bene�t is individuals with cardiovascular diseases. Despite the hetero-geneity of the data in the review presented here, the study con�rms the principles that guided the indication of in�uenza vaccination, i.e. to re-duce mortality due to cardiovascular diseases and their complications.

Juvencio José Duailibe Furtado. Professor of Infectious Diseases at Fa-culdade de Medicina do ABC (FMABC), and Head of the Department of Infectious Diseases at Heliópolis Hospital, São Paulo (SP), Brazil.

Sao Paulo Med J. 2015; 133(4):I-V I

SÃO PAULO MEDICAL JOURNAL/EVIDENCE FOR HEALTH CARE

Indexing and scope�e São Paulo Medical Journal/Evidence for Health Care was

founded in 1932. Its articles are indexed in Medline, Lilacs, SciELO, Science Citation Index Expanded, Journal Citation Reports/Science Edition (ISI) and EBSCO Publishing.

Published bimonthly by the Associação Paulista de Medicina, the journal accepts articles in the �elds of clinical health science (internal medicine, gynecology and obstetrics, mental health, surgery, pediatrics and public health). Articles will be accepted in the form of original articles (clinical trials, cohort, case-control, prevalence, incidence, accuracy and cost-e�ectiveness studies and systematic reviews with or without meta-analysis), narrative reviews of the literature, case reports, short communi-cations and letters to the editor. Papers with a commercial objective will not be accepted.

�e Journal’s policy and proceduresA�er receipt of the article by the Scienti�c Publications Sector, the

authors will be provided with a protocol number. �is number serves to maintain good understanding between the authors and the Scien-ti�c Publications Sector. Following this, the article will be read by the Editor, who will verify whether it is consonant with the journal’s pol-icy and interests, i.e. whether the research or review is within the �elds of health or public health.

Next, the Scienti�c Publications Sector will verify whether the text complies with the journal’s Instructions for Authors. If the text is incomplete or if it is not organized as required, the authors will be asked to resubmit their text a�er resolving such problems. When its format is acceptable, the Scienti�c Publications Sector will submit the manuscript to closed peer review, in which the reviewers will not sign their verdict and will not know the names of the authors. Each paper will be reviewed by at least three reviewers: one expert in the �eld, one associate editor (who will evaluate the article from the reader’s per-spective) and one ad hoc editorial advisor (who will assess method-ological aspects of the study).

�e authors will then receive the reviewers’ evaluation and will be asked to resolve all the problems that have been pointed out. Once the Scienti�c Publications Sector receives the manuscript again, the text will be sent to the scienti�c editor and the proofreader, who will point out problems with sentence construction, spelling, grammar, bibliographical references and other matters. �e authors should then provide all further information and corrections requested and should mark in the text all the points at which modi�cations have been made, using di�erent colors or electronic text marking systems, so that these modi�cations are easy to see.

When the text is considered acceptable for publication, and only then, it will enter the queue for publication and the author will receive a letter of acceptance of the article. �e Scienti�c Publications Sector will provide a proof, including any tables and �gures, for the authors to approve. No article is published without this last procedure.

Instructions for authorsGeneral guidelines: for all types of articles Texts must be submitted exclusively through the Internet,

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�e manuscript must be submitted in English. Nonetheless, it must also include a summary and �ve key words both in Portuguese and in English. �e key words must be selected from the DeCS and MeSH lists only, as explained in detail below (no other key words will be accepted).

Papers submitted must be original and therefore all the authors need to declare that the text has not been and will not be submitted for publication in any other journal. Papers involving human beings (individually or collectively, directly or indirectly, totally or partially, including the management of information and materials) must be accompanied by a copy of the authorization from the Research Ethics Committee of the institution in which the experiment was performed.

All articles submitted must comply with the editorial standards established in the Vancouver Convention (Uniform Requirements for Manuscripts Submitted to Biomedical Journals)1 and the speci�c qual-ity guidelines for papers reporting on clinical trials (CONSORT),2 sys-tematic reviews and meta-analyses (PRISMA),3,4 observational stud-ies (STROBE)5,6 and accuracy studies on diagnostic tests (STARD).7,8

�e style known as the “Vancouver Style” is to be used not only for the format of the references, but also for the whole text. �e Editors recommend that authors should familiarize themselves with this style by accessing http://www.icmje.org.

Abbreviations must not be used, even those in common use. Drugs or medications must be referred to using their generic names, avoiding unnecessary mention of commercial or brand names, and should be followed by the dosage and posology. Any product cited in the Methods section, such as diagnostic or therapeutic equipment, tests, reagents, instruments, utensils, prostheses, orthoses and intra-operative devices must be described together with the manufactur-er’s name and place (city and country) of manufacture in parentheses.

Grants, bursaries and any other �nancial support for studies must be mentioned separately a�er the references, in a section named “Acknowledgements”, along with any other acknowledgements to individuals or professionals who have helped in producing the study but whose contribution does not constitute authorship (we recom-mend that the item “Authorship” at http://www.icmje.org should be read to obtain clari�cations regarding the criteria for authorship).

For any type of study, all statements in the text that are not results from the study presented for publication in the São Paulo Medi-cal Journal/Evidence for Health Care, but are data from other stud-ies already published elsewhere must be accompanied by citations of the pertinent literature. �us, statements about the incidence or prevalence of diseases, costs, frequency of use of certain therapies

These instructions are updated periodically. We recommend that they are consulted online at: www.scielo.br/spmj

II Sao Paulo Med J. 2015; 133(4):I-V

and epidemiological data in general should be followed by the refer-ences for the surveys that generated this information, even if the data come from government institutions or databases, given that these are data from other studies.

FormatFirst page (cover page)�e �rst page must contain: 1) the type of paper (original article, review or updating article,

short communication or letter to the editor); 2) the title of the paper in English and Portuguese, which must

be short but informative; 3) the full name of each author (the editorial policy of the São

Paulo Medical Journal is that abbreviations for authors’ names must not be used; thus, names should either be sent complete or with middle names omitted, for example: an author whose full name is John Richard Smith can be presented as John Smith or John Richard Smith, but not as John R. Smith; likewise, use Christopher Smith and not Chris Smith, or William Smith and not Bill Smith, and so on)), his/her academic titles (abbreviated in English), in the order obtained (for example: MD for medi-cal doctor, MSc for holders of a master’s title, PhD for holders of a doctorate or BSc for bachelor of science, such as in biology), and the positions currently held (for example, Doctoral Stu-dent, Attending Physician, Adjunct Professor, Associate Profes-sor, Head of Department, etc.), in the department and institu-tion where he/she works, and the city and country;

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Second page: abstract (English and Portuguese) and key words�e second page must include the title and an abstract (Eng-

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1) context and objective; 2) design (type of study) and setting (place where the study was

developed); 3) methods (described in detail);

4) results; and 5) conclusions. �e abstract (both in English and in Portuguese) should contain

�ve key words. �e English terms must be chosen from the Medical Subject Headings (MeSH) list of Index Medicus, which are available on the internet (http://www.ncbi.nlm.nih.gov/sites/entrez?db=mesh).10 �e Portuguese terms must be chosen from the Descritores em Ciên-cias da Saúde (DeCS), developed by Bireme, which are available on the internet (http://decs.bvs.br/).11

References�e list of references (in the “Vancouver style”, as indicated by the

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In the list of references, all the authors must be listed if there are up to and including �ve authors; if there are six or more, the �rst three should be cited, followed by the expression “et al.” For books, the city of publication and the name of the publishing house are mandatory. For texts published on the internet, the complete uniform resource locator (URL) or address is necessary (not only the main home page of a website or link), so that by copying the complete address into their computer internet browsers, the journal’s readers will be taken to the exact document cited, and not to a general website. �e following are some examples of the most common types of references:

Article in journal- Hurt AC, Hardie K, Wilson NJ, et al. Community transmis-

sion of oseltamivir-resistant A(H1N1)pdm09 in�uenza. N Engl J Med. 2011;365(26):2541-2.

Chapter of book- Miller WI, Achernabb JC, Fluck CE. �e adrenal cortex and

its disorder. In: Sperling M. Pediatric endocrinology. 3rd ed. Elsevier Health Sciences; 2008. p. 444-511.

Text on the internet- Centers for Disease Control and Prevention. Children’s food

environment State Indicator Report, 2011. Available from: http://www.cdc.gov/obesity/downloads/ChildrensFoodEnvi-ronment.pdf. Accessed in 2012 (Mar 7).

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Sao Paulo Med J. 2015; 133(4):I-V III

Microso� Word �le, the images should also be sent separately. Graphs must be prepared in Microso� Excel (do not send them in image for-mats) and must be accompanied by the tables of data from which they have been generated. �e number of illustrations must not exceed the total number of pages minus one.

All �gures and tables must contain legends or titles that precisely describe their content and the context or sample from which the infor-mation was obtained (i.e. what the results presented are and what the kind of sample or setting was). �e legend or title sentence should be short but comprehensible without depending on reading the article.

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Original articles Clinical trials, cohort, case-control, prevalence, incidence, accu-

racy and cost-e�ectiveness studies, and systematic reviews with or without meta-analysis, are considered to be original articles.

The São Paulo Medical Journal/Evidence for Health Care sup-ports the clinical trial registration policies of the World Health Organization (WHO) and the International Committee of Med-ical Journal Editors (ICMJE) and recognizes the importance of these initiatives for registration and international dissemination of information on randomized clinical trials, with open access. Thus, from 2008 onwards, manuscripts on clinical trials have been accepted for publication only if they have received an identifica-tion number from one of the clinical trial registers that have been validated in accordance with the criteria established by WHO and ICMJE. Authors of randomized clinical trials must thus register their studies before submitting them for publication in the São Paulo Medical Journal/Evidence for Health Care. The addresses for these registers are available from the ICMJE website (http://www.icmje.org). The identification number should be declared at the end of the abstract.

Authors will be required to comply with the guidelines for writing each type of original article, as follows:

1. Observational articles: STROBE Statement;5,6 2. Clinical trials: CONSORT Statement;2

3. Accuracy studies on diagnostic tests: STARD Statement;7,8 4. Systematic reviews of the literature and meta-analyses:

PRISMA4

�e São Paulo Medical Journal takes the view that these guide-lines not only aid in writing and organizing the content of articles in a standardized manner, thereby improving their quality and facilitat-ing reading and assessment, but also these guidelines help to avoid

situations in which important information on the methodology of studies remains outside of the manuscript.

As a partner institution of the Cochrane Collaboration and the Brazilian Cochrane Center, the Associação Paulista de Medicina con-siders that production of articles in accordance with these guidelines also aids in future production of systematic reviews of the literature and meta-analyses. �us, articles submitted for publication that are not in accordance with these norms may be returned to their authors for adjustment before the peer review process begins.

Original articles must be structured so as to contain the follow-ing parts: Introduction, Objective, Methods, Results, Discussion and Conclusion. �e text must not exceed 5,000 words (excluding tables, �gures and references), from the introduction to the end of the con-clusion, and must include a structured abstract with a maximum of 250 words.9 “Structured abstract” means that the abstract must con-tain the following items: Context and objective, Design and setting, Method, Results and Conclusion.

�e structure of the document should follow the format laid out below:1) Title and abstract: the study design and/or the way partici-

pants were allocated to interventions, for example “random-ized” or “retrospective” study, should be mentioned in the title and in the abstract. �e abstract should provide a summary of what was done and what was found.

2) Introduction: specify the reasons for carrying out the study, describing the present state of knowledge of the topic. Describe the scienti�c background and “the state of the art”. Do not include here any results or conclusions from the study. Use the last paragraph to specify the principal question of the study, and the principal hypothesis tested, if there is one. Do not include discussions about the literature in the introduc-tion; the introduction section should be short.

3) Objective: describe brie�y what the main objective or ques-tion of the study was. Clearly describe the pre-speci�ed hypotheses.

4) Methods4.1) Type of study: describe the design of the study and specify,

if appropriate, the type of randomization (the way in which draws were conducted), the blinding (how this was ensured), the diagnostic test standards (gold standard or range of nor-mal values) and the time direction (retrospective or prospec-tive). For example: “randomized clinical trial”, “double-blind placebo-controlled clinical trial”, “cross-sectional accuracy study”, “retrospective cohort study”, “cross-sectional preva-lence study” or “systematic review of clinical trials”.

4.2) Sample, participants or patients: describe the eligibility cri-teria for participants (inclusion and exclusion criteria) and the sources and procedures for selection or recruitment. In case-control studies, describe the rationale for distributing the subjects as cases and controls, and the matching crite-ria. �e numbers of patients at the beginning and end of


IV Sao Paulo Med J. 2015; 133(4):I-V

the study (a�er exclusions) must be made clear. A �ow dia-gram showing the initial recruitment, the exclusions and the �nal sample of patients included should be produced and inserted in the article.

4.3) Setting: indicate the place where the study was carried out, including the type of healthcare provided (i.e. whether pri-mary or tertiary; and whether in a private or in a public hospi-tal). Avoid stating the name of the institution where the study was developed (for blinding purposes in the peer review). Only the type of institution should be made clear, for exam-ple: “public university hospital” or “private clinic”.

4.4) Procedures (intervention, diagnostic test or exposure): describe the principal characteristics of any intervention, including the method, the timing and the duration of its administration or of data collection. Describe the di�erences in interventions administered to each group (if the study is controlled). Detail the procedures in such a way that other researchers will be able to repeat them in other localities.

4.5) Main measurements, variables and outcome: state what the primary and secondary outcomes analyzed in the study are. Describe the method of measuring the primary result, in the way in which it was planned before data collection. For each variable of interest, detail the assessment methods. If the hypothesis of the study was formulated during or a�er data collection (and not before), this needs to be declared. Describe the methods used to enhance the quality of meas-urements (for example, multiple observers, training, etc.) and to avoid bias. Explain how quantitative variables were handled in the analyses.

4.6) Sample size and statistical analysis: describe the sample size calculation method, or the study period in the event that patients were consecutively admitted over a period. Read-ers need to understand why a given number of patients was used. �e planned statistical analysis, the statistical tests used and their signi�cance levels, along with any post hoc analy-ses, should be presented in this section. Describe the meth-ods used to control for confounding factors and variables, and explain how missing data and cases lost from the follow-up were dealt with.

4.7) Randomization: describe the method used to implement the random allocation sequence (for example, sealed envelopes containing random sequences of numbers or so�ware for generating random numbers). If appropriate, report that the study used “quasi-randomization”.12 In addition, describe who generated the random sequence, who assigned the partici-pants to each group (in the case of controlled trials) and who recruited the participants.

5) Results: describe the main �ndings. If possible, these should be accompanied by their 95% con�dence intervals and the exact level of statistical signi�cance (it is not enough to write

“P < 0.05”: the exact P value should be supplied). For com-parative studies, the con�dence interval must be stated for the di�erences between the groups.

5.1) Participant �ow diagram: describe the �ow of participants through each stage of the study (inclusions and exclusions) and the follow-up period, and the number of participants completing the study (or lost from the follow-up). Use a �ow diagram to demonstrate the numbers of patients, from the initial recruitment to the end of the study, and the reasons for exclusions. If there was any “intention-to-treat” analysis, describe it.

5.2) Deviations: if there was any deviation from the protocol, away from what was initially planned, describe it and the reasons for it.

5.3) Adverse events: describe any side e�ect, adverse event or complication.

6) Discussion: provide an interpretation of the results, tak-ing into account the study hypotheses and conclusions. Emphasize the new and important factors encountered in the study, which will form part of the conclusion. Do not repeat data presented in the introduction or results in detail. Mention any limitations of the findings that should be noted and any possible implications for future research. Describe any potential bias. Report any relevant findings from other studies: it is important to review the recent literature to seek new evidence that may have been pub-lished, which needs to be discussed. State whether the find-ings can be generalized to populations (i.e. whether the findings have external validity). It is recommended that the last two paragraphs should contain implications for prac-tice and for further research.

7) Conclusions: specify only the conclusions that can be sus-tained by the results, together with their clinical signi�cance (avoiding excessive generalization). Draw conclusions based on the objectives and hypotheses of the study. �e same emphasis should be placed on studies with positive and nega-tive results.

Systematic reviews with or without meta-analyses should comply with the same publication norms established for original articles, and be produced in accordance with PRISMA4 and the Cochrane Collab-oration’s systematic review Handbook.13 �e text should not exceed 5,000 words (excluding tables, �gures and references)

Short communications, case reports or case series Short communications and case reports must be limited to 3,000

words (from the introduction to the end of the conclusion). Short com-munications are reports on the results from ongoing studies or stud-ies that have recently been concluded for which urgent publication is important. �ey should be structured thus: Introduction, Objective, Methods, Results, Discussion and Conclusion, like in original articles.


Sao Paulo Med J. 2015; 133(4):I-V V

Individual case reports should contain: Introduction, Case Report, Dis-cussion and Conclusion. Reports on case series constitute observational studies and these should be structured in accordance with the norms of the STROBE Statement.5

Both short communications and case reports must be submitted with abstracts and key words. �e abstracts in short communications should be structured with: Context and objective, Design and set-ting, Methods, Results and Conclusion, like in original articles. �e abstracts in case reports and case series should contain: Context, Case Report (with a description of the case and a pertinent discussion) and Conclusion.

�e São Paulo Medical Journal/Evidence for Health Care is inter-ested in publishing rare or instructive case reports, accompanied by a systematic search of the literature, in which relevant studies found (based on their level of evidence) are presented and discussed.14 �e results from the systematic search of the main databases — Medline (via PubMed), Embase, Lilacs and Cochrane Library — should be presented in a table with the search strategy for each database and the number of articles obtained.

Narrative reviewsNarrative reviews may be accepted by the São Paulo Medical Jour-

nal/Evidence for Health Care and should be structured with: Intro-duction, Objectives, Methods, Results, Discussion and Conclusions. �e abstract must be structured with: Context and objective, Design and setting, Methods, Results and Conclusions, like in original arti-cles. �e manuscript must comply with the norms of the Vancouver style1 and must include a systematic search in the main databases: Medline, Embase, Lilacs and Cochrane Library. �e search strat-egy for each database and the number of articles obtained from each database should be presented in a table. �e access route to the elec-tronic databases used should be stated (for example, PubMed, OVID, Elsevier or Bireme). For the search strategies, MeSH terms must be use for Medline, LILACS and Cochrane Library. DeCS terms must be used for LILACS. EMTREE terms must be used for Embase. Also, for LILACS, search strategy must be performed, at the same time, with English (MeSH), Spanish (DeCS) and Portuguese (DeCS) terms. �e search strategies must be presented exactly as they were used dur-ing the search, including parentheses, quotation marks and Boolean operators (AND, OR, AND NOT).

Letters to the editorLetters to the editor may address articles published in the São

Paulo Medical Journal/Evidence for Health Care publication or may deal with health issues of interest. Case reports must not be submit-ted as letters. In the category of letters to the editor, the text has a free format, but must not exceed 500 words and �ve references.

Documents cited1. Internal Committee of Medical Journal Editors. Uniform requirements for

manuscripts submitted to biomedical journals, writing and editing for

biomedical publications. Available from: http://www.icmje.org. Accessed

in 2012 (Aug 6).

2. The CONSORT Statement. Available from: http://www.consort-statement.

org/consort-statement/. Accessed in 2012 (Aug 6).

3. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of

meta-analyses of randomised controlled trials: the QUOROM statement.

Lancet. 1999;354(9193):1896-900. Available from: http://www.thelancet.

com/journals/lancet/article/PIIS0140-6736(99)04149-5/abstract. Accessed

in 2012 (Aug 6).

4. PRISMA. Transparent Reporting of Systematic Reviews and Meta-Analyses.

Available from: http://www.prisma-statement.org/index.htm. Accessed in

2012 (Aug 6).

5. STROBE Statement. Strengthening the reporting of observational studies

in epidemiology. What is strobe? Available from: http://www.strobe-

statement.org/. Accessed in 2012 (Aug 6).

6. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting

of Observational Studies in Epidemiology (STROBE) statement:

guidelines for reporting observational studies. J Clin Epidemiol.

2008;61(4):344-9.

7. STARD Statement. STAndards for the Reporting of Diagnostic accuracy

studies. Available from: http://www.stard-statement.org/. Accessed in

2012 (Aug 6).

8. Rennie D. Improving reports of studies of diagnostic tests: the STARD

initiative. JAMA. 2003;289(1):89-90.

9. Haynes RB, Mulrow CD, Huth EJ, Altman DG,

Gardner MJ. More informative abstracts revisited. Ann Intern Med.

1990;113(1):69-76.

10. National Library of Medicine. Medical Subject Headings: annotated

alphabetic list. Bethesda: NLM; 1998. Available from: http://www.

ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=mesh. Accessed in 2012

(Aug 6).

11. BVS Biblioteca Virtual em Saúde. Descritores em Ciências da Saúde.

Available from: http://decs.bvs.br/. Accessed in 2012 (Aug 6).

12. Reeves BC, Deeks JJ, Higgins JPT, Wells GA. Including non-randomized

studies. In: Cochrane Non-Randomised Studies Methods Group. The

Cochrane Book Series. England: John Wiley & Sons; 2008. Available from:

http://hiv.cochrane.org/sites/hiv.cochrane.org/�les/uploads/Ch13_NRS.

pdf. Accessed in 2012 (Aug 6).

13. The Cochrane Collaboration. Cochrane Handbook for Systematic Reviews

of Interventions. Available from: http://www.cochrane.org/training/

cochrane-handbook/. Accessed in 2012 (Aug 6).

14. Phillips B, Ball C, Sackett D, et al. Oxford Centre for Evidence-based

Medicine Levels of Evidence (May 2001). Available from: http://www.

cebm.net/index.aspx?o=1047. Accessed in 2012 (Aug 6).

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