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INDEX Editorial

131 Willingness to pay... What??? Alessandro Wasum Mariani, Paulo Manuel Pêgo-Fernandes

Original article

133 Carotid body tumor: retrospective analysis on 22 patients André Luís Maion Casarim, Alfio José Tincani, André Del Negro, Camila Guimarães Aguiar, Renato Ventura Fanni, Antonio Santos Martins 140 Anemia in inflammatory bowel disease: prevalence, differential diagnosis and association with clinical and laboratory variables Rodrigo Andrade Alves, Sender Jankiel Miszputen, Maria Stella Figueiredo 147 Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study Thaiana Aragão Santana, Felipe Melo Cruz, Damila Cristina Trufelli, João Glasberg, Auro Del Giglio 152 Prevalence of risk factors for stuttering among boys: analytical cross-sectional study Cristiane Moço Canhetti Oliveira, Paula Roberta Nogueira 158 Genetic diversity among volunteer donors of bone marrow in southeastern Brazil, according to the HLA system Letícia Sarni Roque, Rodolpho Telarolli Junior, Leonor Castro Monteiro Loffredo 163 Translation and cross-cultural adaptation of the Scleroderma Health Assessment Questionnaire to Brazilian Portuguese Aline Cristina Orlandi, Fernanda Pontes Cardoso, Lucas Macedo Santos, Vaneska da Graça Cruz, Anamaria Jones, Cristiane Kyser, Jamil Natour

Short communication

170 Methods of cognitive function investigation in the Longitudinal Study on Adult Health (ELSA-Brasil) Valéria Maria de Azeredo Passos, Paulo Caramelli, Isabella Benseñor, Luana Giatti, Sandhi Maria Barreto 178 Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement Pedro Domingues Goi, Julia Domingues Goi, Kariny Larissa Cordini, Keila Mendes Ceresér, Neusa Sica da Rocha

Case report

184 Hemorrhagic shock secondary to button battery ingestion Naomi Andreia Takesaki, Marcelo Conrado dos Reis, Maria Luisa Ferreira de Miranda, Emílio Carlos Elias Baracat

Letter to editor

189 A medical illusion from Pinocchio José Baddini-Martinez 191 Effects of underwater birth on the newborn Slobodan Sekulic

Cochrane highlights

193 Physical training for asthma Kristin V. Carson, Madhu G. Chandratilleke, Joanna Picot, Malcom P. Brinn, Adrian J. Esterman A., Brian J. Smith Comments: Mônica Corso Pereira 195 Exercise programs for people with dementia Dorothy Forbes, Emily J. Thiessen, Catherine M. Blake, Scott S. Forbes, Sean Forbes Comments: Maysa Seabra Cendoroglo Correspondence to:

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EDITORIAL

DOI: 10.1590/1516-3180.2014.1323844

Willingness to pay... What??? Vontade de pagar… O quê??? Alessandro Wasum MarianiI, Paulo Manuel Pêgo-FernandesII Instituto do Coração (InCor), Hospital das Clínicas (HC), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

MD. Thoracic Surgeon, Instituto do Coração (InCor), Hospital das Clínicas (HC), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.

I

II MD, PhD. Associate Professor, Discipline of Thoracic Surgery, Instituto do Coração (InCor), Hospital das Clínicas (HC), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.

Willingness to pay is a term used in economics, which can be defined as the maximum amount a person would be prepared to pay, sacrifice or exchange in order to receive goods or services or to avoid something that is undesired. It can be used in medicine as a method for assessing the value of health benefits in a cost-benefit analysis. One indication of the importance of this concept is the progressive appearance of this term in the National Institutes of Health’s PubMed database. The first appearance was in 1972, but it then remained uncommon, with less than 10 mentions per year until the 1990s. From 2000 to 2010, the numbers of appearances of this term grew from 69 times a year to 213 times a year. In 2013, this term appeared 355 times in the PubMed database. The greatest usages of willingness to pay within medicine are in Pharmacoeconomics and Health Economics. Nonetheless, this term can be a valuable addition within any field in which cost-benefit analysis is desired. Examples of this usage in 2013, retrieved from PubMed, include: a) Patients’ willingness to pay for Alzheimer’s disease medication in Canada.1 b) Parent preference in Switzerland for easy-to-use attributes of growth hormone injection devices quantified according to willingness to pay.2 c) Willingness to pay for anterior cruciate ligament reconstruction.3 Some authors have taken the view that willingness to pay is a valuable tool in performing cost-benefit analysis for evaluating new healthcare interventions. One of the advantages of willingness to pay is its relative simplicity, given that it can be ascertained through a simple survey.4 In 2001, Olsen and Smith published a paper on a major review in which 71 willingnessto-pay surveys relating to healthcare that had been published in English between 1985 and 1998 were gathered together. The authors’ aim was to evaluate willingness to pay against another tool (quality-adjusted life-years) as a measurement of the benefit of healthcare programs. According to these authors, the most important argument for using willingness to pay was that it enabled a more comprehensive valuation of benefits than was possible with quality-adjusted life-years.5 However, not all authors have agreed regarding the validity and usefulness of willingness to pay. Burrows and Brown6 defended the position that willingness-to-pay analysis can produce widely varying values. They emphasized that there are too few studies to validate the technique, and that the methodologies for eliciting values are underdeveloped. In the conclusion of their paper, they stated: “until its validity has been established, willingness to pay must be rejected as a measure of economic value”.6 We can conclude that willingness to pay is an interesting concept that may be very helpful in defining the directions of healthcare policies, especially with regard to publicly-funded healthcare. However, like any other research tool, it has limitations. Better understanding of the willingness-to-pay concept, among medical researchers, can be profitable for all of society.

Sao Paulo Med J. 2014; 132(3):131-2

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EDITORIAL | Mariani AW, Pêgo-Fernandes PM

REFERENCES

Sources of funding: None

1. Oremus M, Tarride JE, Pullenayegum E, et al. Patients’ willingness-

Conflict of interest: None

to-pay for an Alzheimer’s disease medication in Canada. Patient. 2013;6(3):161-8. 2. Meinhardt U, Eiholzer U, Seitz L, Bøgelund M, Kappelgaard AM. Parent preference in Switzerland for easy-to-use attributes of growth

Date of first submission: February 19, 2014 Last received: March 24, 2014 Accepted: March 25, 2014

hormone injection devices quantified by willingness to pay. Expert Rev Med Devices. 2014;11(1):31-8. 3. Hall MP, Chiang-Colvin AS, Bosco JA 3rd. Willingness to pay for

Alessandro Wasum Mariani

anterior cruciate ligament reconstruction. Bull Hosp Jt Dis (2013).

Rua Treze de Maio, 1.217 — apto 31

2013;71(3):218-21.

Bela Vista — São Paulo (SP) — Brasil

4. Bala MV, Mauskopf JA, Wood LL. Willingness to pay as a measure of health benefits. Pharmacoeconomics. 1999;15(1):9-18. 5. Olsen JA, Smith RD. Theory versus practice: a review of ‘willingnessto-pay’ in health and health care. Health Econ. 2001;10(1):39-52. 6. Burrows C, Brown K. Are any numbers better than no numbers? The sorry state of willingness-to-pay and some major methodological shortcomings. Aust Health Rev. 1992;15(2):135-44.

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Address for correspondence:

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CEP 01327-001 E-mail: [email protected]

ORIGINAL ARTICLE

DOI: 10.1590/1516-3180.2014.1323452

Carotid body tumor: retrospective analysis on 22 patients Tumor de corpo carotídeo: análise retrospectiva de 22 pacientes André Luís Maion CasarimI, Alfio José TincaniII, André Del NegroII, Camila Guimarães AguiarI, Renato Ventura FanniI, Antonio Santos MartinsII Head and Neck Surgery Service, Department of Surgery, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil

MD. Attending Physician, Head and Neck Surgery Service, Department of Surgery, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil. I

MD, PhD. Associate Professor, Head and Neck Surgery Service, Department of Surgery, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.

II

KEY WORDS: Paraganglioma. Neoplasms. Carotid body tumor. Head and neck neoplasms. Carotid artery diseases. PALAVRAS-CHAVE: Paraganglioma. Neoplasias. Tumor do corpo carotídeo. Neoplasias de cabeça e pescoço. Doenças das artérias carótidas.

ABSTRACT CONTEXT AND OBJECTIVE: Carotid body tumors, or chemodectomas, are the most common head and neck paragangliomas, accounting for 80% of the cases. They may present minor symptoms; however, they deserve special attention in order to achieve accurate diagnosis and adequate treatment. The objectives of this study were to show the approach towards chemodectomas and evaluate the complications of the patients treated surgically without previous embolization. DESIGN AND SETTING: Retrospective study on chemodectomas followed up at the Head and Neck Surgery Service, Department of Surgery, Unicamp. METHODS: Twenty-two patients were evaluated between 1983 and 2009. The diagnosis was based on clinical findings and imaging methods. The epidemiological characteristics, lesion characteristics, diagnostic methods, treatment and complications were analyzed. RESULTS: The paragangliomas were classified as Shamblin I (9%), II (68.1%) and III (22.7%). Angiography, magnetic resonance imaging and computed tomography confirmed the diagnosis in 20 patients (90.9%). Five (22.7%) had significant bleeding during the surgery, while four (18.1%) had minor bleeding. Four patients (18.1%) developed neurological sequelae. Seven (31.8%) needed ligatures of the external carotid artery. Three patients (13.6%) underwent carotid bulb resection. The postoperative follow-up ranged from 3 months to 14 years without recurrences or mortality. CONCLUSIONS: In our experience and in accordance with the literature, significant bleeding and neurological sequelae may occur in chemodectoma cases, particularly in Shamblin III patients. The complications from treatment without previous embolization were similar to data in the literature data, from cases in which this procedure was applied prior to surgery. RESUMO CONTEXTO E OBJETIVO: O tumor de corpo carotídeo, ou quimiodectoma, é o paraganglioma mais comum em cabeça e pescoço, com aproximadamente 80% dos casos. Pode apresentar poucos sintomas; no entanto, necessita atenção especial para o diagnóstico e tratamento adequado. Os objetivos deste estudo são mostrar a abordagem do quimiodectoma e avaliar as complicações nos pacientes tratados cirurgicamente sem embolização prévia. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo de quimiodectomas acompanhados pelo Serviço de Cirurgia de Cabeça e Pescoço, Departamento de Cirurgia, Unicamp. MÉTODOS: Vinte e dois pacientes foram avaliados entre 1983 e 2009. O diagnóstico foi baseado em achados clínicos e métodos de imagens. Foram analisados aspectos epidemiológicos, características das lesões, métodos diagnósticos, tratamento e complicações. RESULTADOS: Os paragangliomas foram classificados em Shamblin I (9%), II (68,1%) e III (22,7%). Angiografia, ressonância nuclear magnética e tomografia computadorizada confirmaram o diagnóstico em 20 pacientes (90,9%). Cinco (22,7%) tiveram sangramento significativo durante a cirurgia, enquanto quatro (18,1%) tiveram sangramento mínimo. Quatro pacientes (18,1%) tiveram sequelas neurológicas. Sete (31,8%) necessitaram de ligadura da artéria carótida externa. Três (13,6%) foram submetidos a ressecção do bulbo carotídeo. O acompanhamento variou de 3 meses a 14 anos, sem recorrências ou óbitos. CONCLUSÕES: Em nossa experiência e de acordo com a literatura, sangramentos significativos e sequelas neurológicas podem ocorrer nos quimiodectomas principalmente em pacientes Shamblin III. As complicações do tratamento sem embolização prévia foram similares aos relatos observados na literatura nos quais se aplicou tal procedimento antes da cirurgia.

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ORIGINAL ARTICLE | Casarim ALM, Tincani AJ, Del Negro A, Aguiar CG, Fanni RV, Martins AS

INTRODUCTION Paragangliomas are tumors located along the human body’s sympathetic and parasympathetic chains. They may grow along these fibers, and may be located in various parts of the body, such as the abdomen, chest, mediastinum, retroperitoneum and head and neck regions, but mostly associated with adrenal gland. The head and neck region is the most common site of extra-adrenal paragangliomas, accounting for approximately 70% of  the cases, and the carotid body is responsible for the majority of these cases.  Because of their location and vascularization, they can pose a great technical challenge for surgeons.1 These tumors are often benign, presenting slow growth,2 and are located in the upper cervical region. There is no evidence of gender predominance. They may only present minor symptoms, commonly only a pulsatile mass in the neck. However, they can cause local discomfort, dysphagia, hoarseness, stridor, vertigo and paralysis of the cranial nerves, and sometimes attain large volumes (some authors have described tumors as large as 10 cm).1 They can be divided into tumors with either sporadic or familial traits. In the sporadic type, bilaterality has been reported in 5 to 10% of the cases.3 The familial form is manifested through a dominant autosomal gene, and in these cases, bilaterality may reach up to 30%.4 Recent studies have described a mutation along germinative lines, which may explain the etiology, through identification of six specific genes (RET, VHL, NF1 and subunits of SDH).4 The hereditary form is mostly correlated with mutations in the SDHD gene.5,6 The incidence in the general population is difficult to estimate. However, according to Rodriguez-Cuevas,7 the incidence in the general population is about 0.01%. Since 1969, when Árias-Stella demonstrated carotid body enlargement in highaltitude Peruvian populations (due to the low oxygen pressure), it has been known that chronic hypoxia is an important factor in the etiology of this neoplasm.8 The malignant potential is about 6% and the criteria are based on cell atypia, mitosis, local invasions and, especially, by the presence of metastasis.9-11 The diagnosis is based on clinical history, physical examination, imaging methods (such as ultrasound, computed tomography and magnetic resonance) and vascular evaluations (including angiography, tomographic angiography and magnetic resonance angiography).12,13 In this context, based on the Shamblin classification, Arya et al. used magnetic resonance imaging to pre-classify carotid body tumors before surgical treatment.14 This could improve preoperative management and reduce the complication rate.9 The best treatment for carotid body paragangliomas is a surgical approach. The literature shows that patients may or may not undergo prior embolization. Some authors have justified using embolization because it reduces complications such as bleeding

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or neurological sequelae,15 although this procedure is not without its own inherent complications.16 OBJECTIVES The objectives of this study were to present an academic institution’s experience of dealing with carotid body paragangliomas, such as the diagnostic methods, complementary examinations and treatment, and to show the possible complications that may occur over the natural evolution of the disease or in relation to surgery without previous embolization. METHODS This was a retrospective study based on patients with carotid body tumors who were treated at the Head and Neck Surgery Service, Department of Surgery, Universidade Estadual de Campinas (Unicamp). This study was submitted to and approved by this institution’s Research Ethics Committee. Twenty-two patients with carotid body paragangliomas were evaluated between 1983 and 2009. These patients were treated and followed up by the institution’s Head and Neck Surgery Service. The parameters analyzed were sex, age at the time of diagnosis, symptoms, presence of bilateral involvement, tumor size, diagnostic methods, treatment and complications. The diagnosis was based on the clinical findings, fine needle aspiration (FNA) and imaging methods, such as cervical ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) and angiography. Bleeding was measured in our study and was classified as minimal (less than 200 ml), moderate (ranging from 200 to less than 1000 ml) and significant (over 1000 ml), according to the need for blood transfusion. Thus, when the bleeding was minimal, blood transfusion was not needed. In cases of moderate bleeding, one or two red blood cell units were infused. Finally, when the bleeding was significant, more than two red blood cell units were infused. The tumors were divided by means of the Shamblin classification,8 according to the involvement of the carotid wall and difficulty of surgical resection. Shamblin I was reserved for tumors that were relatively small and easy to resect, with minimal or no adherence to the carotid wall. Shamblin II consisted of tumors with partial involvement of the carotid wall, and Shamblin III completely involved the carotid bifurcation. All the patients underwent surgical treatment, without embolization or prior radiotherapy. The resection was complete in all patients, with a sub-adventitial avascular approach (Figure 1). RESULTS Our study included two patients with Shamblin I (9%), 15 with Shamblin II (68.1%) and five with Shamblin III (22.7%). Fourteen patients (63.6%) were female. The patients’ ages ranged from 23

Carotid body tumor: retrospective analysis on 22 patients | ORIGINAL ARTICLE

to 77 years (average of 43 years) and all of them had an asymptomatic cervical mass at the initial presentation. The mass diameter ranged from 3 to 8 centimeters (mean of 4.3 cm). Two cases (9%) were bilateral, without any other signs or symptoms. The length of history ranged from 8 months to 13 years (average of 5 years), with the largest tumor occurring in the patient with the longest history. Six patients (27.2%) had undergone surgery for a biopsy or resection in other services, and all procedures were incomplete and interrupted because of excessive bleeding. In our service, the diagnosis was suspected preoperatively in all patients, with two exceptions (9%). Consequently, 91% were managed with predefined surgical planning. Angiography was performed on 15 patients (68.1%), cervical CT scan on 11 (50%), cervical ultrasonography on nine (40.9%), and MRI on five patients (22.7%) (Figures 2 to 4). The two unsuspected cases, which underwent ultrasonography, had a preoperative diagnosis of branchial cleft cyst and undefined adenopathy. These cases were classified subsequently as Shamblin II and did not have any postoperative sequelae or complications. All the imaging methods with arterial evaluations (angiography, CT and MRI) were diagnostic for the patients who underwent these examinations, with no wrong preoperative diagnoses. Ultrasonography was performed on nine patients (40.9%), and was helpful in diagnosing seven cases (77.7%). However, this examination (particularly when there was no Doppler study) suggested the possibilities of branchial cyst and adenomegaly in two cases that had wrong preoperative diagnoses. Fine needle aspiration (FNA) was performed on five patients (35.7%), and was suggestive of the diagnosis in four cases (80%). In one of the patients, who also underwent ultrasonography without a Doppler study, FNA erroneously diagnosed a branchial cyst. During the surgical procedure, five patients (22.7%) presented significant bleeding (over 1000 ml). Three of these patients were Shamblin III and two were Shamblin II, and the former had incorrect preoperative diagnoses. Among the five Shamblin III patients, three (60%) had postoperative neurological sequelae. One patient had a sympathetic chain deficit that evolved to Horner’s syndrome. The second had a vagus nerve deficit and evolved with hoarseness and the third patient had a transient ischemic attack that resolved completely one day after the symptoms, without late neurological sequelae. Twelve patients (54.5 %) had moderate bleeding (ranging from 200 to less than 1000 ml). Of these, nine patients (75%) were Shamblin II and three (25%) were Shamblin III. In this group, one patient (8.3%) who was classified as Shamblin II evolved with unilateral hypoglossal nerve deficit (close contact with the tumor).

A

B

Figure 1. Tumor mass dissected at the carotid bifurcation. (A) Arrow shows carotid body tumor. (B) Preserved carotid arteries (arrows) after resection of carotid body tumor.

Figure 2. Computed tomography showing left parapharyngeal tumor (arrow).

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ORIGINAL ARTICLE | Casarim ALM, Tincani AJ, Del Negro A, Aguiar CG, Fanni RV, Martins AS

Figure 3. Magnetic resonance angiography with three-dimensional reconstruction, showing a vascular mass at the carotid bifurcation (arrow).

In the five remaining patients (22.7%), the intraoperative bleeding was considered to be minimal (up to 200  ml). These patients were all Shamblin I or II and none had neurological sequelae. In nine of our patients (40.9%), some form of vascular procedure was needed. Seven patients (31.8%) needed external carotid ligation and three of these needed en-block resection of the carotid bulb. In two cases, there was a need for intraluminal vascular shunts for arterial reconstruction. In such cases, the possibilities of distal clot formation and stroke need to be borne in mind, and in one of our patients, this was managed by using distal artery aspiration, with a flexible arterial catheter and a 10 ml syringe. Through this, the clot was removed with immediate reflux of the distal internal carotid artery, without sequelae. The vascular reconstruction was done using a saphenous vein graft in one patient, and end-to-end anastomosis between the common and the internal carotid artery in the other two patients. Intraluminal shunt was used in these cases to prevent stroke. Graph 1 presents the intraoperative bleeding according to the Shamblin classification, and shows the relationship between  the  bleeding and higher Shamblin classification. Considering all the patients, the bleeding ranged from 50 ml to 2,000 ml, with a mean of 667 milliliters. In total, four patients (18.1%) had neurological sequelae (Graph 2). One developed Horner’s syndrome; one presented permanent deficits of the IX, X and XII cranial nerves; another had an isolated permanent XII nerve deficit; and the last had a transient ischemic attack.

10 9 8 7 6 5 4 3 2 1 0 Shamblin I minimum (< 200 ml)

Figure 4. Angiography showing vascular mass at the carotid bifurcation (arrow).

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Shamblin II moderate ( 200 - 1000 ml)

Shamblin III significant (> 1000 ml)

Graph 1. Intraoperative bleeding according to Shamblin classification.

Carotid body tumor: retrospective analysis on 22 patients | ORIGINAL ARTICLE

4

3

2

1

0

Shamblin I

Shamblin II

Shamblin III

Graph 2. Neurological sequelae according to Shamblin classification. Another important complication was intraoperative cardiac arrest due to the carotid bulb manipulation. This affected one patient and was managed immediately with external cardiac massage and infusion of adrenaline and atropine. The cardiac activity returned successfully less than one minute after the intercurrence, and the patient evolved without sequelae. Bilaterality was found in two patients (9%), which was managed surgically in two different settings. One of these patients had an association with chronic hypoxia (severe cardiac valve disease, interventricular communication and a persistent arterial channel). He exhibited frequent hypotension during the postoperative period, possibly secondary to slow adaptation to hypoxia, after resection of the carotid chemoreceptors. The other patient presented cardiac valve disease from rheumatic fever. The postoperative follow-up ranged from 3 months to 14 years, averaging 5.1 years, with no recurrences and no mortality, but with the abovementioned morbidity. DISCUSSION The carotid body is a structure that measures around 2 x 3 x 5 millimeters, located at the common carotid artery bifurcation, in the adventitia between the external and internal carotids. It contains chemoreceptors that are sensitive to hypoxia, hypercapnia and acidosis, and aims to maintain the body’s homeostasis and blood pressure. As reported by Kapoor et al., this structure was first described by Von Haller in 1743.6 The incidence of this tumor is greater at higher altitudes, due to the chronic hypoxia.7 There have been several reports in the literature mentioning absence of significant predominance between the genders, although our series showed predominance of females (63.6%). These tumors are difficult to diagnose because of their rarity and few manifested symptoms. The paramount clinical characteristic is a pulsatile cervical mass. As reported in the literature, the diagnosis can be confused even

with benign conditions, including congenital branchial cysts13 or other benign conditions. Thus, as pointed out in the literature, a pulsatile mass near the carotid bulb, in the absence of any suggestion of metastatic disease, should raise the possible diagnosis of chemodectoma and should be followed by specific arterial imaging studies. FNA was helpful for the diagnosis in the cases of four patients in our study. However, this procedure may be dangerous and performing it is controversial because of the risk of bleeding.2 Ultrasonography and CT scans can be very helpful for the preoperative diagnosis and may show enlargement of the bifurcation and hypervascularized tumors. Some authors have reported that ultrasonography with Doppler flowmetry can help surgeons in the initial approach.17 However, CT scans or magnetic resonance imaging are better for identifying the dimensions and anatomical correlations of the tumor.18 The main diagnostic tool is arterial studies such as contrast angiography, computed angiotomography or magnetic resonance angiography (MRA), thereby confirming or not confirming the suspected diagnosis. The MRA seems to be preferable nowadays.14 In the literature, the best treatment is considered to be surgical, with dissection of the tumor in the sub-adventitial avascular plane of the artery.12 Large tumors (Shamblin II and III) may require vascular procedures, including repairs, sutures and resections of the arterial segments.19 At times, it may be necessary to sacrifice the external carotid artery, perform anastomosis between the internal and common carotid arteries or undertake vascular reconstruction with grafts.11-13,20,21 Some authors have described use of a stent inserted into the internal carotid artery before the surgery, in cases presenting as Shamblin III with complete involvement of this artery.22 Occurrences of technical complications in anastomoses between the common and internal carotid arteries after resection of the carotid body have also been reported in the literature. These cases evolved with several hematomas and, in some cases, with stroke caused by deficits of cerebral irrigation.8,13,23 This complication did not occur in our series. In patients with bilateral tumors, obviously, the procedures should not be done at the same time, but spaced out one from another, especially because of possible vascular or cranial nerve lesions.8 Conservative treatment should be reserved for patients who are not suitable for surgery, such as clinically unstable patients, extremely old patients or those with the certainty of stroke. Some authors have suggested that radiotherapy could be used, but this is not recommended by most institutions. Furthermore, studies have shown that this therapeutic method is ineffective in these tumors.3,24-28 Embolization is another therapeutic method, usually done prior to the surgical procedure, as an attempt to decrease intraoperative bleeding.21,29 However, this demands specialized skill and also has the risk of possible significant vascular complications Sao Paulo Med J. 2014; 132(3):133-9

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and cranial nerve deficits. In our service, the patients were treated without preoperative embolization. In the literature, it is mentioned that vascular complications and cranial nerve deficits can occur in about 33% of the patients.1,11 A famous study at the Mayo Clinic evaluated patients’ complications compared between three periods of that institution’s surgical history. It was concluded that, despite the decreases in vascular complications and mortality over the course of time, through better diagnostic methods and surgical technologies or skills, the rate of neurological injuries was not statistically different between the three periods studied, spanning a total of fifty years.30 In our series, cranial nerve deficits occurred in two patients, involving the IX, X and XII pairs. We had another patient who evolved with sympathetic chain palsy. Power et al. demonstrated that preoperative embolization may have some benefits for the surgical approach, especially relating to surgical bleeding, but the patients that they followed up did not present any differences in definitive neurological sequelae.16 Although our series did not have any cases of malignant chemodectoma, it is important to mention that the malignant potential has been reported to be around 2-6 % in the literature, most frequently with metastasis to regional lymph nodes.8,23 Some authors have prescribed chemotherapy for metastasized cases.31 Finally, although we did not have any cases of mortality, the literature mentions a mortality rate of less than 2%.1

5. Offergeld C, Brase C, Yaremchuk S, et al. Head and neck

CONCLUSIONS Complementary imaging study methods such as ultrasonography, computed tomography, magnetic resonance or, especially, arteriography need to be included in evaluations today, in order to analyze the involvement of the carotid artery and to program the surgical treatment for carotid body tumors. This study, in agreement with the literature, demonstrated that significant bleeding and neurological sequelae may occur, and that this risk increases according to the Shamblin classification, particularly in Shamblin III patients. Even though preoperative embolization may be an important alternative, the complications observed in treatment without previous embolization were similar.

15. Zhang TH, Jiang WL, Li YL, Li B, Yamakawa T. Perioperative approach

paragangliomas: clinical and molecular genetic classification. Clinics (Sao Paulo). 2012;67 Suppl1:19-28. 6. Kapoor N, Pai R, Ebenazer A, et al. Familial carotid body tumors in patients with SDHD mutations: a case series. Endocr Pract. 2012;18(5):e106-10. 7.

Rodriguez-Cuevas H, Lau I, Rodriguez HP. High-altitude paragangliomas: diagnostic and therapeutic considerations. Cancer. 1986;57(3):672-6.

8. Arias-Stella J, Valcarcel J. The human carotid body at high altitudes. Pathol Microbiol (Basel). 1973;39(3):292-7. 9. Shamblin WR, ReMine WH, Sheps SG, Harrison EG Jr. Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg. 1971;122(6):732-9. 10. Padberg FT Jr, Cady B, Persson AV. Carotid body tumor. The Lahey Clinic experience. Am J Sur. 1983;145(4):526-8. 11. Lack EE, Cubilla AL, Woodruff JM. Paragangliomas of the head and neck region. A pathologic study of tumors from 71 patients. Hum Pathol. 1979;10(2):191-218. 12. Anand VK, Alemar GO, Sanders TS. Management of the internal carotid artery during carotid body tumor surgery. Laryngoscope. 1995;105(3 Pt 1):231-5. 13. Williams MD, Phillips MJ, Nelson WR, Rainer WG. Carotid body tumor. Arch Surg. 1992;127(8):963-7; discussion 967-8. 14. Arya S, Rao V, Juvekar S, Dcruz AK. Carotid body tumors: objective criteria to predict the Shamblin group on MR imaging. AJNR Am J Neuroradiol. 2008;29(7):1349-54. in the surgical management of carotid body tumors. Ann Vasc Surg. 2012;26(6):775-82. 16. Power AH, Bower TC, Kasperbauer J, et al. Impact of preoperative embolization on outcomes of carotid body tumor resections. J Vasc Surg. 2012;56(4):979-89. 17. França LHG, Bredt CG, Vedolin A, Back LA, Stahlke Junior HJ. Tratamento cirúrgico do tumor de corpo carotídeo: experiência de 30 anos do Hospital de Clínicas da UFPR [Surgical treatment of the carotid body tumor: a 30-year experience]. J Vasc Br. 2003;2(3):171-6. 18. Demattè S, Di Sarra D, Schiavi F, Casadei A, Opocher G. Role of ultrasound and color Doppler imaging in the detection of carotid paragangliomas. J Ultrasound. 2012;15(3):158-63. 19. Lim JY, Kim J, Kim SH, et al. Surgical treatment of carotid body

REFERENCES 1. Wieneke JA, Smith A. Paraganglioma: carotid body tumor. Head Neck Pathol. 2009;3(4):303-6. 2. Nora JD, Hallett JW Jr, O’Brien PC, et al. Surgical resection of carotid body tumors: long-term survival, recurrence, and metastasis. Mayo Clin Proc. 1988;63(4):348-52. 3. Sanghvi VD, Chandawarkar RY. Carotid body tumors. J Surg Oncol. 1993;54(3):190-2. 4. Brown JS. Glomus jugulare tumors revisited: a ten-year statistical follow-up of 231 cases. Laryngoscope. 1985;95(3):284-8.

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paragangliomas: outcomes and complications according to the shamblin classification. Clin Exp Otorhinolaryngol. 2010;3(2):91-5. 20. Gardner P, Dalsing M, Weisberger E, Sawchuk A, Miyamoto R. Carotid body tumors, inheritance, and a high incidence of associated cervical paragangliomas. Am J Surg. 1996;172(2):196-9. 21. Crespo Rodríguez AM, Hernández Delgado G, Barrena Caballo MR, Guelbenzu Morte S. Paragangliomas de cabeza y cuello: diagnóstico por imagen y embolización [Head and neck paragangliomas: imaging diagnosis and embolization]. Acta Otorrinolaringol Esp. 2007;58(3):83-93.

Carotid body tumor: retrospective analysis on 22 patients | ORIGINAL ARTICLE

22. McDougall CM, Liu R, Chow M. Covered carotid stents as an adjunct in the surgical treatment of carotid body tumors: a report of 2 cases and a review of the literature. Neurosurgery. 2012;71(1 Suppl Operative):182-4; discussion 185. 23. Mitchell RO, Richardson JD, Lambert GE. Characteristics, surgical management, and outcome in 17 carotid body tumors. Am Surg. 1996;62(12):1034-7. 24. Ruby R, Gullane PJ, Mintz D. Chemodectomas of the head and neck. J Otolaryngol. 1981;10(2):126-36. 25. Liapis C, Gougoulakis A, Karydakis V, et al. Changing trends in management of carotid body tumors. Am Surg. 1995;61(11):989-93. 26. Pellitteri PK, Rinaldo A, Myssiorek D, et al. Paragangliomas of the head and neck. Oral Oncol. 2004;40(6):563-75. 27. Boedeker CC, Ridder GJ, Neumann HP, Maier W, Schipper J. Diagnostik, Therapie und Behandlungsergebnisse zervikaler Paragangliome [Diagnosis and management of cervical paragangliomas: the Freiburg experience]. Laryngorhinootologie. 2004;83(9):585-92. 28. Kasper GC, Welling RE, Wladis AR, et al. A multidisciplinary approach to carotid paragangliomas. Vasc Endovascular Surg. 2007;40(6):467-74. 29. Ward PH, Liu C, Vinuela F, Bentson JR. Embolization: an adjunctive measure for removal of carotid body tumors. Laryngoscope. 1988;98(12):1287-91. 30. Hallett JW Jr, Nora JD, Hollier LH, Cherry KJ Jr, Pairolero PC. Trends in neurovascular complications of surgical management for carotid body and cervical paragangliomas: a fifty-year experience with 153 tumors. J Vasc Surg. 1988;7(2):284-91. 31. Lázaro B, Klemz M, Flores MS, Landeiro JA. Malignant paraganglioma swith vertebral metastasis: case report. Arq Neuropsiquiatr. 2003;61(2B):463-7. Sources of funding: None Conflict of interest: None Date of first submission: January 16, 2012 Last received: June 27, 2013 Accepted: July 16, 2013 Address for correspondence: André Luís Maion Casarim Rua Roxo Moreira, 1.234 Cidade Universitária Zeferino Vaz Campinas (SP) — Brasil CEP 13083-591 Tel. (+55 19) 3521-9449 E-mail: [email protected]

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ORIGINAL ARTICLE

DOI: 10.1590/1516-3180.2014.1323568

Anemia in inflammatory bowel disease: prevalence, differential diagnosis and association with clinical and laboratory variables Anemia na doença inflamatória intestinal: prevalência, diagnóstico diferencial e associação com variáveis clínicas e laboratoriais Rodrigo Andrade AlvesI, Sender Jankiel MiszputenII, Maria Stella FigueiredoIII Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil

MSc. Postgraduate Student, Division of Gastroenterology, Department of Medicine, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

I

II PhD. Head of Intestine Sector, Division of Gastroenterology, Department of Medicine, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

PhD. Professor, Discipline of Hematology, Department of Medicine, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

III

KEY WORDS: Anemia. Inflammatory bowel diseases. Prevalence. Association. Diagnosis, differential. PALAVRAS-CHAVE: Anemia. Doenças inflamatórias intestinais. Prevalência. Associação. Diagnóstico diferencial.

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ABSTRACT CONTEXT AND OBJECTIVES: Anemia is the most frequent extraintestinal complication of inflammatory bowel disease. This study aimed to: 1) determine the prevalence of anemia among patients with inflammatory bowel disease; 2) investigate whether routine laboratory markers are useful for diagnosing anemia; and 3) evaluate whether any association exists between anemia and clinical/laboratory variables. DESIGN AND SETTING: Cross-sectional at a federal university. METHODS: 44 outpatients with Crohn’s disease and 55 with ulcerative colitis were evaluated. Clinical variables (disease activity index, location of disease and pharmacological treatment) and laboratory variables (blood count, iron laboratory, vitamin B12 and folic acid) were investigated. RESULTS: Anemia and/or iron laboratory disorders were present in 75% of the patients with Crohn’s disease and in 78.2% with ulcerative colitis. Anemia was observed in 20.5% of the patients with Crohn’s disease and in 23.6% with ulcerative colitis. Iron-deficiency anemia was highly prevalent in patients with Crohn’s disease (69.6%) and ulcerative colitis (76.7%). Anemia of chronic disease in combination with iron deficiency anemia was present in 3% of the patients with Crohn’s disease and in 7% of the patients with ulcerative colitis. There was no association between anemia and disease location. In ulcerative colitis, anemia was associated with the disease activity index. CONCLUSIONS: Most patients present iron laboratory disorders, with or without anemia, mainly due to iron deficiency. The differential diagnosis between the two most prevalent types of anemia was made based on clinical data and routine laboratory tests. In ulcerative colitis, anemia was associated with the disease activity index. RESUMO CONTEXTO E OBJETIVOS: Anemia é a mais frequente complicação extraintestinal na doença inflamatória intestinal. Este estudo objetivou: 1) determinar a prevalência de anemia em portadores de doença inflamatória intestinal; 2) investigar se os marcadores laboratoriais de uso rotineiro são úteis para o diagnóstico da anemia; 3) avaliar se existe associação entre anemia e variáveis clínico-laboratoriais. TIPO DE ESTUDO E LOCAL: Estudo transversal em uma universidade federal. MÉTODOS: Foram avaliados 44 pacientes ambulatoriais com doença de Crohn e 55 com retocolite ulcerativa. Foram investigados aspectos clínicos (índice de atividade da doença, localização da doença e tratamento farmacológico) e laboratoriais (hemograma, ferrocinética, vitamina B12 e ácido fólico). RESULTADOS: Anemia e/ou anormalidades na ferrocinética estavam presentes em 75% dos pacientes com doença de Crohn e em 78,2% dos pacientes com retocolite. Anemia foi observada em 20,5% do grupo com doença de Crohn e em 23,6% do grupo com retocolite. Anemia por deficiência de ferro predominou entre os pacientes com doença de Crohn (69,6%) e com retocolite (76,7%). Anemia de doença crônica associada à anemia ferropriva estava presente em 3% dos pacientes com doença de Crohn e em 7% daqueles com retocolite. Na retocolite, a anemia estava associada com o índice de atividade da doença. CONCLUSÕES: A maioria dos pacientes apresentava alterações na ferrocinética com ou sem anemia, principalmente decorrente da ferropenia. O diagnóstico diferencial entre os dois tipos mais prevalentes de anemia foi baseado nos dados clínicos e nos testes laboratoriais de rotina. Anemia estava associada com o índice de atividade na retocolite.

Anemia in inflammatory bowel disease: prevalence, differential diagnosis and association with clinical and laboratory variables | ORIGINAL ARTICLE

INTRODUCTION Inflammatory bowel diseases (IBD) comprise two main distinct clinical entities: Crohn’s disease (CD) and ulcerative colitis (UC). CD is a chronic transmural inflammation that can affect any segment of the digestive tract and is associated with numerous extraintestinal manifestations.1 UC is the result of chronic inflammation of the colon, affecting one or more of its segments. Generally, the distal segments are affected and all viscera and the distal ileum may eventually be involved.2,3 For a long time, anemia has been considered to be an inevitable complication of CD and UC and its treatment has only recently become a specific objective for the management of such individuals.4 Gasché et al.5 showed that 33% of patients with CD had anemia [defined as hemoglobin (Hb) < 12 g/dl]. Another study reported a prevalence of anemia (Hb < 10 g/dl) of 26% in CD and of 37% in UC.6 Iron deficiency is the most common type of anemia and is generally underdiagnosed. Chronic and occult blood loss through the gastrointestinal tract is the most frequent cause of iron deficiency.7 Malabsorption of iron is uncommon, unless the proximal digestive tract is extensively affected by CD.4,8 Anemia of chronic disease (ACD) is the second most frequent type of anemia in IBD.4,9 This condition is characterized by relative deficiency of erythropoietin which is slightly greater, although still very little in relation to the degree of anemia, when compared with anemia of the same intensity observed in other etiologies.6,9 Cytokines such as interleukin 1 (IL-1), tumor necrosis factor (TNF) and interferon-γ are produced in larger amounts by monocytes and mononuclear cells of the intestinal lamina propria.6 IL-1 and interferon-γ decrease the production of erythropoietin and inhibit erythropoiesis. TNF and IL-1 increase the production of ferritin, thus reducing the amount of iron available for erythropoiesis.10 Moreover, some in vitro and in vivo studies have demonstrated that these cytokines induce resistance to erythropoietin in erythroid precursors.6,11,12 In 2000, a peptide synthesized in the liver, called hepcidin, was isolated from plasma. Expression of this peptide is induced by lipopolysaccharide and IL-6. This peptide increases the capacity of reticuloendothelial cells in the duodenal crypts to take up and retain iron and decreases dietary iron absorption.13,14 Hepcidin exerts its biological function upon binding to the only known cellular iron exporter, ferroportin, thereby leading to ferroportin internalization and degradation. This event blocks transfer of the absorbed iron from the duodenal enterocyte into the circulation and, in parallel, causes retention of iron inside macrophages and monocytes.15 Other causes of anemia, such as vitamin B12 deficiency, generally occur when resection of the ileum exceeds 60 cm. Inadequate ingestion, malabsorption and use of sulfasalazine or methotrexate contribute towards emergence of megaloblastic anemia due

to folic acid deficiency. In addition, drugs such as immunosuppressants, mesalazine and sulfasalazine can cause bone marrow suppression.4,16 Some studies have demonstrated that treatment of anemia has a positive impact on the quality of life of patients with IBD.17,18 The differential diagnosis between iron-deficiency anemia (IDA) and ACD is important since only the former will respond solely to replacement therapy. Moreover, evidence indicates that administration of iron to patients with chronic inflammation may trigger an increase in production of oxygen free radicals, thus propagating tissue injury.8,10,19,20 The high prevalence of anemia among patients with IBD observed in the international literature encouraged the present investigation conducted on Brazilian patients with IBD. Although this abnormality is highly common, its diagnosis and treatment have not received the same attention by physicians as have other complications such as arthritis and osteopathy.20-22 Another objective was to determine whether or not it is possible to establish the etiology of anemia using noninvasive complementary tests that are widely available in clinical practice. In addition, we evaluated whether the presence of these abnormalities is associated with clinical and/or laboratory activity, location of the disease and medications used. OBJECTIVES 1. To determine the prevalence of anemia in a group of Brazilian patients with inflammatory bowel disease; 2. To investigate whether routine laboratory markers are useful for the etiological diagnosis of anemia; 3. To evaluate the association between anemia and clinical/laboratory variables. METHODS Forty-four patients with CD and 55 with UC, who were being regularly followed up at the intestinal sector of the gastroenterology outpatient clinic of a federal university hospital in São Paulo, Brazil, were studied. The diagnoses of Crohn’s disease and ulcerative colitis were based on the usual clinical criteria.1,2 Patients were included as they visited the clinic and if they met the inclusion criteria, from March 2001 to May 2002. Patients with known hemoglobinopathies, myelodysplastic syndromes, sideroblastic anemia, kidney failure, liver disease and hypothyroidism, and patients requiring hospital admission were excluded. The study protocol was approved by the hospital’s ethics committee, and all patients or their legal representatives signed an informed consent form to participate in the study. The Harvey and Bradshaw index23 and the Truelove and Witts index24 were used to quantify clinical disease activity in patients with CD and UC, respectively. The disease location

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ORIGINAL ARTICLE | Alves RA, Miszputen SJ, Figueiredo MS

in CD was defined by the Vienna classification of Crohn’s disease.25 Blood was collected during regular pharmacological treatment (aminosalicylates, corticosteroids, antibiotics and/or immunomodulators). Iron supplementation was discontinued for at least one week before blood collection in patients taking oral iron and for one month in those receiving parenteral iron.26 The following laboratory parameters were evaluated: complete blood count, erythrocyte sedimentation rate, reticulocyte count, serum iron, transferrin concentration, ferritin, bilirubins, lactate dehydrogenase, vitamin B12 and folic acid. The transferrin saturation was calculated according to the formula of Turati et al.27 Hemoglobin electrophoresis was carried out in the cases of patients with microcytosis and normal serum iron.28-30 Anemia was defined as Hb levels of less than 13 g/dl in males and less than 12 g/dl in females.31 Iron deficiency was defined based on reduced serum ferritin concentration (< 30 ng/ml) and/ or low transferrin saturation (< 16%). In the presence of clinical or biochemical evidence of inflammation, the lower limit of serum ferritin consistent with normal iron stores was 100 ng/dl. The diagnostic criteria for ACD were serum ferritin > 100 ng/ml and transferrin saturation < 16%, in the presence of biochemical or clinical evidence of inflammation. The definition of functional iron deficiency (FID) was the same, but with Hb levels within the normal range. The association between IDA and ACD was characterized by transferrin saturation < 16% and serum ferritin between 30 and 100 ng/dl.32 Macrocytosis was defined as a mean corpuscular volume > 95.1 fl in males and > 98.3 fl in females. The term hematological abnormality was used to define alterations in iron laboratory values (relating to iron deficiency or to functional iron deficiency observed in chronic diseases), with or without associated red blood cell abnormalities. This term was also used when referring to macrocytosis. By accepting an alpha of 5% with statistical power of 90% and anemia as the main outcome, a sample of 37 cases for each group of diseases was estimated. A virtual calculator was used, which was obtained through the following site: http://www.lee.dante.br/ pesquisa/amostragem/amostra.html. Statistical analysis The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) for Windows software, versions 10.0.1 and 13.0 (SPSS, Chicago, IL, USA). Numerical variables were expressed as the mean, median, standard deviation and range. Nominal variables were reported as absolute (n) and relative (%) frequencies. Student’s t test was used to compare numerical variables between the two groups of patients. Nominal variables were compared using the χ2 test or Fisher’s exact test, when necessary. The level for rejection of the null hypothesis was set at 0.05 or 5%.

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RESULTS Demographic and clinical characteristics Women predominated in both the CD and the UC group, with no significant difference between the groups. No difference in mean age was observed between the two groups. With respect to the location of the disease, the ileal-colonic (L3) (47.7%) and ileal (L1) (40.9%) forms predominated in patients with CD, whereas pancolitis (34.7%) and rectosigmoid involvement (30.9%) were more frequent in patients with UC (P < 0.01). The prevalence of individuals who had previously undergone intestinal and/or colon resection was higher among CD patients (61.4%), whereas only two patients (3.6%) in the UC group had undergone resection (P < 0.01). Active disease was more prevalent among patients of the UC group than in those of the CD group (P < 0.01) (Table 1). Etiology of hematological abnormalities and prevalence of anemia No difference in the etiological factor of hematological abnormalities was observed between patients with CD and those with Table 1. Demographic and clinical characteristics of the patients with Crohn’s disease (CD) and ulcerative colitis (UC) Gender Male Female Total Age (years) Mean ± SD Median (range) 95% confidence interval Disease location Ileum (LI)‡ Ileum-colon (L3)‡ Colon (L2)‡ Pancolitis (L2)‡ Rectosigmoid Rectum Total Surgical resection None Distal ileum Ileum Right colon Ileum and right colon Total colectomy Total Disease activity Active Remission Total *

CD

UC

P-value

15 (34.1%) 29 (65.9%) 44 (100%)

22 (40.0%) 33 (60.0%) 55 (100%)

P = 0.67*

41.6 ± 10.7 43 (22-70) 38.4 - 44.9

43.8 ± 14.0 43 (17-81) 40.0 - 47.2

P = 0.40†

18 (40.9%) 21. (47.7%) 4 (9.1%) 1 (2.3%) 44 (100%)

1 (1.8%) 7 (12.7%) 19 (34.7%) 17 (30.9%) 11 (20%) 55 (100%)

P < 0.01§

17 (38.6%) 9 (20.5%) 2 (4.5%) 4 (9.1%) 12 (27.3%) 44 (100%)

53 (96.4%) 2 (3.6%) 55 (100%)

P < 0.01§

11 (25%) 33 (75%) 44 (100%)

47 (85.5%) 8 (14.5%) 55 (100%)

P < 0.01*

Fisher’s exact test; Student’s t test; Vienna Classification for CD; §χ2 test. †

‡

Anemia in inflammatory bowel disease: prevalence, differential diagnosis and association with clinical and laboratory variables | ORIGINAL ARTICLE

UC (P = 0.77). In the CD group, 25% of the patients did not present hematological abnormalities. The most frequent types of hematological abnormalities were iron deficiency (ID) (without anemia) in 45.4% and iron deficiency anemia (IDA) in 24.2%. In the UC group, 21.8% of the patients did not present any hematological abnormality. ID was present in 53.5%, IDA in 23.2 % and ID + FID in 9.3% (Table 2). Hemoglobin levels below the lower limit of normal were observed in 22 patients, including 9 with CD and 13 with UC (P = 0.36) (Table 3). Associations Activity versus hematological abnormalities No association between clinical disease activity and hematological abnormalities was observed in patients with CD (P = 0.47) (Table 4). In the UC group, 93% (40/43) of the patients with hematological abnormalities presented mild or moderate activity. Three of the eight individuals in remission showed hematological abnormality (P = 0.03) (Table 5). Location of the disease versus hematological abnormalities No association between the location of the disease and the presence or absence of hematological abnormalities was observed in the CD group (P = 0.54) or in the UC group (P = 0.41) (Table 6). Pharmacological treatment versus hematological abnormalities No association between the type of pharmacological treatment and the presence or absence of hematological abnormalities was observed in either group (P = 0.32 in CD and 0.73 in UC) (data not shown). DISCUSSION Although a high prevalence of anemia among patients with IBD has been recognized in the international literature for decades, many services do not possess a protocol for its investigation. Measurement of hemoglobin levels and serum iron alone is insufficient: hemoglobin measurements only allow diagnosing of the third and last stage of IDA, while iron measurement does not allow differentiation between IDA and ACD. In a study conducted in the 1980s involving hospitalized patients, only 11 of the 29 patients initially diagnosed with IDA had iron deficiency and most of them actually presented ACD.33 One important fact is that iron deficiency is 2 to 5 times more frequent than IDA.31 Thus, it is possible that the prevalence of iron deficiency is underestimated, especially if measurement of serum ferritin is not part of the routine diagnosis. The present study demonstrated that most patients with IBD had some type of hematological abnormality, with no difference in the distribution of these abnormalities between CD and UC (Table 2). A cross-sectional study does not provide information

about the mean duration of episodes of anemia. However, analysis of these patients provides an overview of the burden of anemia in a population with IBD during the natural history of the disease. Among the 22 patients with hemoglobin levels below the normal limit, 9 had CD and 13 had UC. The prevalence of anemia Table 2. Etiology of hematological abnormalities in patients with Crohn’s disease (CD) and ulcerative colitis (UC) (n = 76) CD UC Total ID 15 (45.4%) 23 (53.5%) 38 (50.0%) ID + FID 3 (9.1%) 4 (9.3%) 7 (9.2%) FID 3 (9.1%) 2 (4.6%) 5 (6.6%) IDA 8 (24.2%) 10 (23.2%) 18 (23.7%) IDA + ACD 1 (3.0%) 3 (7.0%) 4 (5.2%) Macrocytosis 3 (9.1%) 1 (2.3%) 4 (5.2%) Total 33 (100%) 43 (100%) 76 (100%) ID = iron deficiency (without anemia); FID = functional iron deficiency (without anemia); IDA = iron-deficiency anemia; ACD = anemia of chronic disease. χ2 test. P = 0.77.

Table 3. Prevalence of anemia in male and female patients with Crohn’s disease (CD) and ulcerative colitis (UC) (n = 22) CD Male (Hb < 13 g/dl) 1 (4.5%) Female (Hb < 12 g/dl) 8 (36.4%) Total 9 (40.9%) Hb = hemoglobin. Fisher’s exact test; P = 0.36.

UC 4 (18.2%) 9 (40.9%) 13 (59.1%)

Total 5 (22.7%) 17 (77.3%) 22 (100%)

Table 4. Association between clinical disease activity and hematological abnormalities in patients with Crohn’s disease (n = 44) Hematological abnormality Activity Remission Total None 1 (2.3%) 10 (22.7%) 11 (25%) ID 3 (6.8%) 12 (27.3%) 15 (34.1%) ID + FID 1 (2.3%) 2 (4.5%) 3 (6.8%) FID 1 (2.3%) 2 (4.5%) 3 (6.8%) IDA 3 (6.8%) 5 (11.4%) 8 (18.2%) IDA + ACD 1 (2.3%) 1 (2.3%) Macrocytosis 1 (2.3%) 2 (4.5%) 3 (6.8%) Total 11 (25%) 33 (75%) 44 (100%) ID = iron deficiency (without anemia); FID = functional iron deficiency (without anemia); IDA = iron-deficiency anemia; ACD = anemia of chronic disease. χ2 test; P = 0.47.

Table 5. Association between clinical-laboratory activity and hematological abnormalities in patients with ulcerative colitis (n = 55) Activity Hematological Total abnormality Remission Mild Moderate None 5 (9.1%) 5 (9.1%) 2 (3.6%) 12 (21.8%) ID 3 (5.5%) 12 (21.8%) 8 (14.5%) 23 (41.8%) ID + FID 3 (5.5%) 1 (1.8%) 4 (7.3%) FID 1 (1.8%) 1 (1.8%) 2 (3.6%) IDA 2 (3.6%) 8 (14.5%) 10 (18.2%) IDA + ACD 3 (5.5%) 3 (5.5%) Macro 1 (1.8%) 1 (1.8%) Total 8 (14.5%) 23 (41.8%) 24 (43.6%) 55 (100%) ID = iron deficiency (without anemia); FID = functional iron deficiency (without anemia); IDA = iron-deficiency anemia; ACD = anemia of chronic disease; Macro = macrocytosis. χ2 test; P = 0.03. Sao Paulo Med J. 2014; 132(3):140-6 143

ORIGINAL ARTICLE | Alves RA, Miszputen SJ, Figueiredo MS

was similar in the CD and UC groups (Table 3). Two  aspects of this result should be highlighted: first, the predominance of female patients (77.3%), which probably reflects their predominance in the present sample as a whole; second, the lack of a difference between CD and UC, which might be due to the relatively small number of anemic subjects. Therefore, the prevalence of anemia observed in this study, i.e. 20.5% among patients with CD and 23.6% among patients with UC (data not shown), was lower than that reported in some other studies.5,6 However, in a review published by Wilson et al.,34 the prevalence of anemia ranged from 10.2% to 72.7% among outpatients with CD and from 8.8% to 66.6% among patients with UC. In the CD group, 23/33 patients (69.6%) with hematological abnormalities presented some degree of iron deficiency. The  same was observed for 33/43 patients (76.7%) of the UC group (Table 2). Coexistence of ID + FID was found in 9.1% of patients with CD and in 9.3% of the UC group. However, this difference was not statistically significant. According to a review by Kulnigg and Gasche,7 the prevalence of iron deficiency in patients with CD ranged from 36% to 90% according to the sample studied and to the definition of iron deficiency. No difference in the prevalence of ACD was observed between patients with CD and those with UC (Table 2). ACD associated with IDA was present in 3.0% of the patients with CD (1/33) and in 7.0% of the patients with UC (3/43). Although ACD is the second leading cause of hematological abnormalities in IBD, studies reporting the true prevalence of this complication are scarce. In the study by Schreiber et al.,6 the prevalence of ACD was 15% among patients with CD and 10% among those with UC. Lakatos et al.35 reported prevalences of 17.7% and 9.6%. In the present study functional iron deficiency was presented in 9.1% with CD and in 4.6% of the patients with UC. Coexistence of IDA and ACD has been reported in the literature mainly for patients with rheumatoid arthritis. Ahluwalia et al.36 observed this association in 64% of women over the age of 70 years. A recent study among patients with IBD indicated that the combination IDA/ACD was the third most frequent

pathological condition underlying anemia.11 In the present investigation, this condition was observed in only one patient with CD and in three patients with UC (Table 2). We believe that this low prevalence is due to the difficulty in detecting this association in routine tests. Nevertheless, when both types of hematological abnormality occur together, microcytosis is more frequent and anemia tends to be more intense. The ratio between soluble transferrin receptor concentration and log ferritin level might be a useful parameter. A ratio < 1 suggests ACD, whereas a ratio > 2 suggests iron deficiency coexisting with ACD.14 Four patients who were not anemic had macrocytosis, including three women with CD, one of them also presenting iron depletion, and one man with UC (Table 2). The mean corpuscular volume was 111.9 fl for patients with CD and 97.3 fl for the patient with UC (data not shown). Lakatos et al.35 found macrocytosis in 4.0% of patients with CD and UC, a prevalence slightly lower than that observed in the present study (5.2%) (Table 2). One CD patient had a normal serum level of vitamin B12 and low folic acid level. The second CD patient presented a low level of vitamin B12 and normal level of folic acid. The last patient showed normal levels of vitamin B12 and folic acid. The UC patient had low levels of vitamin B12 and folic acid (data not shown). One of the objectives of this investigation was to evaluate associations between hematological abnormalities and some clinical characteristics of IBD. No association was observed between hematological abnormalities and the clinical activity index in CD, probably because most patients (75%) were in remission. Interestingly, there was a high prevalence of hematological abnormalities in patients in remission (69.7%) and in those presenting clinical activity (90.9%) (Table 4). In contrast, an association between clinical-laboratory activity and the presence of hematological abnormalities was found in the UC group (Table 5), such that 93% of the patients with hematological abnormalities presented mild or moderate activity, whereas three of the eight patients in remission presented hematological abnormalities (iron deficiency as etiology). The other patients with iron deficiency, as well the patients with ACD, FID and the patient with macrocytosis, presented mild

Table 6. Association between disease location and hematological abnormalities in patients with Crohn’s disease (CD) and ulcerative colitis (UC) CD Location Ileum Ileum-colon Colon Pancolitis Rectosigmoid Rectum Total χ2 test; CD: P = 0.54; UC: P = 0.41.

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With hematological abnormalities 13 (29.5%) 17 (38.6%) 2 (4.5%) 1 (2.3%) – – 33 (75%)

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UC Without hematological abnormalities 5 (11.4%) 4 (9.1%) 2 (4.5%) – – – 11 (25%)

With hematological abnormalities – 1 (1.8%) 6 (10.9%) 17 (30.9%) 11 (20.0%) 8 (14.5%) 43 (78.2%)

Without hematological abnormalities – – 1 (1.8%) 2 (3.6%) 6 (10.9%) 3 (5.5%) 12 (21.8%)

Anemia in inflammatory bowel disease: prevalence, differential diagnosis and association with clinical and laboratory variables | ORIGINAL ARTICLE

or moderate activity. Since  the Truelove-Witts index24 is influenced by Hb, this result is not unexpected. Gasché et al.5 studied a group of 49 patients with CD and did not observe any difference in the activity index between patients with and without anemia. Similar results were obtained in the present study, although those authors used the CDAI and we chose to use the Harvey-Bradshaw index. However, other authors6,11 have demonstrated an association between the severity of anemia and disease activity indices in CD and UC patients. Another intriguing finding was the possibility of an association between the location of IBD and hematological abnormalities. No such association was observed in the CD group or in the UC group (Table 6). In the latter group, 39.5% of the patients with hematological abnormalities had pancolitis, whereas less extensive areas such as the rectosigmoid predominated among patients without hematological abnormalities. No association was observed between the type of pharmacological treatment and the presence of hematological abnormalities (data not shown). This assessment was carried out because anemia is considered to be an adverse effect of some drugs used for the treatment of IBD, especially sulfasalazine, which inhibits folic acid absorption, and azathioprine, which can cause pancytopenia and macrocytosis. There may be a tendency to look upon anemia as an unavoidable accompaniment to IBD. Only in recent years has its correction been highlighted as a specific therapeutic aim in these patients. It should not be assumed that some level of anemia is a normal finding in IBD patients. Thus, the World Health Organization definitions of anemia apply to patients with IBD.21 For patients in remission or with mild disease, laboratory screening should be performed every 6 or 12 months. The minimum workup should include complete blood count, serum ferritin, serum iron, transferrin concentration, transferrin saturation, lactate dehydrogenase and reticulocyte count. In outpatients with active disease, such measurements should be performed at least every three months. Patients at risk of vitamin B12 or folic acid deficiency (e.g. small bowel disease or resection) need proper surveillance. Serum levels of vitamin B12 and folic acid should be measured at least annually, or if macrocytosis is present.32 However, even the results from

observed in 20.5% of the patients with Crohn’s disease and in 23.6% with ulcerative colitis. Anemia of chronic disease in combination with iron deficiency anemia was present in 3% of the patients with Crohn’s disease and in 7% of the patients with ulcerative colitis. The differential diagnosis between the two most prevalent types of anemia, IDA and ACD, was made based on clinical data and routine laboratory tests. However, no marker that exclusively helped with or confirmed this diagnosis could be identified. There was no association between anemia and disease location and between anemia and pharmacological treatment. In ulcerative colitis cases, anemia was associated with the disease activity index.

recently available tests such as measurement of soluble transferrin receptor indicate that there is a need for other laboratory tests that are able to distinguish between IDA and ACD. In this regard, standardization of the different kits used for measurement of soluble transferrin receptor, or even the soluble transferrin receptor/ log ferritin ratio, might be a solution for this problem.

10. Weiss G. Iron and anemia of chronic disease. Kidney Int Suppl.

REFERENCES 1. Kornbluth A, Sachar DB, Salomon P. Crohn’s disease. In: Feldman M, Scharschmidt BF, Sleisenger MH, editors. Gastrointestinal and liver disease, 6th ed. Philadelphia: Saunders; 1998. p. 1708-34. 2. Miszputen SJ, Cutait R. Doenças inflamatórias intestinais. In: Prado FC, Ramos J, Ribeiro do Valle J, editors. Atualização terapêutica, 23rd ed. São Paulo: Artes Médicas; 2007. p. 399-405. 3. Jewell DP. Ulcerative colitis In: Feldman M, Scharschmidt BF, Sleisenger MH, editors. Gastrointestinal and liver disease. 6th ed. Philadelphia: Saunders; 1998. p. 1735-61. 4. Cronin CC, Shanahan F. Anemia in patients with chronic inflammatory bowel disease. Am J Gastroenterol. 2001;96(8):2296-8. 5. Gasché C, Reinisch W, Lochs H, et al. Anemia in Crohn’s disease. Importance of inadequate erythropoietin production and iron deficiency. Dig Dis Sci. 1994;39(9):1930-4. 6. Schreiber S, Howaldt S, Schnoor M, et al. Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease. N Engl J Med. 1996;334(10):619-23. 7. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn’s disease. Aliment Pharmacol Ther. 2006;24(11-12):1507-23. 8. Oldenburg B, Koningsberger JC, Van Berge Henegouwen GP, Van Asbeck BS, Marx JJ. Iron and inflammatory bowel disease. Aliment Pharmacol Ther. 2001;15(4):429-38. 9. Gasche C, Waldhoer T, Feichtenschlager T, et al. Prediction of response to iron sucrose in inflammatory bowel disease-associated anemia. Am J Gastroenterol. 2001;96(8):2382-7. 1999;69:S12-7. 11. Bergamaschi G, Di Sabatino A, Albertini R, et al. Prevalence and pathogenesis of anemia in inflammatory bowel disease. Influence of anti-tumor necrosis factor-alpha treatment. Haematologica. 2010;95(2):199-205. 12. Spivak

CONCLUSIONS Anemia and/or iron disorders were important systemic complications in the group of IBD patients studied here. Anemia was

JL.

The

blood

in

systemic

disorders.

Lancet.

2000;355(9216):1707-12. 13. Means RT. Hepcidin and cytokines in anaemia. Hematology. 2004;9(5-6):357-62.

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14. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011-23. 15. Weiss G, Gasche C. Pathogenesis and treatment of anemia in inflammatory bowel disease. Haematologica. 2010;95(2):175-8. 16. Sandborn W. Erythropoietin for inflammatory bowel disease anemia. Gastroenterology. 1997;112(2):660-1. 17. Gasché C, Dejaco C, Waldhoer T, et al. Intravenous iron and erythropoietin for anemia associated with Crohn disease. A randomized, controlled trial. Ann Intern Med. 1997;126(10):782-7.

32. Gasche C, Berstad A, Befrits R, et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel disease. Inflamm Bowel Dis. 2007;13(12):1545-53. 33. Arthur CK, Isbister JP. Iron deficiency. Misunderstood, misdiagnosed and mistreated. Drugs. 1987;33(2):171-82. 34. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med. 2004;116 Suppl 7A:44S-49S. 35. Lakatos L, Pandur T, David G, et al. Association of extraintestinal

18. Wells CW, Lewis S, Barton JR, Corbett S. Effects of changes in

manifestations of inflammatory bowel disease in a province of

hemoglobin level on quality of life and cognitive function

western Hungary with disease phenotype: results of a 25-year follow-

in inflammatory bowel disease patients. Inflamm Bowel Dis. 2006;12(2):123-30. 19. Gasche C, Dejaco C, Reinisch W, et al. Sequential treatment of anemia in ulcerative colitis with intravenous iron and erythropoietin.

up study. World J Gastroenterol. 2003;9(10):2300-7. 36. Ahluwalia N, Lammi-Keefe CJ, Bendel RB, et al. Iron deficiency and anemia of chronic disease in elderly women: a discriminant-analysis for differentiation. Am J Clin Nutr. 1995;61(3):590-6.

Digestion. 1999;60(3):262-7. 20. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004;53(8):1190-7. 21. Gomollón F, Gisbert JP. Anemia and inflammatory bowel diseases. World J Gastroenterol. 2009;15(37):4659-65. 22. Teixeira GJT, Silva JH, Teixeira MG, et al. Manifestações extra-intestinais

Acknowledgement: This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Universidade Federal de São Paulo. The sponsors had no role in the study design, in collection, analysis and interpretation of data, in writing the manuscript or in the decision to submit the manuscript for publication

após tratamento cirúrgico da retocolite ulcerativa [Extra-intestinal manifestations after ulcerative colitis surgical treatment]. Rev Bras

Sources of funding: Coordenação de Aperfeiçoamento de Pessoal de

Colo-proctol. 2001;21(1):9-18.

Nível Superior (CAPES) and Universidade Federal de São Paulo (Unifesp)

23. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity.

Conflict of interest: None

Lancet. 1980;1(8167):514. 24. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955;2(4947):1041-8. 25. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal

Date of first submission: July 27, 2012 Last received: June 14, 2013 Accepted: July 16, 2013

classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55(6):749-53. 26. Massey AC. Microcytic anemia. Differencial diagnosis and

Rodrigo Andrade Alves

management of iron deficiency anemia. Med Clin North Am.

Rua Renato Dias, 300/901

1992;76(3):549-66.

Bom Pastor — Juiz de Fora (MG) — Brasil

27. Turati C, Tursini P, Franzini C, et al. Saturazione della transferrina del siero e sovraccarico di ferro. Biochim Clin. 1997;21:10-5. 28. Weatherall DJ, Clegg JB. The thalassaemia syndromes. 3rd ed. Oxford: Blackwell Scientific Publications; 1981. 29. Marengo-Rowe AJ. Rapid electrophoresis and quantitation of haemoglobins on cellulose acetate. J Clin Path. 1965;18(6):790-2. 30. Pembrey ME, MacWade P, Weatherall DJ. Reliable routine estimation of small amounts of foetal haemoglobin by alkali denaturation. J Clin Pathol. 1972;25(8):738-40. 31. World Health Organization. Iron deficiency anemia: assessment, prevention and control. A guide for programme managers. Geneva: World Health Organization; 2001. Available from: http://whqlibdoc. who.int/hq/2001/who_NHD_01.3.pdf. Accessed in 2013 (May 23).

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Address for correspondence:

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CEP 36021-610 Tel. (+55 32) 3212-2017 E-mail: [email protected]

ORIGINAL ARTICLE

DOI: 10.1590/1516-3180.2014.1323600

Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study Carbamazepina para prevenção de náusea e vômito induzidos por quimioterapia: um estudo piloto Thaiana Aragão SantanaI, Felipe Melo CruzII, Damila Cristina TrufelliI, João GlasbergIII, Auro Del GiglioIV Fundação e Faculdade de Medicina do ABC, Santo André, Brazil

MD. Oncology Fellow, Faculdade de Medicina do ABC (FMABC), São Paulo, Brazil.

I

II MD, MSc. Attending Physician, Discipline of Oncology, Faculdade de Medicina do ABC (FMABC), São Paulo, Brazil. III MD. Attending Physician, Discipline of Oncology, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil. IV MD, MSc, PhD. Titular Professor, Discipline of Oncology, Faculdade de Medicina do ABC (FMABC), São Paulo, Brazil.

KEY WORDS: Antiemetics. Vomiting. Nausea. Carbamazepine. Prevention and control [subheading]. PALAVRAS-CHAVE: Antieméticos. Vômito. Náusea. Carbamazepina. /prevenção & controle.

ABSTRACT CONTEXT AND OBJECTIVE: Nausea and vomiting are major inconveniences for patients undergoing chemotherapy. Despite standard preventive treatment, chemotherapy-induced nausea and vomiting (CINV) still occurs in approximately 50% of these patients. In an attempt to optimize this treatment, we evaluated the possible effects of carbamazepine for prevention of CINV. DESIGN AND LOCATION: Prospective nonrandomized open-label phase II study carried out at a Brazilian public oncology service. METHODS: Patients allocated for their first cycle of highly emetogenic chemotherapy were continuously recruited. In addition to standard antiemetic protocol that was made available, they received carbamazepine orally, with staggered doses, from the third day before until the fifth day after chemotherapy. Considering the sparseness of evidence about the efficacy of anticonvulsants for CINV prevention, we used Simon’s two-stage design, in which 43 patients should be included unless overall complete prevention was not achieved in 9 out of the first 15 entries. The Functional Living Index-Emesis questionnaire was used to measure the impact on quality of life. RESULTS: None of the ten patients (0%) presented overall complete prevention. In three cases, carbamazepine therapy was withdrawn because of somnolence and vomiting before chemotherapy. Seven were able to take the medication for the entire period and none were responsive, so the study was closed. There was no impact on the patients’ quality of life. CONCLUSION: Carbamazepine was not effective for prevention of CINV and also had a deleterious sideeffect profile in this population. CLINICAL TRIAL REGISTRATION: NCT01581918. RESUMO CONTEXTO E OBJETIVO: Náusea e vômito são inconvenientes importantes para pacientes submetidos a quimioterapia. A despeito do tratamento preventivo padrão, náuseas e vômitos induzidos por quimioterapia (NVIQ) ocorrem em aproximadamente 50% dos pacientes. Na tentativa de otimizar este tratamento, avaliamos os possíveis efeitos da carbamazepina na prevenção de náuseas e vômitos induzidos por quimioterapia. TIPO DE ESTUDO E LOCAL: Estudo fase II, prospectivo, não randomizado, aberto, realizado em um serviço público brasileiro de oncologia. MÉTODOS: Recrutaram-se continuamente pacientes alocados para o primeiro ciclo de quimioterapia altamente emetogênica. Além do protocolo anti-emético padrão disponibilizado, os pacientes receberam carbamazepina, por via oral, em doses escalonadas, a partir do terceiro dia anterior até o quinto dia após a quimioterapia. Dada a escassa evidência de eficácia dos anticonvulsivantes na prevenção de NVIQ, adotamos o desenho de Simon em duas fases, que deveria incluir 43 pacientes a não ser que prevenção completa global não fosse alcançada em 9 dos primeiros 15 participantes. O questionário “Functional Living Index-Emesis” foi usado para avaliar o impacto na qualidade da vida. RESULTADOS: Nenhum dos 10 pacientes (0%) apresentou prevenção completa global. Três tiveram a carbamazepina suspensa por sonolência e vômito antes da quimioterapia. Sete foram capazes de tomar a medicação por todo o período proposto e nenhum obteve resposta, sendo então interrompido o estudo. Não houve impacto na qualidade da vida. CONCLUSÃO: Carbamazepina não foi efetiva para prevenção de NVIQ e apresentou perfil deletério de efeitos adversos nesta população. REGISTRO DE ENSAIO CLÍNICO: NCT01581918.

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ORIGINAL ARTICLE | Santana TA, Cruz FM, Trufelli DC, Glasberg J, Giglio AD

INTRODUCTION Nausea and vomiting are major inconveniences for patients undergoing cancer therapy. These symptoms, which are both common and stressful, are reported by almost half of such patients, either as a consequence of the illness itself, or as a treatment side effect.1 They have a strikingly negative impact on these patients’ functional, emotional, social and nutritional status, ultimately leading to impairment of quality of life.2,3 Several factors have been implicated in development of chemotherapy-induced nausea and vomiting (CINV), i.e. the intrinsic emetogenicity of some chemotherapeutic agents, either alone or in combination.2,4,5 CINV is classified according to the timing of the occurrence: acute — occurs and resolves within  the  first  24  hours after chemotherapy; or delayed — occurs after the first 24 hours after chemotherapy administration.5,6 Because of the severity of the acute phase, this has been more often targeted in therapeutic intervention studies. However, although the symptoms in the delayed period are less marked than those observed in acutely started nausea and vomiting, its course can be more protracted, resulting in poor hydration and nutrition control, in addition to poor performance status.7,8 According to the American Society of Clinical Oncology (ASCO) guidelines for antiemetic management in cancer patients, the standard preventive treatment for CINV is based on selective 5-HT3-receptor antagonists (5HT3AR), corticosteroids and neurokinin-1-receptor antagonists (NK1AR), combined to match the intensity of chemotherapy-induced vomiting.9-14 Despite the use of such therapy, approximately 50% of patients still present CINV.15 However, treatment with these three drugs has a high cost and some of them are unavailable in centers where healthcare funding is provided by the government. In most Brazilian cities, for instance, cancer patients covered by the national healthcare system have no sponsorship for use of either 5HT3RA or NK1RA while being treated in outpatient clinics. In this setting, because medicines are unaffordable for most of these patients, CINV control is even more poorly accomplished. Efforts to improve CINV prevention have led to investigation of other drugs that can be added to the standard treatment, thus retaining the effectiveness of antiemetics at lower cost. With this purpose, Cruz et al. developed a phase II randomized trial in which they demonstrated that the preventive antiemetic action of gabapentin increased when it was included in the combined treatment during the first cycle of highly emetogenic chemotherapy. Although the mechanism of action of gabapentin has not been well clarified, this trial suggested that anticonvulsant drugs could be promising for prevention of CINV.16 Carbamazepine was reported by Strohscheer and Borasio as being completely successful in combating CINV in one patient with meningeal carcinomatosis.17

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OBJECTIVE In the present study, the primary objective was to evaluate the possible effects of carbamazepine in preventing nausea and vomiting induced by highly emetogenic chemotherapy. The secondary objective was to evaluate the side effects of this treatment and its possible influence on patients’ quality of life. METHODS Patients were continuously recruited at a Brazilian public oncology service. Between December 2011 and March 2012, patients ≥ 18 years of age, with Eastern Oncology Group (ECOG) grade ≤ 2, who were scheduled to receive their first cycle of moderately or highly emetogenic chemotherapy (defined as cisplatin, doxorubicin or epirubicin at doses higher than 60 mg/m2, 50 mg/m2 and 50 mg/m2 respectively) were selected to enter the study group after signing an informed consent form. The exclusion criteria were as follows: presence of concurrent diseases as possible causes of nausea and vomiting; concomitant radiotherapy; regular use of opioids, corticosteroids, benzodiazepines, tricyclic antidepressants or cannabinoids before chemotherapy; and failure to attend follow-up visits. This study was approved by our local ethics committee. All patients received the standard antiemetic treatment that was available, which was based on intravenous ondansetron (8 mg), dexamethasone (10 mg) and ranitidine (50 mg) before chemotherapy infusion, followed by oral dexamethasone (4 mg), twice a day on days 2 and 3. Carbamazepine was added to this treatment in accordance with the following schedule: one tablet (200 mg) four times a day on the third day before chemotherapy; one tablet twice a day on the second day before chemotherapy; and one tablet three times a day starting on the day before chemotherapy and continuing until the fifth day after chemotherapy. The patients were asked to record vomiting episodes on diary cards, starting on the day of chemotherapy infusion (0 h) and continuing until the morning of day 6 (120 h). In case of need, participants were free to take a “rescue therapy”, and the components of this were also to be recorded. The rescue medications included 5HT3RA, phenothiazines, butyrophenones and domperidone. Complete prevention of nausea and vomiting was defined as the absence of any episode of these events and no use of rescue medication. Symptoms were defined as acute (occurring during the first 24 hours after chemotherapy), delayed (occurring from day 2 to day 5 after chemotherapy) or overall (occurring over the full 120 hours of the study).18,19 Since NK1AR is not provided to Brazilian patients through the public healthcare system, this drug was not used. The patients filled out the Functional Living Index-Emesis (FLIE) questionnaire on days 1 and 6, as backing for measurement

Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study | ORIGINAL ARTICLE

of the impact of CINV on their quality of life.18 Adverse events were recorded up to the visit on day 6 after chemotherapy. Considering that there is a lack of evidence regarding the efficacy of anticonvulsants for CINV prevention, Simon’s optimal two-stage design19 was used. Based on the previous trial by Cruz et al.16 at our institution, which resulted in a 42.5% control rate in the placebo group, we used a control rate < 50% as the null hypothesis to be tested and a rate > 70% as the alternative hypothesis, since the previous trial showed a 20% benefit from associating gabapentin. The initial end point to be pursued was full control for a minimum of 9 patients out of the 15 in the first stage of the study. Fulfillment of this aim would maintain accrual of an additional 28 patients as a second phase. At the end of the study, in accordance with its design, achievement of complete control in 27 or more patients would be required to reject the null hypothesis. This design had 80% power while maintaining an α error rate of 5%. Summary statistics, including means, standard deviations and medians, were generated for continuous variables.19,20 RESULTS Twelve patients were enrolled in the first phase of the study. These patients were continuously recruited and were all women who had been assigned to receive a highly emetogenic chemotherapeutic regimen of doxorubicin and cyclophosphamide for treatment of breast cancer (100%). The mean age was 48 years (Table 1). Two patients were excluded because of refusal to sign the consent statement and opioid use during the study period. Three patients could not complete the intended treatment due to the advent of untoward manifestations before starting chemotherapy: two presented vomiting before chemotherapy infusion and one had excessive (grade 3) somnolence. The primary objective of the study was not accomplished, since seven patients proved unresponsive to their properly taken trial treatment throughout the intended time span. Since this finding precluded the alternative hypothesis (> 70%), the study was discontinued. Other adverse events are displayed in Table 2. Acute complete control failed in all cases. One patient (10%) achieved acute control of vomiting and this same patient also achieved delayed complete protection (10%). Rescue medications were necessary for nine patients (90%) (Table 3). There was no impact on patients’ quality of life, according to results from the FLIE questionnaire. DISCUSSION The present study showed that carbamazepine was ineffective for CINV prevention. All patients failed to attain complete control of their symptoms, and most (90%) needed rescue medications. Moreover, carbamazepine was associated with more side effects

than expected, such as somnolence and dizziness, in addition to induction of vomiting before chemotherapy infusion onset in approximately 20% of the patients. Table 1. Patients’ characteristics All patients (n = 10) Gender Female 10 (100%) Mean age (years) 48 ECOG score 0 10 (100%) 1 0 (0%) 2 0 (0%) Type of chemotherapy AC 10 (100%) ECOG = Eastern Oncology Group; AC = adriamycin (doxorubicin) and cyclophosphamide.

Table 2. Adverse events Type of toxicity Anorexia Grade 1 Grade 2 Grade 3 Constipation Grade 1 Grade 2 Grade 3 Dysgeusia Grade 1 Grade 2 Grade 3 Dyspepsia Grade 1 Grade 2 Grade 3 Fatigue Grade 1 Grade 2 Grade 3 Somnolence Grade 1 Grade 2 Grade 3 Dizziness Grade 1 Grade 2 Grade 3

n (%) 1 (10%) 1 (10%) 0 2 (20%) 0 0 0 2 (20%) 0 1 (10%) 0 0 3 (30%) 1 (10%) 0 4 (40%) 3 (30%) 1 (10%) 1 (10%) 3 (30%) 1 (10%)

Table 3. Complete control over nausea and vomiting and use of rescue medication, according to study phase Control over nausea and vomiting Use of rescue medication

Acute 0 9 (90%)

Delayed 1 (10%) 5 (50%)

Overall 0 9 (90%)

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At our institution, Cruz et al. conducted a prospective, double-blinded, placebo-controlled study that showed that adding gabapentin to the standard preventive antiemetic treatment for moderately and highly emetogenic chemotherapy was effective (65% vs. 42.5%; P = 0.04).16 Their trial demonstrated that the acute complete control rate and use of gabapentin were independent factors for achieving an overall complete response. These results suggested that gabapentin might be a cost-effective well-tolerated alternative to NK1RA, with a safety profile similar to that of the placebo. However, despite the anticonvulsant action of carbamazepine, this drug failed to relieve symptoms in our study, given that nausea and vomiting were not curbed in any of the participants, and that this drug was even hazardous to 30% of them because it elicited grade II dizziness and somnolence. The only patient who achieved delayed complete control had previously achieved acute control of vomiting. Although the antiemetic mechanism of action of gabapentin remains unknown, the reason for the different results from these two studies, which were carried out with similar methods in overlapping groups of subjects, could be that over the therapeutic concentration range, carbamazepine does not affect the GABA or glutamate-mediated neuronal pathways.21 GABA-related drugs need to be reassessed in future trials in order to establish their value as adjuvants in dealing with CINV. Strohscheer and  Borasio reported on a patient who achieved complete cessation of therapy-refractory nausea and vomiting through use of carbamazepine.17 This patient presented meningeal carcinomatosis and paroxysmal syndrome as the causes of the symptoms. Our patients did not have any evidence of central nervous system involvement and failed to control nausea and vomiting when treated with carbamazepine. Further studies will be needed in order to better understand why carbamazepine hinders nausea and vomiting in meningeal carcinomatosis patients but, contradictorily, is disappointing in unaffected patients. Phase III studies have already shown that benzodiazepines and olanzapine are effective for improving control over CINV when combined with standard treatment based on 5HT3RA and corticosteroids.22-24 In the present study, we used Simon’s optimal two-stage design because of the lack of evidence regarding carbamazepine use for preventing CINV. This is an innovative methodology for investigating nausea and vomiting, and its main advantage is that it avoids exposure of too many patients to an ineffective treatment. It should be reappraised in future pilot trials concerning prevention of CINV.19,25 Furthermore, other comparative studies with larger samples may be necessary to corroborate these data and evaluate the safety of carbamazepine.

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CONCLUSION Carbamazepine failed to prevent CINV and also presented a deleterious side-effect profile among the patients studied. Based on these data, carbamazepine is not advisable as an antiemetic medication for patients undergoing chemotherapy outside of experimental settings. REFERENCES 1. Warr DG. Chemotherapy-and cancer-related nausea and vomiting. Curr Oncol. 2008;15(Suppl 1):S4-9. 2. Herrstedt J, Dombernowsky P. Anti-emetic therapy in cancer chemotherapy: current status. Basic Clin Pharmacol Toxicol. 2007;101(3):143-50. 3. Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol. 2006;24(27):4472-8. 4. Wickham R. Best practice management of CINV in oncology patients: II. Antiemetic guidelines and rationale for use. J Support Oncol. 2010;8(2 Suppl 1):10-5. 5. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-94. 6. Frame DG. Best practice management of CINV in oncology patients: I. Physiology and treatment of CINV. Multiple neurotransmitters and receptors and the need for combination therapeutic approaches. J Support Oncol. 2010;8(2 Suppl 1):5-9. 7. Roila F, Donati D, Tamberi S, Margutti G. Delayed emesis: incidence, pattern, prognostic factors and optimal treatment. Support Care Cancer. 2002;10(2):88-95. 8. Kris MG, Roila F, De Mulder PH, Marty M. Delayed emesis following anticancer chemotherapy. Support Care Cancer. 1998;6(3):228-32. 9. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189-98. 10. Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapyinduced emesis. Support Care Cancer. 2007;15(9):1023-33. 11. Bonneterre J, Chevallier B, Metz R, et al. A randomized doubleblind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy. J Clin Oncol. 1990;8(6):1063-9. 12. Fujii M, Kanke M, Arai Y, et al. [A randomized crossover comparison of azasetron alone and azasetron plus dexamethasone for the prevention of nausea and vomiting by chemotherapy including cisplatin]. Gan To Kagaku Ryoho. 2000;27(10):1557-63. 13. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a metaanalysis of randomized evidence. J Clin Oncol. 2000;18(19):3409-22.

Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study | ORIGINAL ARTICLE

14. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-

Sources of funding: None

induced emesis by a selective neurokinin-1-receptor antagonist.

Conflict of interest: None

L-754,030 Antiemetic Trials Group. N Engl J Med. 1999;340(3):190-5. 15. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of

Date of first submission: September 17, 2012

aprepitant for the prevention of chemotherapy-induced nausea and

Last received: July 8, 2013

vomiting in patients with breast cancer after moderately emetogenic

Accepted: July 16, 2013

chemotherapy. J Clin Oncol. 2005;23(12):2822-30. 16. Cruz FM, de Iracema Gomes Cubero D, Taranto P, et al. Gabapentin for

Address for correspondence:

the prevention of chemotherapy- induced nausea and vomiting: a

Thaiana Aragão Santana

pilot study. Support Care Cancer. 2012;20(3):601-6.

Rua Calixto da Mota, 106 — apto 94

17. Strohscheer I, Borasio GD. Carbamazepine-responsive paroxysmal

Vila Mariana — São Paulo — Brasil

nausea and vomiting in a patient with meningeal carcinomatosis.

CEP 04117-100

Palliat Med. 2006;20(5):549-50.

Tel. (+55 11) 3807-1578

18. Decker GM, DeMeyer ES, Kisko DL. Measuring the maintenance of daily life activities using the functional living index-emesis (FLIE) in

Cel. (+5511) 99891-6585 E-mail: [email protected]

patients receiving moderately emetogenic chemotherapy. J Support Oncol. 2006;4(1):35-41, 52. 19. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1-10. 20. Hahn NM, Zon RT, Yu M, et al. A phase II study of pemetrexed as second-line chemotherapy for the treatment of metastatic castrateresistant prostate cancer (CRPC); Hoosier Oncology Group GU03-67. Ann Oncol. 2009;20(12):1971-6. 21. Lasoń W, Dudra-Jastrzębska M, Rejdak K, Czuczwar SJ. Basic mechanisms of antiepileptic drugs and their pharmacokinetic/ pharmacodynamic interactions: an update. Pharmacol Rep. 2011;63(2):271-92. 22. Tan L, Liu J, Liu X, et al. Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res. 2009;28:131. 23. Harousseau JL, Zittoun R, Bonneterre J, Hedouin M, Ouvry J. Amélioation du contrôle des nausées et vomissements lors d’une chimithérapie modérément émétisnate, par l’association ondansétron méthylprednisolone

et

lorazépam,

antiémétique

antérieure

[Improvement in the control of chemotherapy induced emesis with ondansetron, methylprednisolone and lorazepam combination in patients treated by a moderate emetic treatment and uncontrolled by a previous antiemetic combination]. Bull Cancer. 2000;87(6):491-7. 24. Meden H, Meissner O, Conrad A, Kuhn W. Improved control of nausea and emesis with a new bromazepam-containing ondansetron regimen in ovarian cancer patients receiving chemotherapy with carboplatin and cyclophosphamide. Eur J Gynaecol Oncol. 1996;17(2):114-22. 25. Mander AP, Thompson SG. Two-stage designs optimal under the alternative hypothesis for phase II cancer clinical trials. Contemp Clin Trials. 2010;31(6):572-8.

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ORIGINAL ARTICLE

DOI: 10.1590/1516-3180.2014.1323617

Prevalence of risk factors for stuttering among boys: analytical cross-sectional study Prevalência dos fatores de risco para gagueira entre meninos: estudo transversal analítico Cristiane Moço Canhetti OliveiraI, Paula Roberta NogueiraII Fluency Studies Laboratory, Department of Speech and Hearing Disorders, Universidade Estadual Paulista, Marília, São Paulo, Brazil 

PhD. Professor, Postgraduate Program on Speech and Hearing Disorders, Department of Speech and Hearing Disorders, Universidade Estadual Paulista (Unesp), Marília, São Paulo, Brazil. I

Speech Therapy Student, Department of Speech and Hearing Disorders, Universidade Estadual Paulista (Unesp), Marília, São Paulo, Brazil.

II

KEY WORDS: Stuttering. Risk factors. Speech disorders. Genetics. Speech, language and hearing sciences. PALAVRAS-CHAVE: Gagueira. Fatores de risco. Distúrbios da fala. Genética. Fonoaudiologia.

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ABSTRACT CONTEXT AND OBJECTIVE: There have been few studies on the risk factors for subgroups of stuttering. The aim of this study was to characterize the risk factors for developmental familial stuttering among boys who stutter and who do not stutter, such as disfluency types, associated quality and communication factors, emotional and physical stress, familial attitudes and personal reactions.  DESIGN AND SETTING: Analytical cross-sectional study with a control group, performed at the Fluency Studies Laboratory of the Department of Speech and Hearing Disorders of a public university. METHODS: The parents of 40 age-matched stuttering and non-stuttering boys took part in this study. The participants were divided into two groups: stuttering children (SC) and non-stuttering children (NSC), with ages between 6 years 0 months and 11 years 11 months. Initially, all of the participants underwent a fluency assessment and then data were gathered using the Protocol for the Risk of Developmental Stuttering. RESULTS: There were no differences in the physical stress distribution factors and personal reactions between the groups. Inappropriate familial attitudes were presented by 95% of the SC and 30% of the NSC. Four risk factors analyzed were not shown by the NSC, namely stuttering-like disfluency, quality factors, physical stress and emotional stresses. CONCLUSIONS: The findings suggest that the presence of stuttering-like disfluency, associated quality and communication factors, emotional stress and inappropriate family attitudes are important risk factors for familial developmental stuttering among boys. RESUMO CONTEXTO E OBJETIVO: Há poucos estudos sobre os fatores de risco para os subgrupos de gagueira. O objetivo deste estudo foi caracterizar os fatores de risco para a gagueira desenvolvimental familial em meninos que gaguejam e que não gaguejam como tipologia das disfluências, fatores qualitativos e comunicativos associados, estresse físico e emocional, atitude familiar e reação pessoal. TIPO DE ESTUDO E LOCAL: Estudo transversal analítico com um grupo controle, realizado no Laboratório de Estudo da Fluência, que faz parte do Departamento de Fonoaudiologia de uma universidade pública. MÉTODOS: Pais de 40 meninos com e sem gagueira pareados por idade fizeram parte do estudo. Os participantes foram divididos em dois grupos: crianças com gagueira e crianças sem gagueira, com idades entre 6 anos 0 meses e 11 anos 11 meses Inicialmente todos os participantes foram submetidos a uma avaliação de fluência e depois os dados foram coletados por meio do Protocolo de Risco para a Gagueira do Desenvolvimento. RESULTADOS: Não foi observada diferença nos fatores de estresse físicos e reações pessoais entre os grupos. As atitudes inadequadas familiares foram apresentadas por 95% das crianças com gagueira e 30% das crianças sem gagueira. Quatro fatores de risco analisados não ocorreram nas crianças sem gagueira, a saber, disfluências gagas, fatores qualitativos, estresse físico e emocional. CONCLUSÕES: Os achados sugerem que a presença de disfluências gagas, fatores qualitativos e comunicativos associados, estresse emocional e atitude familiar inadequada são fatores de risco importantes para a gagueira desenvolvimental familial em meninos.

Prevalence of risk factors for stuttering among boys: analytical cross-sectional study | ORIGINAL ARTICLE

INTRODUCTION Stuttering is a multifactorial and complex disorder that results from the influence of many factors, which include genetic predisposition, motor speech skills, linguistic skills and cognitive, emotional and environmental factors.1 It is know that the spectrum of risk factors for stuttering is wide and heterogeneous.2 Stuttering typically begins during the preschool years, which suggests that many important factors act during this developmental process.3 There is a clinically important reason for identifying stuttering among preschoolers. It has been shown that young stuttering children respond well to direct intervention, thereby helping to prevent the disorder from developing into a more intractable chronic form.4,5 Therefore, early diagnosis and intervention are important and, for this reason, the risk factors for persistent developmental stuttering need to be investigated.6-8 A wide range of possible risk factors has been proposed in the literature, including age; gender; type and manner of onset; duration of the disfluency; type of disfluency; associated communicative and qualitative factors; physical and emotional stress; family history of stuttering; personal, familial and social reaction; and family attitudes.9 Gender is an important risk factor for stuttering, given that stuttering is more prevalent among males.3,10,11 This risk among boys is higher when any communication disorder is present, independent of the family history.8 Associated qualitative factors, such as body and facial muscle tension, rapid speech rate, uncoordinated breathing and/or vocal intensity and vocal frequency variation may be present together with the disfluency seen among children who stutter.12 Regarding physical stress, some authors11,13 have reported that the origin of sporadic stuttering (without a family history of stuttering) may be found in perinatal or childhood physical trauma that perhaps caused some brain dysfunction. Some examples of the physical stress that occurs just prior to the onset of stuttering have included such conditions as respiratory problems, surgery or illness requiring hospitalization, asthma requiring medical treatment, and acute illness.3 In the same way, emotional stress can contribute towards the beginning of stuttering, such as divorcing of parents, moving, death of a beloved pet, birthdays, family vacations or excessive sibling rivalry.3 Other communicative disorders can occur together with persistent developmental stuttering, like phonological or myofunctional disorders. Moreover, some studies have shown higher scores in vocabulary tests associated with stuttering beginning in young children.3,14 The disfluency of stuttering consists of repetition of sounds or syllables and blockage or prolongation of sounds.15,16

Several studies over past decades have shown that genetic factors are involved in transmission of susceptibility to stuttering.17,18 A positive family history may play an important role in the diagnosis process, since it increases the risk of persistent developmental stuttering.3,6 Family attitudes and inappropriate behavior regarding childhood disfluency can also have an influence through increasing the disruptions exhibited by such children.19-21 Another important point to be considered in this risk factor analysis is the personal reaction. People who are perfectionists or anxious, shy and insecure are more likely to suffer from persistent stuttering when it is associated with other risk factors.9 There have been few studies on the risk factors for subgroups of stuttering. Thus, it is very important to identify risk factors for stuttering and make comparisons with controls in order to check which are the primary risk factors for the disorder. Knowledge of these factors is important in adopting preventive measures and more appropriate treatment for stuttering. OBJECTIVE The aim of this study was to characterize the risk factors for developmental familial stuttering among boys who stutter and who do not stutter, such as the type of disfluency, associated quality and communication factors, emotional and physical stress factors, family attitudes and personal reactions.  METHODS This was an analytical cross-sectional study with a control group that was conducted at the Fluency Studies Laboratory of the Department of the Speech and Hearing Disorders of a public university clinic. This study included boys who stuttered with ages between 6 years 0 months and 11 years 11 months. The present study used a non-probabilistic convenience sample that originally comprised 45 stutterers who were seen at the Fluency Studies Laboratory between April 2012 and September 2012, of whom 36 were children between 6 years 0 months and 11 years 11 months of age, but 9 were girls. Thus, the group was initially composed of 27 boys who stuttered. However, only 20 of them met the inclusion criteria. The procedure for selecting the 20 boys who did not stutter consisted of recruitment among the students at a public school who met the inclusion criteria. In this manner, the study sample was composed of 40 boys aged 6 years 0 months and 11 years 11 months, of whom 20 were stutterers and 20 were non-stutterers. The protocol for this study was approved by the institution’s Ethics Committee (no 0396/2011), and the adults responsible for these children signed a consent statement. 

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Subjects Forty age-matched stuttering and non-stuttering children and their parents took part in this study. The participants who stuttered were invited when attending the Fluency Studies Laboratory, which is part of the speech clinic at a public university. Fluent control participants were recruited through contacting students at a public school in Marília, Brazil, the city where the study was developed. The participants were divided into two groups: stuttering children (SC) and non-stuttering children (NSC), in order to investigate whether there were any differences in relation to any of the risk factors for persistent developmental stuttering that were analyzed. The SC group was composed of 20 boys with ages between 6  years 0 months and 11 years 11 months, with a diagnosis of stuttering. The NSC group was composed of 20 boys who were age-matched with the SC. The inclusion criteria for the two groups were as follows: age between 6 years 0 months and 11 years 11 months, male gender and speakers of Brazilian Portuguese, without any other associated communication, neurological, hearing, visual or cognitive shortfall. The inclusion criteria for the SC group were as follows: stuttering disorders reported by both parents; developmental stuttering present before 10 years of age; minimum duration of disfluency of 12 months, without remission (persistent); demonstration of stuttering in at least 3% of the syllables in the speech sample obtained by the examiner;22-24 score of 11 points or more (i.e. severity equivalent to at least “mild”) on the Stuttering Severity Instrument 3 (SSI-3).25 The selection criterion for the NSC were as follows: no personal or family history of stuttering and/or cluttering; presentation of not more than two instances of stuttering-like disfluency per 100 syllables of conversational speech; and a total overall score of 10 points or lower (i.e. a severity equivalent of less than “mild”) on the Stuttering Severity Instrument 3 (SSI-3).25 Procedures Initially, all of the boys underwent a fluency assessment to separate them into the two groups (SC and NSC) and then data were gathered using the Protocol for the Risk of Developmental Stuttering (PRGD).26 Speech samples were obtained in situations of spontaneous speech. Each speech sample was audiotaped and contained at least 200 fluent syllables. The samples were transcribed literally.26 The types of disfluency were analyzed to differentiate between other disfluencies (OD) and stuttering-like disfluencies (SLD), in accordance with the Fluency Profile Assessment,26 and thus to calculate the percentage of stuttered syllables.

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The stuttering severity was determined by means of an international instrument (the Stuttering Severity Instrument, SSI-3).25 This test assesses the frequency and duration of speech disruptions, and also the presence of physical concomitants associated with these disruptions. Based on these parameters, the stuttering severity index was determined as very mild, mild, moderate, severe or very severe. Any histories of important risk factors for persistent developmental stuttering, like age, type of disfluency, associated communicative and qualitative factors, physical and emotional stress, family history, family attitudes and personal reactions (Protocol for the Risk of Developmental Stuttering, PRGD)9 were elicited from all the participants’ parents (SC and NSC groups). Statistical analysis The results were expressed as percentages of the presence of each risk factor, analyzed for the two groups. The P values were calculated by means of the chi-square test. Descriptive values below 5% (P value < 0.05) were considered statistically significant. The data were analyzed using the Statistical Package for the So­cial Sciences (SPSS) 20.0 software (SPSS Inc., Chicago, USA). RESULTS With regard to the purpose of this study, the data obtained are presented in table form. Table 1 shows the individuals’ ages, the total number of stuttering-like disfluencies (SLDs), the percentage of stuttered syllables (%ss) and the total score of the Stuttering Severity Instrument (SSI-3).25 Table 2 describes the risk factors for persistent developmental stuttering among the SC and NSC. There were no differences in the distribution of physical stress or personal reactions between the groups. Inappropriate family attitudes were shown by 95% of the SC and 30% of the NSC. Four risk factors that were analyzed were not shown by the NSC, i.e. stuttering-like disfluency, quality factors (rapid speech rate, uncoordinated breathing or associated stress), communication factors (phonological or myofunctional disorders) and emotional stress (parental death, parental divorce or familial or parental disease or illness). Table 1. Means and standard deviations (SD) of age and speech fluency results of the stuttering children (SC, n = 20) versus non-stuttering children (NSC, n = 20)

Age Stuttering-like disfluency Percentage of stuttered syllables Total score for Stuttering Severity Instrument

SC Mean (SD) 7.50 (1.43) 14.0 (8.80) 7.00 (4.40)

NSC Mean (SD) 7.55 (1.43) 2.00 (1.84) 1.00 (0.92)

23.0 (6.87)

6.00 (1.10)

Prevalence of risk factors for stuttering among boys: analytical cross-sectional study | ORIGINAL ARTICLE

Table 2. Prevalence of risk factors among stuttering and non-stuttering children, with P-values Risk factors Stuttering-like disfluencies Quality factors Communicative factors Physical stress factors Emotional stress factors Family attitudes Personal reactions

Stuttering Non-stuttering P-value children children 100% 0% < 0.001 100% 0% < 0.001 75% 0% < 0.001 35% 10% 0.058 50% 0% < 0.001 95% 30% < 0.001 95% 100% 0.0311

DISCUSSION Several studies have shown that, in cases of stuttering, the earlier an intervention is instituted, the more favorable the outcome is.4,5 Therefore, studying the risk factors for this disorder is very important for clinical practice and for improving the knowledge of developmental stuttering. Our study showed the importance of studying risk factors for developmental stuttering in Brazil.8,27,28 The present study on the risk factors for persistent developmental stuttering forms an important part of the process of diagnosing fluency disorders. These data, together with fluency assessment data will lead to precise diagnosis and support for the therapeutic process. In this study, some significant factors were associated with familial persistent developmental stuttering among boys, such as stuttering-like disfluency (SLD) and quality, communication and emotional stress factors, as well as family attitudes. This suggests that occurrences of these factors are associated with a higher risk of stuttering for this subgroup. Furthermore, the results showed that there were no differences between the groups (SC versus NSC) with regard to physical stress factors and personal reactions. Regarding stuttering-like disfluencies (SLDs; i.e. soundsyllable repetition, prolongation and blockage), our study confirmed that observable speech disruption is a central feature of this disorder.29 Thus, this is considered to be a chronic disorder that involves involuntary disruptions in fluent speech.30 Developmental stuttering presents as a chronic disruption of an individual’s ability to produce smooth, effortless and forwardmoving speech.31 In other words, the principal manifestation of the stuttering, regardless of gender, is stuttering-like disfluencies (SLDs). Therefore, this is not specifically a characteristic of the subgroup of boys. All the children who stuttered presented at least one of the quality factors, while all the children who did not stutter did not present these, according to their parents’ reports. A previous study correlated the associated quality factors, such as body and facial muscle tension, rapid speech rate, uncoordinated breathing and/or vocal intensity and vocal frequency variation,

with disfluencies among SC.9 In the present study, we confirmed that disfluencies among SC can be followed by quality factors. The majority of our children who stuttered presented some communication factors, and all the children who did not stutter did not present these, according to their parents’ reports. These results are in accordance with another study that reported that children who stuttered frequently presented other associated communication factors such as phonological or myofunctional disorders.9 The present study confirmed the findings previously published regarding speakers of Brazilian Portuguese, in relation to emotional stress factors. This previous study also found a significant relationship between persistent developmental stuttering among boys and emotional stress factors.28 Our study presents evidence that stuttering is associated with multiple factors, like many other authors have previously shown.1,2 In our study, we found that family attitudes were inappropriate in the cases of 95% of the children who stuttered and 30% of the controls. Therefore, this finding confirmed that the prevalence of inappropriate family attitudes among children who stuttered was higher than among the controls. In another cross-sectional study carried out in São Paulo, Brazil, it was found that the highest risk factor for worse stuttering was the quality of the parents’ behavior, with significant differences.9 Like in the present study, other authors have also demonstrated that among the families of children who stuttered, inappropriate family attitudes were commonly found.9,19 For example, faster speaking rates among mothers were associated with greater stuttering severity in their children.21 We also found that in this subgroup of persistent developmental stuttering, there was no difference between the SC and NSC in relation to physical stress factors. This finding is similar to that of another study on Brazilian children with familial stuttering, which showed no relationship between their stuttering and physical stress factors.28 This result is also in line with the findings of Poulos and Webster,13 in which physical stress factors were correlated with the subgroup of sporadic developmental stuttering, i.e. individuals without any positive family history of stuttering. With regard to personal reactions, there was no significant difference between SC and NSC. This finding suggests, like in other studies, that personal reactions should not be considered to be a causal factor for development of stuttering.32,33 Thus, when the population consists of children, these reactions are not always clear. Although there are many studies on personality and temperament among people who stutter,34-37 there is still no consensus on whether stuttering indeed has any significant impact on people’s personalities. One reason for the contradictory results obtained in this field is the lack of use of standardized questionnaires.38 These results corroborate other studies and will be an

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essential tool in designing and implementing future clinical protocols for diagnosing childhood stuttering in order to determine the risk of this disorder that children present. In order to critically evaluate this study, it is necessary to consider the limitations inherent to the research design and analysis of the study. Firstly, the method of parental reporting that was used to study the risk factors has certain limitations. Although the parents’ answers were restricted in an attempt to gather unambiguous responses, the reporting remains the result of the parents’ perceptions, sensitivity, memory and interpretation, thereby adding some variance to the data. The presence of the researcher during the face-to-face interviews may have influenced the information given by the parents, since they may have provided answers that they thought the researcher wished to hear. Secondly, all the participants were students at a public school and thus were of lower socioeconomic level. Lastly, the findings from this study are subtle and based on a subgroup of developmental stuttering, i.e. familial persistent developmental stuttering among boys, and hence the ability to generalize these results to the wider population of children who stutter may be limited. These limitations, as well as the findings from the current study, suggest important areas for future research. For example, replication of this type of study among girls who stutter might elicit additional data with regard to gender differences among  children who stutter. Furthermore, because the participants were children at a public school, it was not possible to explore different sociocultural factors. Therefore, another suggestion for future research is to study the risk factors in two groups: one composed of children from public schools and another of children from private schools.

4. Bothe AK, Davidow JH, Bramlett RE, Ingham RJ. Stuttering treatment research 1970-2005: I. Systematic review incorporating trial quality assessment of behavioral, cognitive, and related approaches. Am J Speech Lang Pathol. 2006;15(4):321-41. 5. Einarsdóttir J, Ingham RJ. The effect of stuttering measurement training on judging stuttering occurrence in preschool children who stutter. J Fluency Disord. 2008;33(3):167-79. 6. Dworzynski K, Remington A, Rijsdijk F, Howell P, Plomin R. Genetic etiology in cases of recovered and persistent stuttering in an unselected, longitudinal sample of young twins. Am J Speech Lang Pathol. 2007;16(2):169-78. 7. Brosch S, Winkler S. Diagnostik und Therapie bei stotternden Kindern

[Diagnostics

and

therapy

of

stuttering

children].

Laryngorhinootologie. 2008;87(7):511-8; quiz 519-23. 8. Oliveira CMC, Souza HA, Santos AC, Cunha D, Giacheti CM. Fatores de risco na gagueira desenvolvimental familial e isolada [Risk factors in the familial and sporadic developmental stuttering]. Rev CEFAC. 2011;13(2):205-13. 9. Andrade CRF. Gagueira infantil: risco, diagnóstico e programas terapêuticos. Barueri: Pró Fono; 2006. 10. Ambrose NG, Cox NJ, Yairi E. The genetic basis of persistence and recovery in stuttering. J Speech Lang Hear Res. 1997;40(3):567-80. 11. Felsenfeld S, Kirk KM, Zhu G, et al. A study of the genetic and environmental etiology of stuttering in a selected twin sample. Behav Genet. 2000;30(5):359-66. 12. Yairi E, Ambrose NG, Niermann R. The early months of stuttering: a developmental study. J Speech Hear Res. 1993;36(3):521-8. 13. Poulos MG, Webster WG. Family history as a basis for subgrouping people who stutter. J Speech Hear Res. 1991;34(1):5-10. 14. Reilly S, Onslow M, Packman A, et al. Predicting stuttering onset by the age of 3 years: a prospective, community cohort study. Pediatrics. 2009;123(1):270-7.

CONCLUSION The findings suggest that the presence of stuttering-like disfluencies, quality and communication factors, emotional stress factors and inappropriate family attitudes are important risk factors for familial developmental stuttering among boys. Identifying these risk factors might make it possible to define the cases that require intervention, and thus, to provide earlier therapy.

15. Sawyer J, Yairi E. The effect of sample size on the assessment of stuttering severity. Am J Speech Lang Pathol. 2006;15(1):36-44. 16. Suresh R, Ambrose N, Roe C, et al. New complexities in the genetics of stuttering: significant sex-specific linkage signals. Am J Hum Genet. 2006;78(4):554-63. 17. Kang C, Riazuddin S, Mundorff J, et al. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N Engl J Med. 2010;362(8):677-85.

REFERENCES 1. Smith A, Kelly E. Stuttering: A dynamic, multifactorial model. In: Curlee RF, Siegel GM. Nature and treatment of stuttering: new directions. Allyn & Bacon; 1997. p. 204-17. 2. Ajdacic-Gross V, Vetter S, Müller M, et al. Risk factors for stuttering: a secondary analysis of a large data base. Eur Arch Psychiatry Clin Neurosci. 2010;260(4):279-86. 3. Yairi E, Ambrose NG. Early childhood stuttering: for clinicians by clinicians. Austin: Pro-Ed; 2005.

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18. Drayna D, Kang C. Genetic approaches to understanding the causes of stuttering. J Neurodev Disord. 2011;3(4):374-80. 19. Oliveira CM, Araujo FG, Vocurca MC. Atitudes verbais e não verbais de pais de crianças com queixa de gagueira [Familiar counseling and its effects on childhood stuttering]. Revista da Sociedade Brasileira de Fonoaudiologia. 2000;5(7):3-10. 20. Millard SK, Nicholas A, Cook FM. Is parent-child interaction therapy effective in reducing stuttering? J Speech Lang Hear Res. 2008;51(3):636-50.

Prevalence of risk factors for stuttering among boys: analytical cross-sectional study | ORIGINAL ARTICLE

21. Dehqan A, Bakhtiar M, Panahi SS, Ashayeri H. Relationship between

Acknowledgement: The authors would like to thank all the participants,

stuttering severity in children and their mothers speaking rate.

and the director of the public school that the non-stuttering boys

Sao Paulo Med J. 2008;126(1):29-33.

attended, along with the parents who took part in this study  

22. Yairi E, Ambrose N. A longitudinal study of stuttering in children: a preliminary report. J Speech Hear Res. 1992;35(4):755-60. 23. Bloodstein O. A handbook on stuttering. Chicago: National Easter Seal Society; 1995.

Sources of funding: This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp, no. 2012/00540-2) Conflict of interest: None

24. Yairi E, Ambrose N, Cox N. Genetics of stuttering: a critical review. J Speech Hear Res. 1996;39(4):771-84. 25. Riley GD. Stuttering severity instrument for children and adults. Austin: Pro Ed; 1994.

Date of first submission: October 22, 2012 Last received: July 3, 2013 Accepted: July 16, 2013

26. Andrade CRF. Perfil da fluência da fala: parâmetros comparativo diferenciado por idade para crianças, adolescentes, adultos e idosos.

Address for correspondence:

Barueri: Pró-Fono; 2006.

Cristiane Moço Canhetti Oliveira

27. Oliveira CMC, Souza HA, Santos AC, Cunha DS. Análise dos fatores de

Rua Santa Helena, 1967 — casa 23

risco para gagueira em crianças disfluentes sem recorrência familial

Jardim Estoril — Marília (SP) — Brasil

[Analysis of the risk factors for stuttering in disfluent children without

CEP 17514-410

familial recurrence]. Revista CEFAC. 2012;14(6):1028-35.

E-mail: [email protected]

28. Oliveira CMC, Cunha DS, Santos AC. Fatores de risco para gagueira em crianças disfluentes com recorrência familial [Risk factors for stuttering in disfluent children with familial recurrence]. Audiol Commun Res. 2013;18(1):43-9. 29. Yaruss JS. Assessing quality of life in stuttering treatment outcomes research. J Fluency Disord. 2010;35(3):190-202. 30. Tran Y, Blumgart E, Craig A. Subjective distress associated with chronic stuttering. J Fluency Disord. 2011;36(1):17-26. 31. de Andrade CR, Cervone LM, Sasso FC. Relationship between the stuttering severity index and speech rate. Sao Paulo Med J. 2003;121(2):81-4. 32. Iverach L, O’Brian S, Jones M, et al. The five factor model of personality applied to adults who stutter. J Commun Disord. 2010;43(2):120-32. 33. Bloodstein O, Bernstein Ratner N. A handbook on stuttering. 6th ed. Clifton Park: Thomson/Delmar Learning; 2008. 34. Alm PA, Risberg J. Stuttering in adults: the acoustic startle response, temperamental traits, and biological factors. J Commun Disord. 2007;40(1):1-41. 35. Anderson JD, Pellowski MW, Conture EG, Kelly EM. Temperamental characteristics of young children who stutter. J Speech Lang Hear Res. 2003;46(5):1221-33. 36. Schwenk KA, Conture EG, Walden TA. Reaction to background stimulation of preschool children who do and do not stutter. J Commun Disord. 2007;40(2):129-41. 37. Seery CH, Watkins RV, Mangelsdorf SC, Shigeto A. Subtyping stuttering II: contributions from language and temperament. J Fluency Disord. 2007;32(3):197-217. 38. Bleek B, Montag C, Faber J, Reuter M. Investigating personality in stuttering: results of a case control study using the NEO-FFI. J Common Disord. 2011;44(2):218-22.

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DOI: 10.1590/1516-3180.2014.1323619

Genetic diversity among volunteer donors of bone marrow in southeastern Brazil, according to the HLA system Diversidade genética entre doadores voluntários de medula óssea no sudeste do Brasil, segundo o sistema HLA Letícia Sarni RoqueI, Rodolpho Telarolli JuniorII, Leonor Castro Monteiro LoffredoIII Regional Center for Hematology, Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil

MSc. Biomedical Scientist in the Regional Center for Hematology, Hospital of the Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil. I

II MD, PhD. Adjunct Professor, Department of Biological Sciences, Universidade Estadual Paulista (Unesp), Araraquara, São Paulo, Brazil.

MD, PhD. Adjunct Professor, Department of Social Dentistry, Universidade Estadual Paulista (Unesp), Araraquara, São Paulo, Brazil.

III

KEY WORDS: Histocompatibility antigens. Transplantation. HLA antigens. Bone marrow. Public health. PALAVRAS-CHAVE: Antígenos de histocompatibilidade. Transplante. Antígenos HLA. Medula óssea. Saúde Pública.

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ABSTRACT CONTEXT AND OBJECTIVE: Checking the histocompatibility of the molecules of the human leukocyte antigen (HLA) system is vital for performing bone marrow transplantation with allogeneic material. The objective of this study was to characterize bone marrow donors according to gender, age, ethnicity and HLA groups at a regional hemotherapy center in Brazil. DESIGN AND SETTING: Descriptive study on registered donors at a regional hemotherapy center in a public university hospital in the southeastern region of Brazil. METHODS: The records of 66,780 donors who were registered between 2005 and June 2011 were consulted, and the variables studied were tabulated. RESULTS: There were equal numbers of male and female donors and 82.8% of them were under 45 years of age. In terms of ethnicity, 77.3% declared themselves to be white, 15.0% mixed race, 5.7% black and 2% others. In terms of immunogenetic characterization, the most frequent HLA-A allelic group was HLA-A*02, with 39.20% of the donors; in the HLA-B allelic group, the most common was HLA-B*35, with 14.18%; while in the HLA-DRB1 allelic group, the most frequent was HLA-DRB1*03, with 17.03%. Comparison between these results and data from the Brazilian Bone Marrow Donor Registry (REDOME) showed that there were demographic and immunogenetic differences due to the history of immigration in the region of Ribeirão Preto, in southeastern Brazil. CONCLUSIONS: The results reinforce the importance of understanding the demographic and immunogenic profile of regions of Brazil, in order to reduce the waiting time for a histocompatible donor. RESUMO CONTEXTO E OBJETIVO: Para a realização de transplantes de medula óssea com material alogênico, é necessária a verificação de histocompatibilidade das moléculas do sistema HLA (human leukocyte antigen), fundamental para o sucesso desses transplantes. O objetivo desta pesquisa foi caracterizar os doadores de medula óssea segundo gênero, idade, etnia e grupos HLA de um centro regional de hemoterapia brasileiro. TIPO DE ESTUDO E LOCAL: Estudo descritivo dos doadores cadastrados em um centro regional de hemoterapia de um hospital público universitário da região Sudeste do Brasil. MÉTODOS: Foram consultadas as fichas dos 66.780 doadores cadastrados entre 2005 e junho de 2011 e tabuladas as variáveis estudadas. RESULTADOS: Encontrou-se distribuição equilibrada entre os gêneros, e 82,8% dos doadores tinham até 45 anos de idade. Quanto à etnia auto-referida, 77,3% se apresentaram como brancos, 15,0% como pardos, 5,7% como negros, os 2% restantes dividindo-se em outras etnias. Quanto à caracterização imunogenética, no grupo alélico HLA-A, o mais frequente foi o HLA-A*02, com 39,20%; no grupo alélico HLA-B, o mais comum foi o HLA-B*35, com 14,18%; no grupo alélico HLA-DRB1, o mais frequente foi o HLA-DRB1*03, com 17,03% do total de doadores. Quando esses resultados são comparados com os dados do cadastro nacional de doadores (REDOME), observam-se diferenças demográficas e imunogenéticas, que se explicam pelo histórico de imigração da região de Ribeirão Preto, no Sudeste brasileiro. CONCLUSÕES: Os resultados encontrados reforçam a importância de conhecer o perfil demográfico e imunogenético das regiões do Brasil, para reduzir o tempo de espera por um doador histocompatível.

Genetic diversity among volunteer donors of bone marrow in southeastern Brazil, according to the HLA system | ORIGINAL ARTICLE

INTRODUCTION Organ and tissue transplantation is one of the techniques that have undergone major medical breakthroughs in the last 50 years, thereby modifying the prognoses of millions of patients. In the 21st century, transplantation for therapeutic purposes has become more common because of better understanding of the mechanisms involved in graft rejection and the advent of highly effective immunosuppressive therapies.1 In Brazil, the history of transplantation started in the 1960s, shortly after its introduction in the countries that initiated the technique.2 The number of transplantations performed in Brazil has been growing year by year, according to the Brazilian Association of Organ Transplants (ABTO). During the 10 years from 2002 to 2011, there was an increase of 350% in the number of transplantations, which totaled 47,062, of which 3.68% were of hematopoietic progenitor cells (bone marrow).3 The first bone marrow transplantations were performed in the 1960s, but they became more common in the 1980s, with many applications in cases of diseases such as hematological malignancies or solid tumors, and in other non-hematological disorders such as inborn errors of metabolism, immune deficiencies and other hemoglobinopathies.4,5 In 2011, 1737 bone marrow transplants were performed, of which 1029 were from autologous donors and 708 from allogeneic donors.3 The major histocompatibility complex (MHC) is a set of genes responsible for encoding the histocompatibility molecules in a particular species, which is called the human leukocyte antigen (HLA) in human beings.6 The classical histocompatible molecules not only are involved in the immune response as cells presenting peptides to the surface receptors of T lymphocytes, but also are important for understanding mechanisms associated with susceptibility or resistance to certain diseases. These molecules are also strongly associated with allorecognition antigens in organ transplantation, which trigger activation of lymphocytes and the process of graft rejection. Therefore, HLA typing is very important in relation to success in bone marrow transplantation, in which the degree of immunological compatibility between donor and patient is crucial, unlike in most solid organ transplants.7-9 OBJECTIVE The objective of this study was to characterize the bone marrow of volunteer donors at a regional hemotherapy center in a university hospital in the southeastern region of Brazil (a hospital comprising a complex of healthcare institutions serving the region), according to gender, age, ethnicity and HLA groups. METHODS The data source for this study was the records of volunteer bone marrow donors registered at the Regional Center for Hematology,

in the teaching hospital of the Ribeirão Preto School of Medicine, University of São Paulo (Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, HCFMRP/USP), an institution founded in 1990. In addition to Ribeirão Preto, there are hemotherapy centers in several other cities in the state of São Paulo: Araçatuba, Batatais, Bebedouro, Fernandópolis, Franca, Presidente Prudente, Olympia and Serrana. Data from these cities relating to the study subject were also included in this present study. All 66,780 donors registered between January 2005 and December 2011 were included in the study. After the donors had gone through interviews, they were given information about the study and were asked to sign a consent form before making the donation and before their records were updated in the institution’s database. Descriptive statistics on variables such as gender, age, self-reported ethnicity and HLA typing were included. The donors were immunogenetically classified by extracting DNA from the complete blood count, using precipitated silica. The polymerase chain reaction-single specific primer (PCR-SSP) was then amplified for each locus using agarose gel and, subsequently, hybridization was performed using specific probes for each locus. The readings were taken from a flow cytometer (Luminex platform) and the results from this platform were interpreted using the HLA Fusion 2.0 software.6 RESULTS Among the donors, we observed that there was a balance between male and female donors with a slight prevalence of male (50.62%) over female donors (49.37%). Regarding age groups, 83.8% of the donors were of ages up to 45 years (Table 1). In terms of self-reported ethnicity, 77.3% declared themselves to be white, 15.0% mixed race and 5.7% black, and the remaining 2% fell into other categories. The immunogenetic characterization of the population of bone marrow donors showed a total of 20 different HLA-A alleles for the HLA-A allelic group. HLA-A*02 was the one most frequently present, in 39.20% of the donors, followed by HLA -A*01 in 17.64% (Table 2). In characterizing the HLA-B allelic group, 35 different alleles were found. The most common one was HLA-B*35, accounting for 14.18%, followed by HLA-B*15, with a share of 13.27 % (Table 3). In characterizing the HLA-DRB1 allelic group, 13 different alleles were found, of which HLA-DRB1*03 was the most frequent with a share of 17.03%, followed by HLA-DRB1*04, which was present in 16.58% of the population (Table 4). DISCUSSION To expedite allogeneic transplantation in Brazil, the Brazilian Bone Marrow Donor Registry (REDOME) was created in 1993 and effectively went into operation in 1999 at the National

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Cancer Institute (INCA).8 REDOME is a database in which all bone marrow volunteer donors in Brazil are registered with their personal particulars and HLA typing. From 2005 onwards, the registry began to include registered donors at blood centers and immunogenetic laboratories across the country. This move, coupled with intense social media activities, changed the existing scenario. It led to an exponential growth in the number of registered donors, which totaled 2,307,114 people in June 2011.10 The present study shows differences in numbers, in comparison with those found in REDOME, as conducted by Bouzas:10 while 77.3% of the donors in Ribeirão Preto were white, 73% in REDOME were white. Regarding the black ethnic group, a disparity was observed in the results, with 12% presented in REDOME and 6% in the present study. For the mixed race group, REDOME presented 10% while the Ribeirão Table 1. Ages of volunteer bone marrow donors registered at the Regional Center for Hematology of the teaching hospital of the Ribeirão Preto School of Medicine, University of São Paulo, 2005 to 2011 Age groups (years) 18 to 25 26 to 35 36 to 45 46 to 55 56 and over

Donors (%) 23.4 35.5 24.9 14.9 1.3

Table 2. Frequencies of HLA-A alleles among the volunteer bone marrow donors registered at the Regional Center for Hematology of the teaching hospital of the Ribeirão Preto School of Medicine, University of São Paulo, 2005 to 2011 HLA-A alleles A*01 A*02 A*03 A*11 A*23 A*24 A*25 A*26 A*29 A*30 A*31 A*32 A*33 A*34 A*36 A*43 A*66 A*68 A*69 A*74

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Frequency (%) 17.64 39.20 11.41 6.04 5.00 8.00 0.84 2.2 2.5 2.8 1.5 0.95 0.72 0.2 0.12 0.01 0.19 0.62 0.01 0.05

Preto study presented 15%. The explanation for these differences probably lies in the demographic history of the central region of the state of São Paulo, which received a large number of immigrants from European countries in the nineteenth century and, conversely, a smaller flow of slaves of African origin into the region.11 In terms of gender, there was a significant disparity between the figures of the Ribeirão Preto study and those of REDOME: while there were equal numbers of male and female donors in the former, female donors accounted for 56% and male donors for 44% in the latter.10 Regarding the age group variable, the two databases presented similar compositions, with a predominance of donors between the ages of 18 and 45. This is a very positive sign, since this group of individuals can be considered to be donors for an extended period of time. Among the allelic groups found in Ribeirão Preto, the most common of all the groups was HLA-A*02, with a frequency of 39.20%. Among the donors of REDOME, this allelic group was also the most frequent, present in 25.8% of the records.12 In the B locus, the allele HLA-B*35 was the most frequent, both in Ribeirão Preto (14.2%) and in REDOME (19.1%). Regarding the DRB1 locus, the one most frequently found in Ribeirão Preto was HLA-DRB1*03 (17.02%), while in REDOME it was HLA-DRB1*04, with 11.90%. The pattern found in Ribeirão Preto was the result, once again, of the demographic peculiarities of the region, due to its history of immigration, thus leading to predominance of alleles of European origin. According to Bone Marrow Donors Worldwide (BMDW), an organization that collects the records of bone marrow donors worldwide, there were 18,513,185 registered donors in 47 countries by the end of 2011.13 These donors, of whom 2,307,114 came from Brazil, were dispersed in 21 allelic groups of HLA-A, 35 allelic groups of HLA-B and 13 allelic groups of HLA-DRB1. Since Brazil is a multi-racial country, it is essential to increase the number of registered donors, so that this raises the chances that a Brazilian recipient will be given a histocompatible stem cell transplantation.14 In late 2011, from preliminary investigations on low or intermediate-resolution tests from the bank of registered donors in REDOME, the probability of finding a locus A, B or DRB1 (6 x 6) compatible donor was 70.53%. In countries that are ethnically more homogeneous, such as Germany and Japan, where the national databases reach a million donors, the possibility of finding a donor for the natives is 85 to 90%.10 In bone marrow transplantations, unrelated donors are the option most used today.15 However, success in finding a compatible donor depends on race and may be 60 to 70% in the case of Caucasians or only 10 to 20% in the case of other races or mixed race. Using umbilical cord cells is an interesting alternative, but presents the disadvantage of

Genetic diversity among volunteer donors of bone marrow in southeastern Brazil, according to the HLA system | ORIGINAL ARTICLE

Table 3. Frequencies of HLA-B alleles among the volunteer bone marrow donors registered at the Regional Center for Hematology of the teaching hospital of the Ribeirão Preto School of Medicine, University of São Paulo, 2005 to 2011 HLA-B alleles B*07 B*08 B*13 B*14 B*15 B*18 B*27 B*35 B*37 B*38 B*39 B*40 B*41 B*42 B*44 B*45 B*46 B*47 B*48 B*49 B*50 B*51 B*52 B*53 B*54 B*55 B*56 B*57 B*58 B*59 B*67 B*73 B*78 B*81 B*82

Frequency (%) 12.94 9.28 2.89 8.66 13.27 7.58 2.92 14.18 1.12 2.13 2.98 3.74 1.24 1.30 7.34 0.98 0.04 0.11 0.30 1.35 1.05 2.82 0.42 0.54 0.01 0.20 0.02 0.29 0.14 0.05 0.07 0.00 0.00 0.01 0.03

Table 4. Frequencies of HLA-DRB1 alleles among the volunteer bone marrow donors registered at the Regional Center for Hematology of the teaching hospital of the Ribeirão Preto School of Medicine, University of São Paulo, 2005 to 2011 HLA-DRB1 alleles DRB1*01 DRB1*03 DRB1*04 DRB1*07 DRB1*08 DRB1*09 DRB1*10 DRB1*11 DRB1*12 DRB1*13 DRB1*14 DRB1*15 DRB1*16

Frequency (%) 15.70 17.03 16.58 15.42 5.54 1.66 1.81 15.59 1.06 6.46 1.32 1.66 0.17

only containing a small number of progenitor cells, which would be insufficient for individuals of greater weight.16 Hence, it is important to increase the number of registered bone marrow donors, as well as to better understand the demographics and immunogenetics in different regions of Brazil. In this manner, the waiting time for a histocompatible unrelated donor can be reduced, considering that searching for unrelated donors worldwide takes time, which may often be fatal. Defining the immunogenetic profile of the population of each region of the country is essential for planning strategic campaigns aimed at increasing the number of recipients benefited.9 With the objective of catering better for the population’s need for bone marrow transplants, future media campaigns aimed at recruiting up donors should take into consideration the characteristics of gender, age, race and the allelic profile of donors already registered in the country’s hemotherapy system. It is also important to carry out further studies analyzing associations between the more frequent alleles and self-reported ethnicity. Creation of REDOME, to which the Regional Center for Hematology of Ribeirão Preto is associated, was a very important step in expediting allogeneic bone marrow transplantation in Brazil. Due to the peculiar characteristics of the population, with a high rate of interracial marriage, it is necessary to have a large number of registered donors in order to find the right donor. Before the creation of this database, it was very common for receivers not to be able to find a compatible unrelated donor in time. CONCLUSIONS There were equal numbers of men and women and predominance of donors under 45 years of age among the donors in this study. More than three quarters of the donors declared themselves to be white and 15% mixed race. In the HLA-A group, HLA-A*02 predominated, accounting for 39.20%, with HLA-A*01 at 17.64%; while in the HLA-B group, HLA -B*35 predominated, accounting for 14.18%, with HLA-B*15 at 13.27%. In the HLA-DRB1 allelic group, HLA-DRB1*03 predominated, accounting for 17.03%, followed by HLA-DRB1*04, present in 16.58% of the population. REFERENCES 1. Benjamin E, Coico R, Sunshine G. Imunologia. 4a ed. Rio de Janeiro: Guanabara Koogan; 2002. 2. Roza BA, Odierna MTAS, Glezer M, SA JR. Captação de órgãos para transplantes. In: Knobel E, org. Condutas no paciente grave. 2a ed. São Paulo: Atheneu; 2006. p. 1753-64. 3. Associação Brasileira de Transplante de Órgãos. Dados numéricos da doação de órgãos e transplantes realizados por estado e instituição no período: janeiro/dezembro 2011. Registro Brasileiro de Transplantes. 2001;XVII(4). Available from: http://www.abto.org. br/abtov03/default.aspx?mn=515&c=900&s=0&friendly=registrobrasileiro-de-transplantes-estatistica-de-transplantes. Accessed in 2013 (Jun 12). Sao Paulo Med J. 2014; 132(3):158-62

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ORIGINAL ARTICLE | Roque LS, Telarolli Junior R, Loffredo LCM

4. Abbas AK, Lichtman AH, Pillai S. Imunologia celular e molecular. 6a ed. Rio de Janeiro: Elsevier; 2008.

Sources of funding: None Conflict of interest: None

5. Zago MA, Falcão RP, Pasquini R. Hematologia: Fundamentos e prática. São Paulo: Atheneu; 2004. 6. Fernandes APM, Maciel LMZ, Foss MC, Donaldi EA. Como entender a associação entre o sistema HLA e as doenças auto-imunes

Date of first submission: October 27, 2012 Last received: June 30, 2013 Accepted: July 16, 2013

endócrinas [How to understand the association of the HLA system and autoimmune endocrine disorders]. Arq Bras Endocrinol Metabol. 2003;47(5):601-11. 7. Bortolotto AS, Petry MF, Krieger EAG, et al. Frequência de alelos HLA

Rodolpho Telarolli Junior Av. Feijó, 1.660 — apto 111

A, B e DRB1 em uma amostra de doadores voluntários de medula

Centro — Araraquara (SP) — Brasil

óssea do estado do Rio Grande do Sul. In: Anais da IV Mostra de

CEP 14801-140

Pesquisa da Pós-Graduação da PUCRS. Porto Alegre: PUCRS; 2009.

Tel. (+55 16) 3331-4242

p. 77-9. Available from: http://www.pucrs.br/edipucrs/IVmostra/

Cel. (+55 16) 9609-5301

IV_MOSTRA_PDF/Biologia_Celular_e_Molecular/71668-ANDREA_

E-mail: [email protected]

SILVEIRA_BORTOLOTTO.pdf. Accessed in 2013 (Jun 12). 8. Castro Júnior CG, Gregianin LJ, Brunetto AL. Transplante de medula óssea e transplante de sangue de cordão umbilical em pediatria [Bone marrow transplantion and blood transplantation in children]. J Pediatr (Rio J.). 2001;77(5):345-60. 9. Voltarelli JC, Donaldi EA, Carvalho IF, et al. Imunologia clínica na prática médica. Rio de Janeiro: Atheneu; 2008. 10. Bouzas LFS. Análise da capacidade do REDOME/RENACORD em suprir as necessidades dos pacientes registrados no REREME. [thesis]. Rio de Janeiro: Programa de Pós-Graduação em Oncologia do Instituto Nacional do Câncer; 2011. Available from: http://bvsms. saude.gov.br/bvs/publicacoes/inca/luis_fernando_bouzasanalise_ da_capacidade.pdf. Accessed in 2013 (Jun 12). 11. Telarolli Junior R. Poder e saúde: as epidemias e a formação dos serviços de saúde em São Paulo. São Paulo: Editora UNESP; 1996. 12. Brasil. Ministério da Saúde. Instituto Nacional de Câncer. Doação de Medula Óssea. REDOME- Registro Nacional de Doadores Voluntários de Medula Óssea. MedulaNet. 2011;21. Available from: http://www1. inca.gov.br/conteudo_view.asp?id=2651. Accessed in 2013 (Jul 16). 13. Bone Marrow Donors Worldwide. Available from: http://www.bmdw. org/uploads/media/BMDW2011.pdf. Accessed in 2013 (Jul 16). 14. Pereira NF, Oliveira DCM, Torres MR, et al. Seleção de doador de medula óssea ou sangue periférico [Bone marrow or peripheral blood donor selection]. Rev Bras Hematol Hemoter. 2010;32(supl. 1):3-5. 15. ABRALE (Associação Brasileira de Linfoma e Leucemia). Transplante de células-tronco hematopoéticas do sangue e da medula óssea. São Paulo. Available from: http:// http://www.abrale.org.br/web/uploads/files/ Transplante%20de%20células%20tronco.pdf. Accessed in 2013 (Jul 16). 16. Saboya R, Dulley FL, Ferreira E, Simões B. Transplante de medula óssea com doador familiar parcialmente compatível [Partially matched family donor allogeneic bone marrow transplantation]. Rev Bras Hematol Hemoter. 2010;32(supl. 1):13-5.

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Address for correspondence:

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ORIGINAL ARTICLE

DOI: 10.1590/1516-3180.2014.1323621

Translation and cross-cultural adaptation of the Scleroderma Health Assessment Questionnaire to Brazilian Portuguese Tradução e adaptação cultural do Scleroderma Health Assessment Questionnaire para a língua portuguesa Aline Cristina OrlandiI, Fernanda Pontes CardosoII, Lucas Macedo SantosIII, Vaneska da Graça CruzIV, Anamaria JonesV, Cristiane KyserVI, Jamil NatourVII Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil

MSc. Student, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

I

II MSc. Occupational therapist, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

Physiotherapist, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

III

IV PhD. Student, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

PhD. Physiotherapist, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

V

VI MD, PhD. Affiliated Professor, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil. VII MD, PhD. Associate Professor, Rheumatology Division, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

KEY WORDS: Scleroderma, systemic. Quality of life. Disability evaluation. Chronic disease. Translating. PALAVRAS-CHAVE: Escleroderma sistêmico. Qualidade de vida. Avaliação da deficiência. Doença crônica. Tradução.

ABSTRACT CONTEXT AND OBJECTIVE: Systemic sclerosis is an autoimmune disease characterized by abnormalities of vascularization that may cause fibrosis of the skin and other organs and lead to dysfunction. It is therefore essential to have tools capable of evaluating function in individuals with this condition. The aim of this study was to translate the Scleroderma Health Assessment Questionnaire (SHAQ) into Portuguese, adapt it to Brazilian culture and test its validity and reliability. DESIGN AND SETTING: The validation of SHAQ followed internationally accepted methodology, and was performed in university outpatient clinics. METHODS: SHAQ was translated into Portuguese and back-translated. In the cultural adaptation phase, it was applied to 20 outpatients. Items not understood by 20% of the patients were modified and applied to another 20 outpatients. Twenty patients were interviewed on two different occasions to determine the validity and reliability of the questionnaire: two interviewers on the first occasion and one interviewer 14 days later. To determine the external validity, comparisons were made with Health Assessment Questionnaire (HAQ), Disabilities of the Arm, Shoulder and Hand (DASH) and short form-36 (SF-36). RESULTS: In the interobserver evaluation, Pearson’s correlation coefficient and the intraclass correlation coefficient were both 0.967. In the intraobserver evaluation, Pearson’s correlation coefficient was 0.735 and the intraclass correlation coefficient was 0.687. Regarding external validity, SHAQ scores were statistically correlated with all measurements, except the general health domain of SF-36 and the work-related score (Q2) of DASH. CONCLUSION: The Brazilian version of SHAQ proved to be valid and reliable for assessing function in patients with diffuse systemic sclerosis. RESUMO CONTEXTO E OBJETIVO: A esclerose sistêmica (ES) é uma doença autoimune caracterizada por anormalidades da vascularização, que podem gerar fibrose da pele e outros órgãos, podendo levar a disfunção. Assim, torna-se imprescindível a elaboração de instrumentos capazes de avaliar a função de indivíduos com ES. O objetivo deste estudo foi traduzir para o português, adaptar à cultura brasileira e testar a validade e confiabilidade do Scleroderma Health Assessment Questionnaire (SHAQ). TIPO DE ESTUDO E LOCAL: A validação do SHAQ seguiu uma metodologia aceita internacionalmente, e foi realizada nos ambulatórios da universidade. MÉTODOS: Foi realizada tradução e contra-tradução do instrumento. Na fase de adaptação cultural, o SHAQ foi aplicado a 20 pacientes. As questões que apresentaram mais de 20% de incompreensão foram modificadas e aplicadas em outros 20 pacientes. Para validade e confiabilidade, 20 pacientes foram entrevistados em dois momentos: no primeiro, por dois entrevistadores e após 14 dias por um deles. Foram aplicados o Health Assessment Questionnaire (HAQ), o Disabilities of the Arm, Shoulder and Hand (DASH) e o short form-36 (SF-36), para a validade externa. RESULTADOS: Na avaliação interobservador, o coeficiente de correlação de Pearson e o coeficiente de correlação intraclasse foram ambos de 0,967. Na avaliação intraobservador o coeficiente de correlação de Pearson foi de 0,735, e o coeficiente de correlação intraclasse foi de 0,687. Na validade externa, os escores do SHAQ foram associados estatisticamente com todos os instrumentos, exceto com o domínio estado geral de saúde do SF-36 e o escore relacionado ao trabalho (Q2) do DASH. CONCLUSÃO: A versão brasileira do SHAQ mostrou ser válida e confiável para a avaliação de função em pacientes com esclerose sistêmica difusa.

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INTRODUCTION Systemic sclerosis is an autoimmune disease of connective tissue characterized by abnormalities in the vascular system, immune system and extracellular matrix. It can lead to fibrosis of the skin and other organs, such as the lungs, gastrointestinal tract, heart and kidneys.1 Systemic scleroderma is a heterogeneous disease ranging from a mild form characterized by lesser involvement of internal organs to a more severe type characterized by greater involvement of these organs and rapid progression, leading to disability and even death in some cases.2 Systemic sclerosis affects women more than men, in proportions of 4:1.3 The prevalence ranges from seven to 489 cases per million individuals. This variation has been correlated to age, region and gender.4 The incidence is greatest among middle-aged women and the main characteristics are Raynaud’s phenomenon, thickening of the skin and dysfunction in internal organs.5 This disease leads to dysfunction and a reduction in life expectancy. Treatment should involve improving quality of life. It is therefore essential to have reliable assessment tools for evaluating function in individuals with systemic scleroderma. However, there are currently no specific tools validated in Brazilian Portuguese for evaluating function in such individuals. The Health Assessment Questionnaire (HAQ)6 has been validated for the Brazilian Portuguese language7 and assesses functional capacity through 20 questions distributed among eight domains, addressing activities performed with the upper and lower limbs. The final score ranges from 0 to 3 points, such that higher scores denote worse functional capacity. This questionnaire has been widely used for evaluating function in individuals with different musculoskeletal diseases, especially rheumatoid arthritis.8 The Scleroderma Health Assessment Questionnaire (SHAQ) is one of the few measurement tools for evaluating function in individuals with systemic scleroderma and has been used in  a number of countries.8-10 Like HAQ, SHAQ is made up of 20 items distributed among eight domains and has five additional domains that assess dysfunctions caused by the symptoms of systemic scleroderma. For this, five visual analogue scales (VASs) are used. The scores on these scales are converted to subscores ranging from 0 to 3 points. The overall score of the questionnaire is the sum of each of the five VAS subscores and the scores for the eight domains, divided by 13.8 OBJECTIVE The aim of the present study was to translate the Scleroderma Health Assessment Questionnaire into Brazilian Portuguese, adapt it to Brazilian culture and test its validity and reliability. METHODS This study was carried out in two stages. The first stage consisted of translation of SHAQ into Brazilian Portuguese and 164

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cross-cultural adaptation to the Brazilian population. The second stage consisted of determining the reliability and external validity of the Brazilian version of SHAQ. This study was approved by our institution’s Research Ethics Committee. Translation and cross-cultural adaptation The translation, validation and adaptation of the questionnaire were carried out following the method proposed by Guillemin et al.11,12 Translation to the Portuguese language SHAQ was translated independently by two teachers of English who were informed about the aim of the study. The two versions of the questionnaire in Portuguese were analyzed and compared by a team made up of two rheumatologists and three physiotherapists, who examined the questionnaire for possible translation problems and analyzed the applicability of each item. This process generated a single translated version of SHAQ (V1). Assessment of initial translation (back translation) V1 was then back-translated into English by two Englishlanguage teachers who were fluent in Portuguese. In this phase, the teachers were unaware of the original questionnaire or the aim of the study. The two back-translated versions were compared with the original questionnaire by the same team, in order to determine the semantic and grammatical equivalence, ensuring the similarity between the original questionnaire and V1, which could be used as the final version of the questionnaire (Annex). Sample A total of 60 male and female patients between 18 and 65 years of age with systemic scleroderma were recruited from our institution’s outpatient clinics. For patients to be included, they needed to fulfill the clinical criteria for the diagnosis of systemic sclerosis.13 Authorization was obtained from the authors of SHAQ for its use in the present study. Assessment of comprehension (cultural equivalence) The final Portuguese version (V1) of SHAQ was applied to 20 patients with systemic scleroderma in order to assess the degree of comprehension of each item. All items that were considered incomprehensible or not applicable by at least 20% of the patients were revised and modified, and were then applied to 20 different patients. Assessment of measurement properties Reliability Following the translation and cross-cultural adaptation of SHAQ, it was applied to a new group of 20 patients with systemic scleroderma. Two evaluations were performed consecutively on the

Translation and cross-cultural adaptation of the Scleroderma Health Assessment Questionnaire to Brazilian Portuguese | ORIGINAL ARTICLE

same day by two researchers in order to determine the interobserver agreement. A third evaluation was carried out by one of the initial researchers after an interval of 7 to 14 days in order to determine the intraobserver agreement. A questionnaire addressing sociodemographic issues was also applied at this stage in order to characterize the sample. External validity The external validity of SHAQ was tested through correlations with other clinical parameters: quality of life, using the short form-36 (SF-36) questionnaire;14 upper limb function using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire;15 and overall function, using the HAQ,7 in the second evaluation. Statistical analysis Descriptive statistics (means and standard deviations) were used to analyze the clinical-demographic data on the patients. Pearson’s correlation coefficient and the intraclass correlation coefficient (ICC) were calculated in order to evaluate the interobserver and intraobserver agreement. Pearson’s correlation coefficient was also used, in order to determine the external validity. RESULTS In the cross-cultural adaptation, two items were not understood by more than 20% of the patients and were changed. In the first item, the patients had difficulty regarding the term “Raynaud’s phenomenon” and the following was added to explain the meaning of this term: “fingers that alternate in color between purple, paleness and red, due to the cold”. In the second item, “digital ulcers” was replaced by “sores on the fingers”. Only these two modified itens were then applied to a new group of 20 patients with systemic scleroderma and were understood by more than 80% of the sample. Assessment of measurement properties Characterization of the sample Table 1 displays the clinical and demographic characteristics of the 20 patients who participated in determining the reliability and validity of SHAQ. All of these 20 patients had a diagnosis of diffuse systemic scleroderma. The mean duration of symptoms was 10.7 years (range: 2 to 36 years) and the mean time that had elapsed since diagnosis was 7.1 years (range: 1 to 19 years). Reliability In the interobserver evaluation, Pearson’s correlation coefficient and the intraclass correlation coefficient were both 0.967 and were considered statistically significant (P < 0.001). The paired

Student’s t test did not show any statistically significant differences in the findings between the two observers (P = 0.320). In the intraobserver evaluation, Pearson’s correlation coefficient was 0.735 and the intraclass correlation coefficient was 0.687. These results were also considered statistically significant (P < 0.001). The paired Student’s t test did not show any statistically significant differences in the findings between the two different evaluations (P = 0.055) (Table 2). External validity To determine the external validity, SF-36,14 DASH15 and HAQ7 were administered to 20 patients. SHAQ scores were statistically associated (P < 0.05) with all measurements, except the general health domain of SF-36 and the work-related score (Q2) of the DASH questionnaire (Table 3). DISCUSSION Two options are available for obtaining new health assessment measurements: developing a new assessment tool that addresses the issue in question; or translating an existing questionnaire that has demonstrated adequate applicability in other countries. The former is considered to be time-consuming and labor-intensive. Thus, translation of good-quality questionnaires is preferable, since the evaluation should be universal, thus enabling Table 1. Clinical and demographic characteristics of the 20 patients who participated in determining the reliability and validity of the Scleroderma Health Assessment Questionnaire Clinical-demographic data Gender – F/M Race (n %) White Nonwhite Age - mean (SD) Marital status (n %) Married Single Others Education level - n (%) Incomplete elementary education Completed elementary education Others Duration of symptoms, years - mean (SD) Time since diagnosis, years - mean (SD)

18/02 11 (55) 9 (45) 43.7 (11.7) 10 (50) 5 (25) 5(25) 9 (45) 4 (20) 6(35) 10.7 (8.9) 7.1 (4.5)

F = female; M = male; SD = standard deviation.

Table 2. Interobserver and intraobserver reliability

PCC (P value) ICC (P value)

Reliability Interobserver 0.967 (< 0.001) 0.967 (< 0.001)

Intraobserver 0.735 (< 0.001) 0.687 (< 0.001)

PCC = Pearson’s correlation coefficient; ICC = intraclass correlation coefficient.

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comparison of data from one population with data from other populations throughout the world.15 A number of questionnaires in Portuguese have been administered to patients with chronic diseases, in order to assess function,7,15,16 but none of them are specific to the symptoms of systemic scleroderma. Since SHAQ is a valid, reliable questionnaire17,18 and has been used in a number of countries,9,10 this questionnaire was chosen for translation into Brazilian Portuguese in the present study. An internationally accepted method that was specially created to systematize translation of questionnaires was used in this study.11,12 This is the only way to ensure that the translation presents an equivalent context, in comparison with the original questionnaire. However, translation alone is insufficient for ensuring that a given questionnaire is reliable. It is also necessary to perform cross-cultural adaptation of the text, which may undergo modifications while respecting the initially proposed context and ideas.11 In the present study, the entire translation and cross-cultural adaptation process was carried out at our institution’ outpatient clinics. Most of the patients in these clinics had lower socioeconomic and schooling levels, thereby representing an important portion of the Brazilian population that receives medical care in this and other reference centers throughout the country. Given the low schooling level of the patients in the present study, SHAQ was applied in interview form, which was done in order to increase the number of people on whom the questionnaire could be used. This method has also been used in previous studies.7,14,15 In the study by Steen et al.,9 who created SHAQ, and Georges et al.,10 who validated the French version, the questionnaires were self-administered. Table 3. Pearson’s correlation between Scleroderma Health Assessment Questionnaire (SHAQ) and short form-36 (SF-36), Health Assessment Questionnaire (HAQ) and Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaires SHAQ SF-36 Physical function Role - physical problems Body pain General health Vitality Social function Role - emotional problems Mental health DASH Component 2: work Component 3: overall score HAQ

Score - mean (SD) 0.910 (0.681) 63.8 (28.1) 47.5 (45.1) 68.2 (30.5) 59.1 (20.1) 52 (50) 83.1 (27) 63.3 (45.8) 63.8 (29.5)

-0.843 -0.684 -0.839 -0.436

< 0.001 0.001 < 0.001 0.054

-0.646 -0.565 -0.656

0.002 0.009 0.002

17.9 (25.9) 25.9 (21.5) 0.844 (0.749)

0.546 0.948 0.96

0.128 < 0.001 < 0.001

Values expressed as mean (standard deviation, SD).

166

Correlation with SHAQ Pearson’s P-value correlation

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HAQ has been used to assess overall physical function and has items addressing different activities of daily living, such as eating, having a bath and walking. Poole and Steen19 administered HAQ to patients with systemic scleroderma and concluded that this measurement was inadequate for assessing all the symptoms and manifestations of the disease. Thus, Steen and Medsger added five visual analogue scales (VASs) to HAQ, thereby creating SHAQ,9 which was validated in France in 2003.10 The addition of these five VASs addressing the symptoms of systemic scleroderma makes SHAQ a specific questionnaire that assesses function in patients with this disease.18 The VAS relating to Raynaud’s phenomenon was not validated in the original questionnaire, but was administered in the study by Georges et al.10 in order to validate the French version of SHAQ. Both HAQ and SHAQ have been applied together in order to compare data and determine the validity of the five VASs that were added to the former.18 This author reported that both questionnaires were sensitive for assessing difficulties in performing activities of daily living, among patients with systemic scleroderma, and that SHAQ enhances HAQ, since it assesses the impact of the symptoms of the disease on daily activities. Following translation, the Brazilian version of SHAQ was found to contain technical terms that were not widely known by the general population and were therefore difficult to understand. Thus, the terms Raynaud’s phenomenon and digital ulcers were changed without altering the meaning of the items. In contrast, no changes had to be made to the French version of the SHAQ.10 In characterizing the sample, the mean age of the 20 participants was 43.7 years; 90% were women and 10% were men. In the study by Georges et al.,10 the mean age was 50 years; 76% of the participants were women and 24% were men. The female gender predominates because this disease affects women more.3 A high level of agreement was found in assessing interobserver reliability, whereas a moderate level of agreement was found in assessing intraobserver reliability. This finding may be attributed to the fact that intraobserver reliability was determined with a 14-day interval between evaluations. Some symptoms of systemic scleroderma are dependent on the weather, such as Raynaud’s phenomenon and lung problems. Changes in the weather within a two-week timeframe are enough to change the symptoms of the disease, which could change the VAS scores, thereby affecting the reproducibility of SHAQ. However, in the study by Georges et al.,10 the interval between the assessments for determining intraobserver reliability ranged from one week to one month, and the authors reported a test-retest coefficient of 0.98, even with the large time interval between evaluations. Despite this difference, the Brazilian version of SHAQ proved to be reproducible.

Translation and cross-cultural adaptation of the Scleroderma Health Assessment Questionnaire to Brazilian Portuguese | ORIGINAL ARTICLE

Quality of life was assessed using the SF-36 questionnaire. The scores on the functional capacity, role-physical, pain, role-emotional, vitality, social aspects and mental health subscales demonstrated strong correlations with the SHAQ score. The  only non-significant correlation was with the general health state subscale. Correlations between these two measurements were expected, since physical impairment is often associated  with reductions in both physical and mental health in patients with systemic scleroderma.20 Moreover, a systematic review has reported that symptoms of depression are found in 36 to 65% of such patients and are strongly associated with joint pain as well as the duration and severity of the disease.21 In the study by Georges et al.,10 all the SF-36 subscales were statistically correlated with the SHAQ score. With chronic disease, inactivity stemming from pain leads to a greater risk of accelerated loss of muscle mass, with consequent reduction in muscle strength and diminished level of independence, thereby contributing towards a reduction in quality of life.22 HAQ was also statistically correlated with SHAQ, and the P-value demonstrated that the scores were directly proportional. This finding was expected, since SHAQ is the same as HAQ with the addition of the five VASs. The mean score for the questionnaire was 0.844. In a study by Singh et al.,23 which assessed productivity among patients with systemic scleroderma, HAQ for patients with the diffuse form of the disease was 1.2 (SD = 0.7). It needs to be borne in mind that higher scores are associated with a lower degree of productivity.23 Georges et al.10 found a very strong correlation between the two questionnaires, as well as strong correlations between these questionnaires and the severity of the disease. The DASH questionnaire is commonly used to assess upperlimb conditions and was used in the present study because thickening of hand skin is one of the most common symptoms of systemic scleroderma and the reason for loss of hand function. This questionnaire proved to be correlated with SHAQ. In the present study, the score for component 1 was not calculated, since this component was only relevant to two patients, which rendered statistical description impossible. Higher SHAQ scores were found in the present study than in the study by Georges et al.,10 who reported a mean score of

Disease duration was similar in the two studies. In the present study, the mean duration of symptoms was 10.7 years, which may explain the low scores found in evaluating upper limb function using DASH, since patients tend to develop adaptations to maintain their activities of daily living. This may also explain the low score on the “role-physical” subscale of the SF-36 questionnaire. The majority of the patients reported typical symptoms of systemic scleroderma throughout the present study, such as Raynaud’s phenomenon, respiratory and digestive problems, digital ulcers and thickening of the skin, which affect the SHAQ score. In the study by Georges et al.,10 68% of the patients had Raynaud’s phenomenon in the final week; approximately 50% had respiratory, digestive and heart problems and only 25% experienced contractures in the hands. These findings may explain the differences in SHAQ scores between the two studies. Although the original questionnaire was tested for both forms of progressive systemic scleroderma, the Brazilian version was produced only using patients with diffuse systemic scleroderma. The Brazilian version probably maintains the original measured performance, but it needs to be tested on cases of limited scleroderma. Previous studies have used other questionnaires that assess function, but these questionnaires are not specific to systemic scleroderma. Thus, validation of SHAQ enables a more specific evaluation of function, directed towards patients with this disease, thereby making this questionnaire an additional assessment tool of considerable value. The successful translation and cross-cultural adaptation of SHAQ will allow future studies to assess function in patients with systemic scleroderma and test the responsiveness of the questionnaire. Moreover, the use of this measurement in different populations allows comparisons of the findings across cultures.

0.02. In the present study, all the patients had diffuse systemic scleroderma, which affects internal organs and commonly presents symptoms of greater severity than is seen in cases of limited scleroderma, thereby increasing these patients’ dysfunction and consequently leading to higher scores in questionnaires that assess this variable. In the study by Georges et al.,10 77% of the patients had diffuse systemic scleroderma and the remaining patients were classified as presenting the limited form of the disease, which may explain the difference in scores between the two studies.

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CONCLUSION In conclusion, the Brazilian version of the Scleroderma Health Assessment Questionnaire proved to be a valid, reliable measurement tool for assessing function in patients with diffuse systemic scleroderma.

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questionnaire in scleroderma trials: an evaluation of their

5. Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem disease. Am Fam Physician. 2008;78(8):961-8. 6. Pincus T, Summey JA, Soraci SA Jr, Wallston KA, Hummon NP. Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum. 1983;26(11):1346-53.

measurement properties. Arthritis Rheum. 2005;53(2):256-62. 19. Poole JL, Steen VD. The use of the Health Assessment Questionnaire (HAQ) to determine physical disability in systemic sclerosis. Arthritis Care Res. 1991;4(1):27-31. 20. Arat S, Verschueren P, De Langhe E, et al. The association of illness perceptions with physical and mental health in systemic sclerosis

7. Ferraz MB. Tradução para o português e validação do questionário

patients: an exploratory study. Musculoskeletal Care. 2012;10(1):18-28.

para avaliar a capacidade funcional “Stanford Health Assessment

21. Thombs BD, Taillefer SS, Hudson M, Baron M. Depression in patients

Questionnaire” [thesis]. São Paulo: Universidade Federal de São

with systemic sclerosis: a systematic review of the evidence. Arthritis

Paulo — Escola Paulista de Medicina; 1990.

Rheum. 2007;57(6):1089-97.

8. Rannou F, Poiraudeau S, Berezné A, et al. Assessing disability and

22. Plasqui G, Boonen A, Geusens P, et al. Physical activity and body

quality of life in systemic sclerosis: construct validities of the Cochin

composition in patients with ankylosing spondylitis. Arthritis Care

Hand Function Scale, Health Assessment Questionnaire (HAQ),

Res (Hoboken). 2012;64(1):101-7.

Systemic Sclerosis HAQ, and Medical Outcomes Study 36-Item Short Form Health Survey. Arthritis Rheum. 2007;57(1):94-102. 9. Steen VD, Medsger TA Jr. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate

23. Singh MK, Clements PJ, Furst DE, Maranian P, Khanna D. Work productivity in scleroderma: analysis from the University of California, Los Angeles scleroderma quality of life study. Arthritis Care Res (Hoboken). 2012;64(2):176-83.

change in systemic sclerosis patients over time. Arthritis Rheum. 1997;40(11):1984-91. 10. Georges C, Chassany O, Mouthon L, et al. Validation of French version

Sources of funding: None Conflict of interest: None

of the Scleroderma Health Assessment Questionnaire (SSc HAQ). Clin Rheumatol. 2005;24(1):3-10. 11. Guillemin F, Bombardier C, Beaton D. Cross-cultural adaptation of health-related quality of life measures: literature review and proposed

Date of first submission: October 29, 2012 Last received: July 12, 2013 Accepted: July 16, 2013

guidelines. J Clin Epidemiol. 1993;46(12):1417-32. 12. Beaton DE, Bombardier C, Guillemin F, Ferraz MB. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine

Jamil Natour

(Phila Pa 1976). 2000;25(24):3186-91.

Disciplina de Reumatologia

13. LeRoy EC, Medsger TA Jr. Criteria for the classification of early systematic sclerosis. J Rheumatol. 2001;28(7):1573-6. 14. Ciconelli RM, Ferraz MB, Santos W, Meinão I, Quaresma MR. Tradução para a língua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36) [BrazilianPortuguese version of the SF-36. A reliable and valid quality of life outcome measure]. Rev Bras Reumatol. 1999;39(3):143-50. 15. Orfale AG. Tradução e validação do disabilities of the arm, shoulder and hand (dash), para a língua portuguesa [dissertation]. São Paulo: Universidade Federal de São Paulo — Escola Paulista de Medicina; 2003. 16. Chiari A, Sardim CC, Natour J. Translation, cultural adaptation and reproducibility of the Cochin Hand Functional Scale questionnaire for Brazil. Clinics (Sao Paulo). 2011;66(5):731-6. 17. Mouthon L, Rannou F, Bérezné A, et al. Patient preference disability questionnaire in systemic sclerosis: a cross-sectional survey. Arthritis Rheum. 2008;59(7):968-73.

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Address for correspondence:

Sao Paulo Med J. 2014; 132(3):163-9

Rua Botucatu, 740 Vila Clementino — São Paulo (SP) — Brasil CEP 04023-900 E-mail: [email protected]

Translation and cross-cultural adaptation of the Scleroderma Health Assessment Questionnaire to Brazilian Portuguese | ORIGINAL ARTICLE

Annex. Scleroderma Health Assessment Questionnaire (SHAQ) questionnaire. Marque com “X” o grau de dificuldade para cada item abaixo. Você é capaz de (grau de dificuldade) Vestir-se, inclusive amarrar os cordões de sapato e abotoar suas roupas? Lavar sua cabeça e seus cabelos? Levantar-se de maneira ereta de uma cadeira de encosto reto e sem braços? Deitar-se e levantar-se da cama? Cortar um pedaço de carne? Levar à boca um copo ou uma xícara cheia de café, leite ou água? Abrir um saco de leite comum? Caminhar em lugares planos? Subir 5 degraus? Lavar e secar seu corpo após o banho? Tomar banho de chuveiro? Sentar-se e levantar-se do vaso sanitário? Levantar os braços e pegar um objeto de aproximadamente 2 kg, que está posicionado um pouco acima da sua cabeça? Curvar-se para pegar suas roupas no chão? Segurar-se em pé no ônibus ou metrô Abrir potes ou vidros de conservas, que tenham sido previamente abertos? Abrir e fechar torneiras? Fazer compras na redondeza aonde mora? Entrar e sair do ônibus Realizar tarefas tais como usar a vassoura para varrer e rodo para água?

Sem qualquer

Com alguma

Com muita

0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1

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

Incapaz de fazer 3 3 3 3 3 3 3 3 3 3 3 3

0

1

2

3

0 0 0 0 0 0 0

1 1 1 1 1 1 1

2 2 2 2 2 2 2

3 3 3 3 3 3 3

ESCALA VISUAL ANALÓGICA Faça uma marca na linha abaixo (10 cm) referente ao grau de limitação apresentada pelo indivíduo.

1. Na semana passada, quanto os seus problemas com o Fenômeno de Raynaud (dedos que alternam de cor entre roxo, pálido e vermelho pelo frio) interferiram nas suas atividades? Faça uma marca na linha para indicar a gravidade desse problema. Limitações Não interfere muito graves 2. Na semana passada, quanto os seus problemas com as feridas nos dedos interferiram nas suas atividades? Faça uma marca na linha para indicar a gravidade desse problema. Limitações Não interfere muito graves 3. Na semana passada, quanto os seus problemas gastrointestinais interferiram nas suas atividades? Faça uma marca na linha para indicar a gravidade desse problema. Limitações Não interfere muito graves 4. Na semana passada, quanto os seus problemas com os pulmões interferiram nas suas atividades? Faça uma marca na linha para indicar a gravidade desse problema. Limitações Não interfere muito graves 5. Na semana passada, quanto o conjunto de seus problemas causados pela esclerodermia interferiram nas suas atividades? Faça uma marca na linha para indicar a gravidade desse problema. Limitações Não interfere muito graves ESCORE 1. Converter cada valor de EVA em subscores de 0-3 2. Somar cada valor do subescore das EVA’s (0-3), com o maior valor de cada um dos 8 domínios 3. Dividir o valor da somatória por 13.

Sao Paulo Med J. 2014; 132(3):163-9 169

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DOI: 10.1590/1516-3180.2014.1323646

Methods of cognitive function investigation in the Longitudinal Study on Adult Health (ELSA-Brasil) Métodos de investigação da função cognitiva no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil) Valéria Maria de Azeredo PassosI, Paulo CaramelliII, Isabella BenseñorIII, Luana GiattiIV, Sandhi Maria BarretoV ELSA-Brasil: Fundação Oswaldo Cruz, Universidade de São Paulo, Universidade Federal da Bahia, Universidade Federal do Espírito Santo, Universidade Federal de Minas Gerais and Universidade Federal do Rio Grande do Sul, Brazil

MD, PhD. Associate Professor, Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.

I

II MD, PhD. Full Professor, Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil. III MD, PhD. Associate Professor, Department of Internal Medicine, School of Medicine, Universidade de São Paulo (USP), São Paulo, Brazil. IV MD, PhD. Adjunct Professor, School of Nutrition, Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil.

MD, PhD. Full Professor, Department of Preventive and Social Medicine, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil.

V

KEY WORDS: Cognition. Prevalence. Incidence. Prognosis. Adult. PALAVRAS-CHAVE: Cognição. Prevalência. Incidência. Prognóstico. Adulto.

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ABSTRACT CONTEXT AND OBJECTIVE: Many uncertainties concerning risk factors and evolution of cognitive disorders remain. We describe the methods and preliminary results from the investigation of the cognitive function in the Longitudinal Study on Adult Health (ELSA-Brasil). DESIGN AND SETTING: Multicenter cohort study on public employees at six public teaching and research institutions. METHODS: The participants were interviewed and examined to obtain a broad range of social, clinical and environmental characteristics. The following standardized tools were used to assess memory, language and visuospatial and executive functions: words or figure memory test; semantic (animals) and phonemic (letter F) verbal fluency tests; and trail test B. RESULTS: 15,101 out of 15,105 participants took the cognitive tests: 54% were women; the mean age was 51 years; and 52% had a university degree. 14,965 participants (99%) did the word test and 136 (1%) did the figure test due to low schooling level. The scores from the semantic verbal fluency tests (mean = 18.42 ± 5.29; median = 18 words) were greater than the scores from the phonemic verbal fluency tests (mean = 12.46 ± 4.5; median = 12 words). The median time taken to perform the trail test was 1.6 minutes. CONCLUSION: The large cohort size, of young age, and the extensive amount of clinical and epidemiological data available will make it possible to investigate the prognostic value of biological, behavioral, environmental, occupational and psychosocial variables over the short and medium terms in relation to cognitive decline, among adults and elderly people. RESUMO CONTEXTO E OBJETIVO: Ainda persistem muitas incertezas relativas a fatores de risco e evolução das desordens cognitivas. Descrevemos métodos e resultados preliminares da investigação da cognição no ELSA-Brasil, Estudo Longitudinal de Saúde do Adulto. TIPO DE ESTUDO E LOCAL: Estudo de coorte, multicêntrico, com servidores públicos de seis instituições públicas de ensino e pesquisa. MÉTODOS: Participantes foram entrevistados e examinados, para obtenção de amplo espectro de variáveis sociais, clínicas e ambientais. Foram utilizados instrumentos padronizados de avaliação da memória, linguagem e funções executiva e visual espacial: teste de memória de palavras ou de figuras, de fluência verbal semântica (animais) e fonêmica (letra F) e teste de trilhas B. RESULTADOS: 15,101 de 15,105 participantes fizeram os testes cognitivos; 54% eram mulheres, a média da idade foi de 51 anos e 52% tinham grau universitário. 14.965 participantes (99%) fizeram o teste de palavras e 136 (1%) o teste de figuras, dado o menor grau de instrução. Os escores dos testes de fluência verbal semântica (média = 18.42 ± 5.29, mediana = 18 palavras) foram maiores que os escores dos testes de fluência verbal fonêmica (média = 12.46 ± 4.5, mediana = 12 palavras). O tempo mediano para execução do teste de trilhas foi de 1,6 minutos. CONCLUSÃO: O grande tamanho da coorte, de idade jovem, e a extensa quantidade de dados clínicos e epidemiológicos disponíveis permitirão a investigação do prognóstico de variáveis de natureza biológica, comportamental, ambiental, ocupacional e psicossociais, em curto e médio prazo, sobre o declínio cognitivo em adultos e idosos.

Methods of cognitive function investigation in the Longitudinal Study on Adult Health (ELSA-Brasil) | SHORT COMMUNICATION

INTRODUCTION The Longitudinal Study on Adult Health (ELSA-Brasil) is a cohort of public employees at six public teaching and research institutions in Brazil: Federal University of Bahia (Universidade Federal da Bahia, UFBA), Federal University of Espírito Santo (Universidade Federal do Espírito Santo, UFES), Federal University of Minas Gerais (Universidade Federal de Minas Gerais, UFMG), University of São Paulo (Universidade de São Paulo, USP) and Oswaldo Cruz Foundation (Fundação Oswaldo Cruz, Fiocruz). This study is investigating the incidence and evolution of chronic diseases, especially cardiovascular diseases and diabetes, among adults.1 In this article, we present the methodology of the cognitive function investigation and the sociodemographic characteristics of the study population. The increases in life expectancy and the rapid aging process observed in developing countries are occurring in a context of social inequalities and structural difficulties, since these countries are institutionally unprepared to meet the great demands associated with ageing. Even though aging is a victory for humanity, it increases the risk of chronic diseases and functional dependency. Over the next few years, an alarming number of Brazilians will reach an age at which the incidence of dementia is high. Estimates from population studies in Latin America and Brazil have shown that the prevalence of dementia increases from less than 10% up to the age of 75 years to more than 40% among individuals aged 85 years or over, which is precisely the age stratum that is expanding most rapidly among elderly Brazilians.2 Dementia is a serious syndrome that compromises the memory and at least one more cognitive function, thereby leading to declining social and occupational capacities. Moreover, cognitive impairment without dementia has emerged as an important clinical entity, and its prevalence is twice as high as the prevalence of all forms of dementia combined. In addition, it has high rates of progression towards dementia, estimated to be 10% to 15% a year, in relation to the rates among individuals without cognitive deficit (1% to 2% a year).3 The question that therefore arises is whether memory loss without dementia is a benign process, with slow progression; or whether it should be understood as the initial phase of more significant cognitive losses, which could lead to dementia. A five-year follow-up study found that people with cognitive impairment, but without dementia presented higher risks of diagnoses of dementia (47% versus 15%), or dying (49% versus 30%), or being admitted to long-term institutional care (29% versus 14%), in comparison with those without cognitive impairment.4 There is evidence that the decline in cognitive function begins during adult ages, even before the age of 50 years, and that its development is continuous over a 20 to 30-year period.4 However, not all components of cognitive function are equally

affected by age: environmental, social and behavioral factors are also determinants in this process. Nonetheless, there are still many doubts regarding the role of risk factors, and the quality and extent of these changes. There are few cohort studies on cognitive disorders in Latin America; most of them are concentrated on the elderly population.2,5,6 Developed countries have already a significant number of community-based cohort studies on adults in the age range of 45-64 years, i.e. “middle-age”, although most studies are still concentrated on the elderly.7-9 Many studies have suggested that cardiovascular risk factors contribute towards development of dementia, and cohort studies have demonstrated a consistent association between midlife health situations and the incidence of late-life dementia. Midlife hypertension presented a more significant association with the incidence of dementia than does late-life hypertension.10-12 Treatment for hypertension has been correlated with lower incidence of dementia, but the results are still difficult to interpret.13,14 Midlife diabetes has been correlated with late-life dementia in seven cohort studies (relative risk, RR: 1.2-1.7), and it persists as a risk factor even during later life. This correlation is higher in long-term diabetes cases.15 Hyperinsulinemia has been significantly correlated with lower cognitive tests scores in cross-sectional data and, after a six-year follow-up, in adults aged from 45 to 65 years.16 Midlife obesity has also been associated with a higher risk of dementia, while doing physical activity seems to contribute to lower risks of mild cognitive impairment, Alzheimer’s disease and any type of dementia.17,18 Current smoking, but not former smoking, has been correlated with higher risks of having Alzheimer’s disease and also with other causes of dementia.19 Ingestion of small quantities of alcohol can be protective against dementia and Alzheimer’s disease, but not against vascular dementia.20 There is also evidence that presence of psychosocial factors of an intellectually stimulating nature throughout life can contribute towards increased cognitive reserve and thus prevent, attenuate or delay dementia. These factors include schooling level, type of occupation, social capital and minor mental disorders. In  a  study among Afro-Americans with low schooling levels, occurrence of adverse medical conditions, particularly stroke, had a great impact on alterations in memory and executive function in adults (51-64 years).21 In a cohort of British middle-aged workers, socioeconomic position during childhood did not reveal any direct effect on performance in cognitive tests, but had an indirect effect, mediated by schooling level and socioeconomic situation during adulthood.22 In this same cohort, it was observed that long working hours (55 hours versus 40 hours per week) negatively affected cognition.23 Low schooling level may be a risk factor for cognitive impairment, but it is also one of the confounders in studies that

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have evaluated cognition tests that have the prerequisites of the ability to read and calculate, and of vocabulary diversity, among others. Studies have demonstrated worse performance among individuals with low schooling levels in verbal fluency tests and the trail-making test.24,25 Common mental disorders, especially anxiety and depression, have great interaction with cognitive function. They can be risk factors for cognitive deficits, confounding factors in performing cognitive tests, or even part of the initial signs of dementia (protopathic bias).26 Despite extensive research, many uncertainties concerning risk factors for dementia remain. These uncertainties include lack of comparability and standardization of the outcomes (performance in tests; dementia or Alzheimer’s disease); study design (cross-sectional, cohort or clinical trial); diversity of the samples included in the studies (Japanese men, nuns, white women and British workers); exposure (throughout life, midlife or late life); and diagnostic instruments (cognitive tests, neurological examinations or brain imaging). There have also been some difficulties in including the diagnoses of certain types of dementia. In 2010, after reviewing the literature on risk factors for Alzheimer’s disease, a panel of specialists took the view that strong evidence only exists regarding genetic factors (variation of the Apo E gene), and that the evidence was weak in relation to the effects of midlife hypertension, diabetes, depression, current smoking, low-fat diets, folic acid intake, moderate alcohol consumption, low social support and never having been married. They also concluded that there was no consistent association between the effects of obesity, metabolic syndrome and blood pressure and use of anti-hypertensive medications, non-steroidal anti-inflammatory drugs or gonadal steroids. They indicated that the following were the main deficiencies of epidemiological studies: difficulty in distinguishing between association and causality; lack of standardization in defining cases; and complexity in establishing whether associated variables, such as depression and weight loss, are risk factors or, in reality, are early signs of Alzheimer’s disease.27 OBJECTIVES The aim here was to present the methodology used to investigate cognitive function and the sociodemographic characteristics of the study population of ELSA-Brasil. METHODS The baseline data collection was completed in 2010, and all participants were interviewed and examined in order to obtain a comprehensive range of psychosocial, environmental and clinical characteristics (Table 1). Since then, telephone followup interviews have been taking place annually and the first

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three-year interval follow-up examinations were conducted in September 2012. The object of the cognitive investigation was to identify changes in cognitive tests, which may be of transitory nature and may or may not be reversible, and to identify irreversible final outcomes such as occurrences of all types of dementia. Other than the abovementioned strategies, it was planned that occurrences of outcomes would be investigated by correlating data with secondary databases such as mortality and hospitalization rates.1 Every public employee at the institutions involved, between the ages of 35 and 74 years, was considered eligible. Individuals who intended to leave the institution, those who presented severe cognitive deficit, pregnant women, those who were retired and those who did not live in one of the six metropolitan regions were excluded. The sample size was calculated based on the incidence of type 2 diabetes and myocardial infarction and resulted in 6,400 participants. The cohort was composed by volunteers and a random sample was derived from it. ELSA has a dual system of recruitment, in which part of the sample consists of volunteers and part is derived from an actively recruited random sample of eligible individuals drawn from lists from the institutions.1 The total sample would be used to examine the association of risk factors with cognitive decline and dementia, while the random sample would make it possible to estimate the frequency and distribution of cognitive deficits. Table 2 shows the psychometric characteristics of the neuropsychological tests. The choice of these tests was based on the following criteria: 1) evaluation of multiple cognitive domains: memory (word learning, retention and recognition tests) and executive functions (verbal fluency tests: semantic (animals) and phonemic (first letter); and trail-making test version B; 2) national and international comparability; 3) adaptation to Portuguese; 4) normative rules for diagnosing cognitive deficits; and 5) compatibility between the time of cognitive test application and the time reserved for the whole ELSA-Brasil questionnaire. A “Standardization Manual for Application of Cognitive Tests” was drawn up to ensure and control the quality of the study. The Consortium to Establish a Registry for Alzheimer’s disease (CERAD) has been adapted for Brazilian studies. It includes a list of ten unrelated words printed in large letters on cards, which are shown at a rate of one every two seconds and are presented in a different order in each of the three learning trials, with immediate recall. After a five-minute delay, retention is tested by means of free recall through the recognition trial, in which the ten previous words are intermixed with ten distractor words.28 A figure test consisting of simple drawings from the Brief Cognitive Screening Battery (BCSB), which follows the same logic as the word test was offered to participants who

Methods of cognitive function investigation in the Longitudinal Study on Adult Health (ELSA-Brasil) | SHORT COMMUNICATION

were unable to read.29 The verbal fluency tests consisted of asking participants to say as many words as possible relating to a specific category of animals (semantic test) or starting with the letter F (phonemic test), in one minute. To perform the trailmaking test version B, the participant was instructed to draw lines connecting letters and numbers in an order that alternated between increasing numeric value and alphabetic order (1, A, 2, B, 3, C etc.). The participant was told to draw as quickly as possible, without lifting the pencil point from the page. The supervisors were instructed to point out the errors. The test score was the total time taken to complete the task, including the time need to correct errors.28 The training and certification for the interviewers were standardized and centralized, and were provided by the same

researcher (VMA Passos). During the training, each interviewer applied a battery of tests to at least three volunteers, who had the same characteristics as the participants regarding sex, age and schooling level. The level of achievement and the basic items used to evaluate each interviewer’s performance were discussed after each interview in order to reach an agreement among the central and local supervisors. This strategy allowed the local supervisors to implement subsequent training, in the event of substitution of members of the team. The certification consisted of a theory test, on topics from the application manual, and a practical test that entailed applying an interview to a volunteer. This process was also followed by each local supervisor, who had been trained to certify new interviewers in the event of alterations to the team during the field work.

Table 1. ELSA (Estudo Longitudinal de Saúde do Adulto) components of interviews, examinations and laboratory measurements that will be available for cognitive investigation1 Variables Sociodemographic characteristics Health and medical history Mental health Occupational exposure Family history Reproductive health Healthcare Psychosocial factors Habits Medication Physical examinations Clinical tests Laboratory tests

Age, sex, race/ethnicity, educational level, income, religion, marital history and childhood living conditions Self-rated health and medical histories of cardiovascular diseases, diabetes, cancer and other selected chronic diseases of interest; investigation of rose angina and intermittent claudication; questionnaires on heart failure and headache Clinical Interview Schedule Revised (CIS-R) Job characteristics (stress, degree of autonomy, access to funds and authority) and retirement situation Cardiovascular disease, diabetes and sudden death Menarche and menopause, contraceptive use, reproductive history and hormone therapy Access to preventive healthcare/examinations, health insurance and healthcare utilization Neighborhood characteristics (leisure, sports and access to food purchasing), stressful life events and self-rated social status Food frequency, smoking, alcohol consumption and current physical activity Prescription and nonprescription drugs, vitamins, dietary supplements and other remedies taken in past month. Weight, height, blood pressure and ankle brachial index Electrocardiography, transthoracic echocardiography and carotid scan Total blood cell count, plasma glucose, oral glucose tolerance test, HbA1c, creatinine, total, HDL and LDL-cholesterol, triglycerides, gamma-glutamyl transferase, AST and ALT, Uric acid, Na, K and Ca, microalbuminuria, high-sensitivity C-reactive protein, thyroid-stimulating hormone, thyroxine, insulin and Chagas disease serology

HDL = High density lipoproteins; LDL = Low density lipoproteins; AST = Aspartate transaminase; ALT = Alanine transaminase.

Table 2. Description of the cognitive tests used in ELSA-Brasil study (Estudo Longitudinal de Saúde do Adulto) Test CERAD word test* (Figure test†) Word recall (Figure recall) Word recognition (Figure recognition) Verbal fluency tests (animals and letter F)

Trail-making test (version B)

Main domain

Domain capacities Immediate learning of new information; retention of information after three trials

Memory

Delayed recall of the learned information Remembering and distinguishing the correct words from a set of distractors

Executive functions

_ Language (also semantic memory) _ Attention to a task over time _ Concentration _ Use of information learned in the test instructions _ Visual-spatial organization; connecting words and numbers _ Speed (of speaking correct words or connecting words and numbers) _ Cognitive flexibility: recognition and correction of possible errors

CERAD words, Brazilian version: poste, motor, carta, braço, manteiga, erva, cabana, árvore, bilhete, praia.28 †Figure test images: shoe, house, comb, airplane, key, bucket, turtle, book, spoon, tree.29

*

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In a test and retest study with a mean interval of 29 days, which was conducted on 160 participants, higher scores were observed in all the retests, as well as a decrease in the average time taken to do the trail-making test version B. The memory tests presented moderate reliability, the verbal fluency tests presented good reliability and the trail-making test version B presented almost perfect reliability.30 The verbal fluency tests require that interviewer should write down all the words said by the participant during a one-minute period. To avoid mistakes in the transcriptions, they were all recorded and checked. The supervisor of each center was also trained to calculate verbal fluency test scores, and a reliability study was designed to ascertain the degree of homogeneity of the interpretation among the ELSA centers. Intraclass correlation coefficients and Bland-Altman plots were used to examine patterns of rating disagreement among the verbal fluency test scores given by the supervisors at the six ELSA research centers, who independently judged 120 category tests (animals) and 120 phoneme tests (letter F). Their scores were compared with a reference standard score that was obtained through independent judgment by two experts. The scores were very similar among the ELSA centers, and  a high level of agreement was observed between each center and the reference standard.31 The data center for delineating and managing the data system was operated by a multidisciplinary team. A web-based system was developed, in order to enable online data entry, verification and editing while maintaining security and confidentiality, as well as in order to incorporate data that had been gathered on paper and obtained from reading centers. Processes for data extraction and cleaning were

also developed in order to create databases in formats that would allow analyses in multiple statistical groups. ELSA-Brasil was approved by the Research Ethics Committee of all the six participating centers and by the National Research Ethics Committee. All the participants signed a free and informed consent statement before collection of any clinical and laboratory data. All international rules regarding data confidentiality during storage and analysis are being followed.1 RESULTS The vast majority of the participants (15,101 out of 15,105) took the cognitive tests; 54% of them were women and 46% were men. There were four cases of refusal to participate. The age range was from 35 to 74 years, with a median age of 51 years. With regard to working status, 80% were active public employees and 20% retired. Over 52% (7,498) had a university degree, 4204 (27.8%) had completed high school, 1898 (12.6%) had completed middle school, 1029 (6.8%) participants had studied in but not completed middle school and 22 (0.2%) were illiterate. Significant differences in the distribution of sociodemographic characteristics according to investigation center were observed. There was an overall predominance of women, with the highest contingents in the states of Bahia and Rio Grande do Sul. The mean age was 52.00 ± 9.08 years, with the youngest participants in the state of Rio de Janeiro, where the number of retired participants was also lower than in the other centers. Only 10% of the participants had attended school for less than five years, and the lowest percentages were found in Rio de Janeiro and Rio Grande do Sul (Table 3).

Table 3. Sociodemographic characteristics of the 15,101 participants in the ELSA study (Estudo Longitudinal de Saúde do Adulto) who attended cognitive tests in baseline examination Investigation centers Variables Sex Male Female

Bahia n (%)

Espírito Santo n (%)

Minas Gerais n (%)

Rio de Janeiro n (%)

Rio Grande do Sul n (%)

São Paulo n (%)

Total n (%)

842 (41.50)

497 (47.20)

1474 (47.32)

853 (47.81)

887 (43.08)

2336 (46.16)

6,892 (45.64)

1187 (49.50)

556 (52.80)

1641 (52.68)

931 (52.19)

1172 (56.92)

2725 (53.84)

8,213 (54.36)

χ2 = 27.99; P < 0.0001 Age Mean Standard deviation

53.62

52.79

52.42

49.52

53.12

51.61

52.09

9.17

8.86

8.97

8.12

9.58

9.05

9.08

F = 51.08; P < 0.0001 Schooling 1-4 years

298 (14.69)

159 (15.10)

296 (9.50)

47 (2.63)

39 (1.89)

801 (15.82)

1640 (10.86)

≥ 5 years

1731 (85.31)

894 (84.90)

2819 (80.50)

1737 (97.37)

1740 (98.11)

4260 (84.18)

13465 (89.14)

χ2 = 26.33; P < 0.0001 Working status Employee Retired

1560 (76.89)

828 (78.63)

2466 (79.16)

1626 (91.14)

1487 (72.22)

4129 (81.58)

12,097 (80.10)

469 (23.11)

225 (21.17)

649 (20.84)

158 (9.86)

572 (27.78)

932 (18.42)

3,008 (19.90)

χ2 = 240.00; P < 0.0001

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14,965 participants (99%) completed the three learning trials of the word memory test, and only 136 (1%) had to be given the figure memory test because of poor literacy skills. In both tests, the participants’ scores increased at the second and third attempts with means of 4 ± 1.6, 7.4 ± 1.6 and 8.2 ±  1.4 for the first, second and third attempts at the word memory test and 5.7 ± 2.1, 7.2 ± 2.4 and 7.3 ± 2.4 for the figure memory test. The scores for the semantic verbal fluency tests (mean = 18.42 ± 5.29 words; median = 18 words) were greater than the scores for the phonemic verbal fluency test (mean = 12.46 ± 4.5 words; median = 12 words). The overall time taken to perform the trail-making test version B, without excluding outliers, ranged from 0.2 minutes to 26 minutes (mean = 2.1 ± 1.45 minutes; median = 1.6 minutes). DISCUSSION Transcultural studies have already identified significant variability in how dementia is expressed in different populations.12 Establishment of a cohort of public employees in six Brazilian states, including adults and elderly people, will make it possible to investigate the influence of various social and clinical characteristics of the participants on their cognition, from middle age onwards. Investigation of cognitive impairment at the baseline will make it possible to evaluate the prevalence and factors associated with cognitive impairment among the adult population by comparing the test results from different age strata, with adjustments for the different intervenient variables investigated. This first approach has the merit of providing an understanding of the distribution of cognitive functions in the study population, but presents the disadvantages inherent to this type of cross-sectional design. The prospective analysis will enable us to compare intrapersonal performance, without the birth cohort effect, thus making it possible to measure the potential influence of risk factors, such as lifestyle, presence of diseases and use of medications. In addition to investigation of the natural evolution of cognition, the longitudinal study will allow us to investigate modifiable risk factors for cognitive decline, which is a public health priority, in an effort to prevent or delay occurrences of dementia. Cognitive tests are used as a proxy for the participants’ cognition. They present an advantage over clinical evaluation, in that they establish standardized scores, thus allowing comparison over time between people and studies. However, for this comparison, it has to be assumed that the cognitive tests have stable and reproducible results, which is not always true. The high consistency of verbal fluency test scores

confirms that these tests are reliable and valid, and assures their use in multicenter studies. As observed, reapplication of these tests, particularly when the interval between applications is short, may lead to an improvement in performance, due to the learning effect. With the aim of minimizing this learning effect in the ELSA follow-up, in 2012, the ten CERAD words used in the memory test will be presented in a different order and the tests of verbal fluency will demand a different category (vegetables) and a different initial letter (A). The trail-making test version B, which presented high reproducibility when reapplied after short period, will be repeated. The baseline cognitive tests will be repeated exactly, in the second ELSA follow-up, after an interval of six years. This strategy will make it possible to investigate the influence of confounder factors on cognition, such as learning effects, on test performance. Always bearing in mind the aphorism Brain function is too complex to be communicated in a single score, many other investigation strategies will be used during the development of the cohort, such as “nested case-control studies”. Other tools for cognitive analysis will also be included, such as clinical-neurological evaluation and imaging tests.32 Multifactorial analysis will be carried out, and the reliable change index will be calculated in order to determine any real and significant changes in cognitive test scores over time.33 CONCLUSION Investigation of cognitive function decline in ELSA-Brasil takes into consideration its insidious onset, its long latency period and the need to identify factors that interact with the evolution of these processes. These approaches are only possible in longitudinal studies that include a large adult population. Such studies make it possible to identify the subclinical processes of dementia and are a source of knowledge for intervening in these risk factors, especially in modifiable ones. REFERENCES 1. Aquino EM, Barreto SM, Bensenor IM, et al. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): objectives and design. Am J Epidemiol. 2012;175(4):315-24. 2. Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatr. 2009;21(4):622-30. 3. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008;148(6):427-34. 4. Tuokko H, Frerichs R, Graham J, et al. Five-year follow-up of cognitive impairment with no dementia. Arch Neurol. 2003;60(4):577-82.

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5. Scazufca M, Menezes PR, Vallada HP, et al. High prevalence of dementia

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6. Costa MF, Uchoa E, Guerra HL, et al. The Bambuí health and ageing

22. Singh-Manoux A, Richards M, Marmot M. Socioeconomic position

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7. Bachman DL, Wolf PA, Linn R, et al. Prevalence of dementia and

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8. Hofman A, Ott A, Breteler MM, et al. Atherosclerosis, apolipoprotein

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9. Brayne C, Gill C, Huppert FA, et al. Vascular risks and incident dementia: results from a cohort study of the very old. Dement Geriatr Cogn Disord. 1998;9(3):175-80. 10. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and

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cognitive decline in middle-aged adults. Neurology. 2001;56(1):42-8.

26. Elliott R, Zahn R, Deakin JF, Anderson IM. Affective cognition and

11. Freitag MH, Peila R, Masaki K, et al. Midlife pulse pressure and

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2011;36(1):153-82. 27. Daviglus ML, Bell CC, Berrettini W, et al. National Institutes of

12. Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascular risk factors

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13. McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering

28. Bertolucci PHF, Okamoto IH, Toniolo Neto J, Ramos LR,

in patients without prior cerebrovascular disease for prevention of

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14. Peters R, Beckett N, Forette F, et al. Incident dementia and blood

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cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008;7(8):683-9. 15. Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes--systematic overview of prospective observational studies. Diabetologia. 2005;48(2):2460-9.

1998;25(2):80-3. 29. Nitrini R, Caramelli P, Herrera Júnior E, et al Performance of illiterate and literate nondemented elderly subjects in two tests of long-term memory. J Int Neuropsychol Soc. 2004;10(4):634-8. 30. Batista JA. Confiabilidade da bateria dos testes de função

16. Young SE, Mainous AG 3rd, Carnemolla M. Hyperinsulinemia

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17. Gunstad J, Paul RH, Cohen RA, Tate DF, Gordon E. Obesity is associated

31. Passos VM, Giatti L, Barreto SM, et al. Reprodutibilidade dos escores

with memory deficits in young and middle-aged adults. Eat Weight

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[Verbal fluency tests reliability in a Brazilian multicentric study, ELSA-

18. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001;58(3):498-504. 19. Peters R, Poulter R, Warner J, et al. Smoking, dementia and cognitive

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study (BHAS): methodological approach and preliminary results of

Brasil]. Arq Neuropsiquiatr. 2011;69(5):814-6. 32. Launer LJ. Counting dementia: There is no one “best” way. Alzheimers Dement. 2011;7(1):10-4. 33. Stein J, Luppa M, Brähler E, König HH, Riedel-Heller SG. The

decline in the elderly, a systematic review. BMC Geriatr. 2008;8:36.

assessment of changes in cognitive functioning: reliable

20. Peters R, Peters J, Warner J, Beckett N, Bulpitt C. Alcohol, dementia

change indices for neuropsychological instruments in the

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elderly - a systematic review. Dement Geriatr Cogn Disord.

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2010;29(3):275-86.

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Acknowledgements: The authors thank the participants and the research team of the baseline study for their contribution to this study Sources of funding: The baseline study was supported by the Ministry of Health (Science and Technology Department) and Ministry of Science and Technology (Financiadora de Estudos e Projetos [Finep] and Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq]) of Brazil (No. 01 06 0278.00 MG) Sandhi M. Barreto, Isabela Benseñor and Paulo Caramelli are research fellows of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Paulo Caramelli and Valéria M. A. Passos are research fellows of the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Fapemig) Conflict of interest: None Date of first submission: December 11, 2012 Last received: May 28, 2013 Accepted: June 19, 2013 Address for correspondence: Valéria Maria de Azeredo Passos Centro de Investigação ELSA-MG Hospital Borges da Costa Av. Alfredo Balena, 110 Belo Horizonte (MG) — Brasil CEP 30130-100 Tel. (+55 31) 3409-9014 E-mail: [email protected]

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DOI: 10.1590/1516-3180.2014.1323653

Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement Avaliando estudos de caso-controle em psiquiatria utilizando o STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement Pedro Domingues GoiI, Julia Domingues GoiI, Kariny Larissa CordiniI, Keila Mendes CeresérII, Neusa Sica da RochaIII Postgraduate Medical Program on Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

MD, MSc. Doctoral Student, Postgraduate Medical Program on Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. I

II Pharm, MSc, PhD. Professor, Postgraduate Medical Program on Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre; Member, INCT for Translational Medicine, Brazil.

MD, MSc, PhD. Professor, Postgraduate Medical Program on Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

III

KEY WORDS: Epidemiology. Psychiatry. Research design. Case-control studies. Biomedical research. PALAVRAS-CHAVE: Epidemiologia. Psiquiatria. Projetos de pesquisa. Estudos de casos e controles. Pesquisa biomédica.

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ABSTRACT CONTEXT AND OBJECTIVE: Case-control studies are important in developing clinical and public health knowledge. The STROBE statement (STrengthening the Reporting of OBservational Studies in Epidemiology) was developed to establish a checklist of items that should be included in articles reporting observational studies. Our aim was to analyze whether the psychiatric case-control articles published in Brazilian journals with CAPES Qualis rating B1/B2 in 2009 conformed with the STROBE statement. DESIGN AND SETTING: Descriptive study on psychiatric papers published in Brazilian journals, within the Postgraduate Medical Program on Psychiatry, at Universidade Federal do Rio Grande do Sul. METHODS: All psychiatric case-control studies from Brazilian Qualis B1/B2 journals of psychiatry, neurology and public health in 2009 were analyzed. The four most specific items of the STROBE statement were used to evaluate whether these studies fitted within the case-control parameters: 1) selection of cases and controls; 2) controlling for bias; 3) statistical analysis; and 4) presentation of results. RESULTS: Sixteen case-control studies were identified, of which eleven (68.75%) were in psychiatryfocused journals. From analysis using the STROBE statement, all of the articles conformed with item 1; two (12.5%) completely conformed with item 2; none completely conformed with item 3; and only three (18.8%) conformed with item 4. CONCLUSION: The case-control studies analyzed here did not completely conform with the four STROBE statement items for case-control design. In view of the inadequate methodology of the published studies, these findings justify focusing on research and methodology and expanding the investigations on adherence of studies to their designs. RESUMO CONTEXTO E OBJETIVO: Estudos de caso-controle são importantes no desenvolvimento do conhecimento clínico e de saúde pública. O STROBE statement (STrengthening the Reporting of OBservational Studies in Epidemiology) foi criado para estabelecer uma lista de itens que devem estar presentes na descrição de estudos observacionais. Nosso objetivo é analisar a adequação de artigos caso-controle psiquiátricos publicados em periódicos brasileiros Qualis B1/B2 CAPES em 2009 utilizando o STROBE statement. TIPO DE ESTUDO E LOCAL: Estudo descritivo de artigos em psiquiatria publicados por periódicos brasileiros, realizado no Programa de Pós-Graduação em Medicina: Psiquiatria, na Universidade Federal do Rio Grande do Sul. MÉTODOS: Todos os estudos de caso-controle psiquiátricos em revistas brasileiras Qualis B1/B2 de psiquiatria, neurologia e saúde pública em 2009 foram analisados. Os quatro itens mais específicos do STROBE statement foram utilizados para avaliar se os estudos se ajustavam aos parâmetros de caso-controle: 1) seleção de casos e controles, 2) controle de vieses, 3) análise estatística e 4) apresentação dos resultados. RESULTADOS: Dezesseis estudos de caso-controle foram identificados, 68,75% (11) deles de periódicos de psiquiatria. Após a análise com base no STROBE statement, todos os artigos adequavam-se ao item 1; 12,5% (2) adequavam-se completamente ao item 2; nenhum ajustava-se completamente ao item 3; e somente 18,8% (3) estavam adequados em relação ao item 4. CONCLUSÃO: Os estudos de caso-controle avaliados aqui não se adequaram completamente aos quatro itens do STROBE statement para o desenho de caso-controle. Tendo em vista a inadequada metodologia dos estudos publicados, os achados justificam direcionar-se o foco para a pesquisa e metodologia, aumentando a investigação da adesão dos estudos aos seus desenhos.

Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement | SHORT COMMUNICATION

INTRODUCTION Rational healthcare practice requires knowledge of the etiology, pathogenesis, diagnostics, prognosis and treatment of illnesses. A substantial portion of clinical and public health knowledge comes from observational research. Nine out of ten articles published in clinical journals describe observational investigations.1 Case-control studies belong to the observational studies group. They emerged within epidemiology as part of the search to identify the risk factors in diseases. A case-control design is modest and less expensive than other models, and can produce surprisingly good results. Case-control studies can be interestingly useful when the outcome studied is rare or delayed and when the exposure is difficult to randomize. However, conducting these studies can be challenging because of the great possibility of bias.2 These studies cannot estimate the incidence or prevalence of a disease, although they provide descriptive information about the characteristics of cases and, most importantly, an estimate of the magnitude of the association between each predicting variable and the presence or absence of disease. These estimates are expressed in the form of odds ratios, which can be approximated to the relative risk if the prevalence of the disease is not too high.3,4 One of the main advantages of case-control studies is the large amount of information that can be rapidly provided from a small number of subjects, which favors studies on rare outcomes and enables generation of hypotheses. Case-control studies also have limitations, such as lacking the ability to directly estimate the incidence or prevalence of the disease and the attributed risk or excess of risk. Another problem is the possibility of studying just one of many possible outcomes. However, their greatest limitation is their enormous susceptibility to bias, which results mainly from isolated sampling of cases and controls and standardization of retrospective predictive variables.4 The ideal case sample is the entire population (the real complete sample) or the one composed of randomly selected subjects from among those who have developed the disease under investigation. In general, sample bias becomes a real problem when the sample misrepresentation is related to the risk factor studied. In practice, case selection is usually a simple process because of the limited number of accessible subjects. However, the more challenging decisions in a case-control study relate to selection of controls. The goal is to sample controls for a population at risk of a disease that is, in other respects, similar to the case population. A good case-control study anticipates the possible forms of bias, which according to Schulz and Grimes is the most difficult task in epidemiology.3 If the case selection is performed in a hospital or ambulatory setting, the selection of controls should be performed in the same location; cases and controls should be paired; there should be some assurance that they are comparable with one another; cases from population-based

samples can be used; and two or more control groups can even be used.3-5 Another important point that should be observed is the bias caused by standardization errors from the retrospective strategies used for measuring predictive variables. Two specific strategies can be used to avoid these types of bias in measuring risk factors in case-control studies: use of data registered prior to the outcome and blinding. Although little information can be found in the PubMed and SciELO databases regarding developmental methodology in this type of study, many published papers have used the case-control design.3 This gives rise to some concern about the quality of these studies, and therefore justifies expanding the discussion on the methodology of case-control studies. Considering the importance of this issue, in 2007 a group of epidemiologists, methodologists, statisticians, researchers and editors became involved in development of the STROBE statement (STrengthening the Reporting of OBservational Studies in Epidemiology). Observational research comprises several study designs and many topic areas. This group aimed to establish a checklist of items that should be included in articles reporting such kind of research. The instrument thus produced can be used for evaluating the quality of reporting observational studies and will be used in the present study.5 It should be noted that in reviewing the literature, we did not find any articles that evaluated published papers within the field of psychiatry using this instrument.  OBJECTIVE The objective of this study was to analyze the appropriateness of the case-control designs of articles that were published in 2009, in journals that had been rated as B1 and B2 in the Qualis system of the Brazilian Federal Agency for the Improvement of Higher Education (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES), using the STROBE statement. Furthermore, this investigation also aimed to analyze secondary data from the distribution of the different publication types among the periodicals. METHODS This was a descriptive study on articles within the field of psychiatry that were published in 2009, in Brazilian periodicals with a major ISI (Thomson Reuters Web of Knowledge, Institute for Scientific Information) international impact. The year of 2009 was selected because the current impact factors refer to articles published that year. A search was performed in the Qualis/ CAPES database to delineate the periodicals that had psychiatric topics within their scope. Qualis is a journal classification system in which the impact factors are based on the CAPES system, which is used to evaluate the scientific production of postgraduate programs.6 Sao Paulo Med J. 2014; 132(3):178-83

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Medical journals are subclassified into three groups: Medicine I, Medicine II (which includes psychiatry) and Medicine III. This database ranks all scientific journals in eight strata (A1, A2, B1, B2, B3, B4, B5 and C), depending on their international indexing. From A1 to B2, stratification is made according to the ISI impact factor. Other Medline journals are classified as B3, Scielo journals as B4, and Lilacs journals as B5. Journals otherwise indexed are classified as C. Psychiatry journals ranked as B1 must have ISI impact factors of between 1.1 and 2.36. Journals classified as B2 must have impact factors of between 0.11 and 1.09. None of the Brazilian psychiatry journals have achieved classifications greater than B1. In order to diminish publication bias, journals that charge for publication (i.e. Clinics [B1] and Brazilian Journal of Medical and Biological Research [B2]) did not enter the analysis. Revista de Psiquiatria Clínica, a B2 psychiatric journal, did not enter the evaluation because its first impact factor came in 2011. Thus, the highest qualifications found were for one journal classified as Qualis B1 and two journals classified as Qualis B2 in the CAPES database. A third Qualis B2 journal, Cadernos de Saúde Pública, was excluded because among its few psychiatric articles, no abstract compatible with a case-control design was identified prior to the article analysis. Three journals stood out partially because of their focus on the subject addressed here. Journal number 1, Revista Brasileira de Psiquiatria, publishes original studies from all areas of psychiatry. Its impact factor in 2009 was 1.391. Journal number 2, Arquivos de Neuro-psiquiatria, publishes original scientific-technological articles in the field of neurology and applied neurosciences. Its impact factor in 2009 was 0.549. Journal number 3, Revista de Saúde Pública, specializes in several interdisciplinary areas of public health, with emphasis on epidemiology. Its impact factor in 2009 was 1.006. Three independent evaluators reviewed the volumes of these journals by reading the abstracts of all the articles, and then classifying the field, the design, and the type of publication of each study. Only original case-control studies within the field of psychiatry that were published in full in Brazilian periodicals with CAPES Qualis B1/B2 ratings in 2009 were included. Articles published in supplements of these journals were excluded, since these are only rarely peer-reviewed. The extent to which each study fitted in with the methodology of the case-control design was evaluated in accordance with the recommendations of the STROBE statement7 and the theoretical basis for case-control methodology that has been described in the literature.4 The STROBE statement checklist (available at http://www.strobe-statement.org) was used to rate the degree of conformity. For instance, checklist items 6a and 6b refer to selection of cases and controls. Checklist item 9 refers to controlling for bias, in which authors should list all potential 180

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bias and clearly state how each of these forms of bias was dealt with. Checklist items 12a, 12b, 12c, 12d and 12e refer to statistical analysis; and checklist items 16a, 16b and 16c refer to presentation of the results. Articles were classified as “conforming” with an item if they completely complied with all subitems of the checklist, and as “non-conforming” if they did not comply with any of the subitems. All other descriptions were classified as “partially conforming”. After this selection, three evaluators independently applied the STROBE statement to all the articles, such that each article was evaluated three times by different evaluators. If there were any discrepancies in the checklist results, the evaluators formed a committee in order to reach a verdict. Instrument The STROBE statement7 is an instrument that was developed to ensure appropriate reporting of observational studies. It consists of 22 points that are considered by specialists to be essential for this purpose. These items involve various aspects of the study, such as the title and the abstract, as well as the detailing of facts presented in the discussion. It also includes other relevant topics, such as the financing of the project. The three types of observational design have 18 items in common, while four items are exclusively associated with each study design type: case-control, cohort and cross-sectional. The present study took into consideration the four items that are exclusive to case-control studies. Item number one refers to the eligibility criteria of the cases and controls, the tallying sources and methods of the cases, and the selection of controls, including an explanation for how each group was chosen. Item number two refers to the efforts to address possible bias, including sampling, pairing and blinding in cases of retrospective studies. Item number three examines the suitability of the statistical methods and recommends that odds ratios should be used. These methods, particularly those that are used to control for confounding variables and manage missing data, should be clearly described. Item four refers to the presentation of results and directs attention to adjusted and non-adjusted estimates. Statistical analysis Correspondence analysis,8 which enables better graphic visualization of the relationships between these variables, was used to study the categorical nominal variables of the initial survey of the published articles. The general purpose of using correspondence analysis is to graphically represent the data frequencies in the form of a contingency table. The output from correspondence analysis is a two-dimensional map that makes it possible to examine associations among several categorical variables, which is not easily possible by just inspecting the frequencies or a contingency table. The distances

Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement | SHORT COMMUNICATION

between rows and columns are expressed using the chi-square measurement.9 The Kolmogorov-Smirnov test was used to investigate the normality of the distributions. The differences between averages obtained from control-case tallying were analyzed by means of the t test. The data were analyzed using the Statistical Package for the Social Sciences version 17.0 for Windows (SPSS Inc., Chicago, Illinois, USA). RESULTS Distribution of published papers The three journals selected generated 486 published papers in 16 volumes in 2009. The publication types were classified as original articles, letters, editorials, book reviews and special articles. The study designs were classified as case-control, clinical trial (longitudinal studies with open or closed intervention, with or without controls, with or without randomization and with or without blinding), review articles (systematic reviews and meta-analyses), case reports or case series, cohorts, other cross-sectional studies, other longitudinal studies, non-psychiatric studies (in other fields within the scope of these journals) and other designs (articles without a definite outline, such as reviews, editorials, comments, errata etc.). Sixteen published psychiatric case-control studies were found in the three selected journals (Figure 1).

486 articles in 3 journals

Excluded: - 61 letters - 26 editorials - 11 reviews - 112 special articles

276 original articles

Excluded: - 210 non-psychiatric studies - 9 clinical trials - 4 review articles - 3 case reports or case series - 31cross-sectional studies - 1 longitudinal study - 1 cohort study - 1 qualitative study 16 case - control studies

Figure 1. Flowchart for case-control article selection.

Degree of conformity of the published papers In relation to each item evaluated, the studies were classified as conforming (1 point), partially conforming (0.5 points) or nonconforming (0 points), as shown in Table 1. No statistically significant differences were found between the journals when the items were evaluated individually. The numbers of points for each item were summed and analyzed, and the results showed that case-control studies published in 2009 in psychiatry-specific journals obtained 2.18 points on average, compared with 1.4 points for the articles published in the neurology journal, which was a difference of 0.78 points: P = 0.031, 95% confidence interval (CI): 0.085-1.478. In relation to item 1 (selection of cases and controls), 68.8% of the articles conformed with the method, 18.8% partially conformed and 12.5% did not conform. Regarding item 2 (strategy for the control of biases), 12.5% conformed, 50% partially conformed and 37.5% did not conform. There were no published papers that completely conformed with item 3 (statistical analysis), although 68.8% partially conformed and 31.2% did not conform. In relation to item 4 (presentation of results), 18.8% conformed, 50% partially conformed and 31.2% did not conform. Relationship between journals and publication types Apart from the main analysis on the case-control studies, this investigation also tested secondary data from the distribution of the different publication types among the periodicals. As mentioned above, correspondence analysis was performed in order to explore the relationship between publication types and periodicals, and also among the different types. To view the relationship between the variables better, a correspondence analysis map was produced (Figure 2). On this map, the graphical display provides a favorable overview of the connections between the variables. It could clearly be seen that journal 2 (neurology) and journal 3 (public health) were closer together, in comparison with the distance to journal 1 (psychiatry). Moreover, clinical trials, case-control studies, review articles, other longitudinal studies and cross-sectional studies were distributed closer to journal 1 than to 2 and 3 (chi-square distribution of two-dimensional correspondence = 223.39; P < 0.0001). DISCUSSION In this study, the appropriateness of the case-control methodology reporting in articles was examined. Sixteen case-control studies were retrieved from among 486 papers published in 2009 in three Brazilian journals. All of these articles, analyzed together, reached a mean score of 1,875 (on a scale from 0 to 4). The psychiatry and neurology journals differed significantly in their mean impact scores: 2.18 versus 1.4 points, respectively.

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Table 1. Conformity of case-control articles published in 2009 to case-control reporting Journal (issue number) 1 (1) 1 (1) 1 (1) 1 (2) 1 (3) 1 (3) 1 (3) 1 (4) 1 (4) 1 (4) 1 (4) 2 (1) 2 (2A) 2 (3A) 2 (4) 2 (4)

Article number within issue 3 4 10 5 3 4 6 3 4 6 9 1 1 1 1 6

Item 1 (selection of cases and controls) Partial No Partial Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Partial

Conformity with items evaluated* Item 2 Item 3 (bias control) (statistical analysis) Partial Partial Partial No Partial Partial Yes Partial No Partial Partial Partial Partial Partial Partial Partial No Partial Yes Partial Partial Partial Partial No No No No No No No No Partial

Item 4 (presentation of results) No No Partial Yes Partial Partial Partial Yes Partial Yes Partial No Partial Partial No No

*Yes = 1, Partial = 0.5, No = 0.

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2 Cohort Case series/report 1 Neurology Clinical trial Dimension 2

This result was in accordance with the impact factor, which was greater in the psychiatry journals. Surprisingly, none of the studies from the Brazilian journals publishing articles on psychiatry that were selected, which had higher CAPES status during this period, satisfied all of the items. None of the studies conformed completely with regard to the statistical analysis (item 3), and only 12.5% completely conformed with the item addressing the care taken in relation to potential bias (item 2). While evaluating the articles, it became clear that little attention had been given to sampling the cases and controls, controlling for possible confounding factors, matching patients and controls and choosing the most appropriate statistical method for data analysis, including the use of odds ratios, confidence intervals and sensitivity analyses. The most striking fact is that, together, these items virtually define the consistency of a case-control study. Confusion about the term case-control study is not unique to the psychiatric literature. Only 75% of the self-declared casecontrol studies were found to meet the standard definitions for this design in pediatric journals,2 and 35% in surgery journals.10 In dermatology,11 case-control studies usually fail in relation to sample size calculations, describing and managing missing data, detailing losses from follow-up, statistical methods and the role of funding bodies in the research. A large, well-conducted survey of the literature among major psychiatric journals (i.e. those with impact factor > 3.0) noted that the reporting of methods in case-control studies is often poor. In that survey, neuroimaging studies had the best descriptions of controlling for bias, while genetic studies had the worst.12 In analyzing secondary data from our sample, we also demonstrated that case-control studies, clinical trials and other

Cross-sectional Other Case-control Psychiatry Review Longitudinal

0

Non-psychiatric Public health

-1

-2

-3

Qualitative research

-3

-2

-1

0

1

2

Dimension 1 Journal Type of Study

Figure 2. Two-dimensional derivation for correspondence analysis. Black circles represent the three journals evaluated. White circles represent the types of study (chi-square distribution of two-dimensional correspondence = 223.39; P < 0.0001). cross-sectional and longitudinal studies were more frequent in psychiatry journals, while cohort studies, case reports and qualitative studies correlated more with other journals. This finding could raise new research questions and insights about what lies behind these associations. Thus, it might be asked whether case reports are uninteresting in relation to psychiatry literature;

Evaluating psychiatric case-control studies using the STROBE (STrengthening the Reporting of OBservational Studies in Epidemiology) statement | SHORT COMMUNICATION

whether there is any difficulty in reporting cohort results in the Brazilian psychiatric literature; or whether the impact factor is associated with specific types of studies. One limitation of the present study was that it was restricted to using 4 of the 22 items of the conformity evaluation instrument, i.e. the STROBE statement on case-control studies. Another important point in the analysis was that it was limited to papers published only in 2009. By increasing the sample size, it might have been possible to identify more eligible studies that were not evaluated. The non-blinding of evaluators in relation to the journals and the authors of the published papers analyzed may also have biased the results. The fact that only Brazilian published papers were evaluated can also be considered to be a limitation, although the results from the present study are important because of its original use of the STROBE statement in psychiatric journals. Furthermore, the results can be extrapolated to countries with similar journals, and may stimulate new studies evaluating the quality of published papers on different continents. The results show that there is a need for more research studies evaluating the appropriateness of case-control studies and other designs, with the intentions of discussing and improving the methodological quality of these studies and upgrading the clinical applicability of the results obtained from psychiatric research. Furthermore, these results should encourage clinicians who use the scientific literature in their practice to acquire basic skills for judging the validity of the articles available, and to become aware of the strengths and limitations of these articles.

5. von Elm E, Altman DG, Egger M, et al. Declaración de la iniciativa STROBE (Strengthening the Reporting of Observational Studies in Epidemiology): directrices para la comunicación de estudios observacionales. [The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies]. Rev Esp Salud Publica. 2008;82(3):251-9. 6. Andriolo A, Souza AF, Farias AQ, et al. Classification of journals in the QUALIS System of CAPES urgent need of changing the criteria! Arq Neuropsiquiatr. 2010;68(2):327-9. 7. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med. 2007;147(8):W163-94. 8. Mota JC, Vasconcelos AG, Assis SG. Correspondence analysis: a method for classifying similar patterns of violence against women. Cad Saude Publica. 2008;24(6):1397-406. 9. Sourial N, Wolfson C, Zhu B, et al. Correspondence analysis is a useful tool to uncover the relationships among categorical variables. J Clin Epidemiol. 2010;63(6):638-46. 10. Mihailovic A, Bell CM, Urbach DR. Users’ guide to the surgical literature. Case-control studies in surgical journals. Can J Surg. 2005;48(2):148-51. 11. Langan SM, Schmitt J, Coenraads PJ, et al. STROBE and reporting observational studies in dermatology. Br J Dermatol. 2011;164(1):1-3. 12. Lee W, Bindman J, Ford T, et al. Bias in psychiatric case-control studies: literature survey. Br J Psychiatry. 2007;190:204-9. Sources of funding: None Conflict of interest: None Date of first submission: January 6, 2013

CONCLUSION The case-control studies analyzed here did not completely conform with the four STROBE statement items for case-control design. In view of the inadequate methodology of the published studies, these findings justify focusing on research and methodology and expanding the investigations on adherence of studies to their designs.

Last received: August 6, 2013 Accepted: August 19, 2013 Address for correspondence: Pedro Domingues Goi Rua Ramiro Barcelos, 2.350 Hospital de Clínicas de Porto Alegre

REFERENCES

Santana — Porto Alegre (RS) — Brasil

1. Vandenbroucke JP, Von Elm E, Altman DG, et al. Mejorar la

CEP 90035-903

comunicación de estudios observacionales en epidemiología

Tel. (+55 51) 3359-8845

(STROBE): explicación y elaboració [Strengthening the reporting of

E-mail: [email protected]

observational studies in epidemiology (STROBE): explanation and elaboration]. Gac Sanit. 2009;23(2):158. 2. Hellems MA, Kramer MS, Hayden GF. Case-control confusion. Ambul Pediatr. 2006;6(2):96-9. 3. Schulz KF, Grimes DA. Case-control studies: research in reverse. Lancet. 2002;359(9304):431-4. 4. Newman TB, Browner WS, Cummings SR, Hulley SB. Designing cross-sectional and case-control studies. In: Hulley S, Cummings SR, Browner WS, et al, editors. Designing clinical research. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 109-26. Sao Paulo Med J. 2014; 132(3):178-83

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CASE REPORT

DOI: 10.1590/1516-3180.2014.1323697

Hemorrhagic shock secondary to button battery ingestion Choque hemorrágico secundário à ingestão de bateria em disco Naomi Andreia TakesakiI, Marcelo Conrado dos ReisII, Maria Luisa Ferreira de MirandaIII, Emílio Carlos Elias BaracatIV Department of Pediatrics, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, and Sumaré State Hospital, São Paulo, Brazil

MD. Attending Physician, Department of Pediatrics, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.

I

II MD, Attending Physician and Head of Pediatric Emergency Service, Hospital de Clínicas, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.

MD, Attending Physician and Head of Pediatric Ward, Hospital Estadual Sumaré, Sumaré, São Paulo, Brazil.

III

IV MD, PhD. Associate Professor, Department of Pediatrics, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, São Paulo, Brazil.

KEY WORDS: Foreign bodies. Electric power supplies. Gastrointestinal hemorrhage. Shock. Child. PALAVRAS-CHAVE: Corpos estranhos. Fontes de energia elétrica. Hemorragia gastrointestinal. Choque. Criança.

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ABSTRACT CONTEXT: Button battery ingestion is a frequent pediatric complaint. The serious complications resulting from accidental ingestion have increased significantly over the last two decades due to easy access to gadgets and electronic toys. Over recent years, the increasing use of lithium batteries of diameter 20 mm has brought new challenges, because these are more detrimental to the mucosa, compared with other types, with high morbidity and mortality. The clinical complaints, which are often nonspecific, may lead to delayed diagnosis, thereby increasing the risk of severe complications. CASE REPORT: A five-year-old boy who had been complaining of abdominal pain for ten days, was brought to the emergency service with a clinical condition of hematemesis that started two hours earlier. On admission, he presented pallor, tachycardia and hypotension. A plain abdominal x-ray produced an image suggestive of a button battery. Digestive endoscopy showed a deep ulcerated lesion in the esophagus without active bleeding. After this procedure, the patient presented profuse hematemesis and severe hypotension, followed by cardiorespiratory arrest, which was reversed. He then underwent emergency exploratory laparotomy and presented a new episode of cardiorespiratory arrest, which he did not survive. The battery was removed through rectal exploration. CONCLUSION: This case describes a fatal evolution of button battery ingestion with late diagnosis and severe associated injury of the digestive mucosa. A high level of clinical suspicion is essential for preventing this evolution. Preventive strategies are required, as well as health education, with warnings to parents, caregivers and healthcare professionals. RESUMO CONTEXTO: A ingestão de bateria em disco é queixa frequente em pediatria. As complicações graves decorrentes de ingestão acidental têm aumentado significativamente nas últimas duas décadas, devido ao fácil acesso aos aparelhos e brinquedos eletrônicos. Nos últimos anos, o aumento do uso de baterias de lítio com diâmetro de 20 mm trouxe novos desafios, por serem mais prejudiciais para a mucosa em comparação com outros tipos, com elevada morbidade e mortalidade. As queixas clínicas, muitas vezes inespecíficas, podem levar ao atraso no diagnóstico, aumentando o risco de complicação grave. RELATO DE CASO: Menino de cinco anos, com queixa de dor abdominal há 10 dias, é trazido ao serviço de emergência com quadro clínico de hematêmese há duas horas. Na admissão, apresentava palidez, taquicardia e hipotensão. Imagem sugestiva de bateria em disco foi visualizada na radiografia simples de abdome. A endoscopia digestiva demonstrou lesão ulcerada profunda no esôfago sem sangramento ativo. Após o procedimento, o paciente apresentou hematêmese profusa e hipotensão grave, seguidos de parada cardiorrespiratória (PCR), revertida. Submetido a laparotomia exploradora de urgência, apresentou novo episódio de PCR, sem reversão. A bateria foi removida por exploração retal. CONCLUSÃO: Este caso descreve a evolução fatal de ingestão da bateria em disco com diagnóstico tardio e associação com lesão grave de mucosa digestiva. Alto nível de suspeita clínica é obrigatório para evitar tal evolução. As estratégias de prevenção são necessárias, bem como a educação em saúde, com alerta aos pais, cuidadores e profissionais de saúde.

Hemorrhagic shock secondary to button battery ingestion | CASE REPORT

INTRODUCTION Accidents during childhood are an important cause of morbidity and mortality among children, and are the primary cause of death between the ages of 1 and 19 years.1,2 Ingestion/aspiration of foreign bodies has been identified as one of the top five types of accidents occurring in the pediatric age group, with peak incidence at between one and three years of age.1-3 Button battery ingestion represents about 2% of foreign body ingestion cases.4,5 Data from the American Poison Control Center has shown that the estimated incidence of button battery ingestion in the US is 1/11.1 million inhabitants, consisting mostly of accidental intake.6 Although the majority of battery ingestion is benign, one in every 1000 cases results in harm, especially when there is esophageal impaction.5,7 Most patients are asymptomatic, and the signs and symptoms are related to the anatomical location of the battery, length of time lodged at this location, size, composition and quantity ingested. In symptomatic cases, coughing, dysphagia, dyspnea, nausea, abdominal pain and vomiting may occur, in addition to nonspecific signs such as fever, irritability and food refusal.4,5,8 Imaging tests may help identify the foreign body and should be carefully analyzed, looking for evidence that suggests the presence of batteries, such as the double-contour sign in the anteroposterior projection of simple x-rays and the “step” sign in lateral view.9,10 Esophageal injury relating to battery ingestion is caused basically by three mechanisms: local electric power generation with burning of the mucosa, mechanical pressure necrosis and alkaline battery content leakage. Although rare, it is possible for poisoning due to absorption of mercury to occur, although this cannot occur in batteries containing lithium, manganese or other metals.4,5,11 The complications relating to ingestion of button batteries include esophageal perforation, perforation of Meckel’s diverticulum, esophageal stenosis, tracheoesophageal fistula, paralysis of vocal cords, spondylodiscitis, mediastinitis, bleeding and death.9,11-20 The therapeutic approach in cases of batteries in the esophagus is to undertake immediate withdrawal by means of endoscopy. For batteries in the stomach, there is still some controversy in the literature regarding case management, but this is mostly guided by the patient’s symptoms.21 After battery withdrawal by means of endoscopy, treatment with anti-reflux drugs, antibiotics or corticosteroids may be administered. Use of esophageal stents is still controversial, with low levels of improvement shown.22 Failure to recognize esophageal foreign bodies or inappropriate management of such cases may lead to life-threatening conditions. In this context, we describe the case of a preschool patient with fatal evolution after accidental ingestion of a button battery. 

CASE REPORT A five-year-old male patient who had been complaining of abdominal pain for the past 10 days was taken to the emergency referral unit of Sumaré State Hospital with a condition of hematemesis (two episodes in the last two hours). No other symptom or important antecedent was reported by the family. The mother said that she had sought medical services twice during the period, and the child had been evaluated and released since there were no symptoms. At admission he presented pallor, tachycardia (150 beats per minute, bpm) and hypotension (60 mmHg), and volume expansion with saline solution was started. The blood tests upon admission showed: hemoglobin (Hb): 8.9 g%; hematocrit: 27%; platelets: 161,000; International Normalized Ratio (INR): 1.09; and Ratio (R): 0.87. Simple abdominal radiography showed a radiopaque image with a double circular halo outline in the distal colon suggestive of a button battery (the mother was unaware of this ingestion) (Figure 1). Within two hours, he presented two more episodes of hematemesis, with Hb falling to 6.8 g%. A transfusion  of  packed red blood cells (10 ml/kg) was administered. Upper gastrointestinal endoscopy was performed in the surgical room (four hours after arrival), which showed a deep ulcerated lesion in the distal third of the esophagus, occupying 70% of the circumference and 5 cm in length. The bottom of the ulcer was covered by fibrin and a large clot had adhered to it, without active bleeding. After withdrawal of the endoscope, he presented new profuse hematemesis, as well as severe hypotension, and a Sengstaken-Blakemore tube was introduced. The case evolved with major abdominal distension and cardiopulmonary arrest, which was reversed by means of chest compressions and adrenaline. Because of the gradually increasing abdominal distension, it was decided that exploratory laparotomy should be performed by the pediatric surgeons. Through this, large amount of blood was found in the stomach, without any perforation of the digestive tract, and no blood was found in the peritoneal cavity. During the

Figure 1. Simple abdominal radiography showed a radiopaque image with double circular halo outline in the distal colon.

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procedure, the child presented a new cardiopulmonary arrest, but did not recover from it. The button battery was removed by means of rectal manipulation during the procedure. DISCUSSION Nowadays, button batteries are part of the technological reality experienced by children. The data show that there has been exponential growth in the frequency and severity of injuries caused by ingestion of these products. Between 1990 and 2009, there were more than 65,000 accidents with batteries among individuals under the age of 18 years in the United States, with an increase from 4 to 7.4 cases/100,000 children over that period.23 Ingestion accounted for the largest contingent, with 76% of the accidents, and also accounted for an increase of 80% in the number of cases over the past 8 years.24 As a result of changes to the types of batteries swallowed, severe complications and deaths due to battery ingestion have increased by around sevenfold, mostly among children younger than 4 years of age.8,25,26 A review of the literature was conducted through an online search for the MeSH terms Electric Power Supplies, Foreign Bodies, Gastrointestinal Hemorrhage and Shock, Hemorrhagic, in Medline (via PubMed); the EMTREE terms Electric Battery, Gastrointestinal Hemorrhage and Hemorrhagic Shock, in Embase (via Elsevier); and the MeSH/DeCS terms Foreign Bodies, Gastrointestinal Hemorrhage and Shock, Hemorrhagic, in Lilacs (via Bireme) (Table 1). The first report of death resulting from ingestion of button batteries was in 1977, which occurred in the case of an infant who ingested a photographic camera battery.27 Since then, numerous reports have been published in the medical literature, with 13 fatal cases identified in a recent review study.28 Exsanguination was shown to be the cause of death in 10 cases, seven of which occurred after 2004, mostly secondary to tracheoesophageal fistula. All cases  of fatal bleeding occurred in the age group from 11 months to 3 years of age, and the average duration of esophageal impaction was from 10 hours to 14 days. In six cases, the battery was removed before bleeding could occur. Evidence of bleeding, such as hematemesis or melena, was present in 70% of the fatal cases in the days or hours prior to the hemorrhage that led to death, which makes it important to search for signs in the clinical histories of stable patients.25,28 

The increasing severity of injuries associated with ingestion of batteries over the last two decades has taken place in parallel with the manufacturers’ transition to production of lithium batteries. Because lithium is a light metal, lithium batteries have higher efficiency, high electrochemical energy-density and longer life, thus making them commonly used in domestic appliances. However, their high voltage (3 V) makes their ingestion more dangerous than conventional batteries (1.5 V). Esophageal lesions have been observed within the first hour of impaction in the esophagus, in experimental studies on dogs.29 In humans, esophageal burns have been described within less than two and a half hours after ingestion, and perforations may occur about five hours after the accident.5,17,25 In addition, the greater diameter of most lithium batteries (20 mm) makes them more susceptible to lodging in the esophagus of children. There was an increase in ingestion of batteries of diameters between 20 and 25 mm, from 1% to 18% between 1990 and 2008, in parallel with increased ingestion of lithium batteries (from 1.3% to 24%) over the same period. About 92% of the batteries identified in cases of greater severity and lethality were lithium batteries of diameter 20 mm.25 Three basic injury mechanisms have been described in cases of battery contact with the mucosa of the gastrointestinal tract: generation of electric current with local burning; mechanical pressure causing necrosis; and leakage of alkaline content. In lithium batteries, their high voltage results in higher electric current generation capacity, with greater amounts of tissue fluid hydrolysis and production of hydroxides higher than in other battery types, which increases the potential for injury. Severe burns are observed in the area adjacent to the negative pole of the impacted battery, since electric current originates at this pole. Thus, battery position in the esophagus works as a predictor of severity.25  Most accidents that have evolved to complications or death present the common factor that the diagnosis was delayed. This  has often been due to the nonspecific presentation, especially in unwitnessed cases, like in the present case. In acute witnessed cases, the battery needs to be removed within two hours in order to avoid injury to the esophagus. This shorter window of opportunity, in comparison with previous descriptions, is probably related to the introduction of new types of batteries.

Table 1. Database search results for foreign body, electric battery, gastrointestinal hemorrhage and hemorrhagic shock on May 22, 2013 Electronic databases Medline (PubMed) Embase (Elsevier) Lilacs (Bireme)

186

Search strategies (Electric Power Supplies) AND (Foreign Bodies) AND (Gastrointestinal Hemorrhage) AND (Shock, Hemorrhagic) (Electric Battery) AND (Gastrointestinal Hemorrhage) AND (Hemorrhagic Shock) ((Foreign Bodies) OR (Cuerpos Extraños) OR (Corpos Estranhos)) AND ((Gastrointestinal Hemorrhage) OR (Hemorragia Gastrointestinal) OR (Hemorragia Gastrointestinal)) AND ((Shock, Hemorrhagic) OR (Choque Hemorrágico) OR (Choque Hemorrágico))

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Results No original articles, case reports or review articles No original articles, case reports or review articles No original articles, case reports or review articles

Hemorrhagic shock secondary to button battery ingestion | CASE REPORT

A simple x-ray examination is the preferred method in cases of suspicion of battery ingestion, whether the patients are symptomatic or not.5 The image must be evaluated properly, looking for the double outline stepped sign in anteroposterior and lateral views. Cases of unknown ingestion with radiological images similar to coins should be assumed to be batteries and conducted as such in order to prevent complications and death. All studies have emphasized that immediate withdrawal by means of endoscopy should be undertaken if the battery is lodged in the esophagus, with direct viewing of the mucosa. In cases in which the battery has already reached the stomach and the patient is asymptomatic, divergences exist with regard to case management. Litovitz et al. suggested that the x-ray examination should be repeated four days later (or sooner if symptoms appear) and, if the battery is still in the stomach, endoscopic withdrawal should then be indicated.25 If, after the withdrawal, lesions are observed in the mucosa, complementary examinations (contrasted x-ray examinations, bronchoscopy or computed tomography) must be performed to evaluate possible complications such as fistula or perforations. In addition, in serious cases, vital signs need to be monitored in a hospital environment even after withdrawal of the battery, given that there have been cases of exsanguination and death occurring 18 days after the endoscopy.25

4. Yardeni D, Yardeni H, Coran AG, Golladay ES. Severe esophageal damage due to button battery ingestion: can it be prevented? Pediatr Surg Int. 2004;20(7):496-501. 5. Litovitz T, Schmitz BF. Ingestion of cylindrical and button batteries: an analysis of 2382 cases. Pediatrics. 1992;89(4 Pt 2):747-57. 6. Litovitz T, Whitaker N, Clark L. Preventing battery ingestions: an analysis of 8648 cases. Pediatrics. 2010;125(6):1178-83. 7. Chang YJ, Chao HC, Kong MS, Lai MW. Clinical analysis of disc battery ingestion in children. Chang Gung Med J. 2004;27(9):673-7. 8. Centers for Disease Control and Prevention (CDC). Injuries from batteries among children aged < 13 years--United States, 1995-2010. MMWR Morb Mortal Wkly Rep. 2012;61(34):661-6. 9. Soccorso G, Grossman O, Martinelli M, et al. 20 mm lithium button battery causing an oesophageal perforation in a toddler: lessons in diagnosis and treatment. Arch Dis Child. 2012;97(8):746-7. 10. Tanigawa T, Shibata R, Katahira N, Ueda H. Battery ingestion: the importance of careful radiographic assessment. Intern Med. 2012;51(18):2663-4. 11. Tan A, Wolfram S, Birmingham M, et al. Neck pain and stiffness in a toddler with history of button battery ingestion. J Emerg Med. 2011;41(2):157-160. 12. Sudhakar PJ, Al Dossary J, Malik N. Spondylodiscitis complicated by the ingestion of a button battery: a case report. Korean J Radiol. 2008;9(6):555-8.

CONCLUSION This case of fatal evolution relating to battery ingestion is presented with the intention of informing pediatricians of the dangers relating to this type of accident. Healthcare professionals need to maintain a high level of suspicion, given that the delayed and sometimes few symptoms can frequently be mistaken for childhood diseases that occur more commonly. Pediatric emergency services must be prepared to act quickly and promptly in cases of complications caused by battery ingestion. Specific guidance for parents and caregivers are also required, and constitute important preventive measures for this type of injury.

13. Harjai MM, Ramalingam W, Chitkara G, Katiyar A. Corrosive tracheoesophageal fistula following button battery ingestion. Indian Pediatr. 2012;49(2):145-6. 14. Mortensen A, Hansen NF, Schiødt OM. Fatal aortoesophageal fistula caused by button battery ingestion in a 1-year-old child. Am J Emerg Med. 2010;28(8):984.e5-6. 15. Jarugula R, Dorofaeff T. Oesophageal button battery injuries: think again. Emerg Med Australas. 2011;23(2):220-3. 16. Ozokutan BH, Ceylan H, Yapici S, Simsik S. Perforation of Meckel’s diverticulum by a button battery: report of two cases. Ulus Travma Acil Cerrahi Derg. 2012;18(4):358-60. 17. Imamoğlu M, Cay A, Koşucu P, Ahmetoğlu A, Sarihan H. Acquired tracheo-esophageal fistulas caused by button battery lodged in the

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clinpedemergencymed.com/article/S1522-8401(10)00040-6/ abstract. Accessed in 2013 (Aug 20). 27. Blatnik DS, Toohill RJ, Lehman RH. Fatal complication from an alkaline battery foreign body in the esophagus. Ann Otol Rhinol Laryngol. 1977;86(5 Pt 1):611-5. 28. Brumbaugh DE, Colson SB, Sandoval JA, et al. Management of button battery-induced hemorrhage in children. J Pediatr Gastroenterol Nutr. 2011;52(5):585-9. 29. Tanaka J, Yamashita M, Yamashita M, Kajigaya H. Esophageal electrochemical burns due to button type lithium batteries in dogs. Vet Hum Toxicol. 1998;40(4):193-6. Sources of funding: None Conflict of interest: None Date of first submission: April 2, 2013 Last received: September 4, 2013 Accepted: September 9, 2013 Address for correspondence: Emílio Carlos Elias Baracat Rua Maria Nassif Mokarzel, 270 Jardim Santa Genebra II (Barão Geraldo) — Campinas (SP) — Brasil CEP 13084-757 Tel. (+55 19) 3521-7322 E-mail: [email protected]

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LETTER TO EDITOR

DOI: 10.1590/1516-3180.2014.1323748

A medical illusion from Pinocchio Uma ilusão médica de Pinocchio José Baddini-MartinezI

MD, PhD. Associate Professor, Division of Pneumology, Department of Internal Medicine, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), São Paulo, Brazil.

I

Training doctors to be more humanistic has become a challenge for medical schools.1-3 Professionals with such training are able to establish better links with patients, thus leading to greater adherence to therapeutic interventions.4 This approach, besides promoting satisfaction and gratitude on the part of patients, also brings greater professional achievement and personal growth for physicians. Teaching humanistic behavior is a difficult task. Each moment of the medical course therefore must be seen as an opportunity for humanistic practice and learning. Some new methods of medical teaching have been developed over recent years.5 Actors are trained to simulate the symptoms of common medical conditions. Sophisticated mannequins make it possible to teach examination techniques, and enable training on invasive procedures for multidisciplinary teams. Certainly, these resources are important for the technical preparation of health professionals, particularly for actions within critical scenarios. However, to what extent these new teaching methods contribute towards improvement of students’ humanistic qualities is still unknown. Knowing the exact role of each member of the team responding to a cardiorespiratory arrest is extremely important, but learning how to deal with family members present at the scene is crucial as well. Learning the proper technique for examining an abdomen is indispensable, just as it is critical to know how to apply this technique to a patient who is in pain and fearful. Most probably, these aspects of physician-patient communication cannot be effectively developed without real human interactions. Thus, we are now faced with an odd situation: the need to develop humanistic qualities in young medical students, alongside ease of access to artificial medical situations in controlled environments. As a consequence, a substantial number of professors and schools of Medicine seem to be experiencing excessive enthusiasm and unreasonable faith in simulation techniques, in what can be termed a medical illusion worthy of Pinocchio. It is worth remembering that Pinocchio was just a wooden puppet, yet with the extraordinary ability to speak and move, whose biggest dream was to become a real human being. Similarly, the excessive use of mannequins in medical education can speed up improvements in technical aspects of the profession but, most probably, does not contribute to the development of its humanistic aspects. What, then, would be the best attitude for ensuring the learning of Medicine in the fullness of its aspects? Of course, invasive procedures should be practiced in simulation sessions, but medical students must be incorporated into service teams as soon as possible, and be given responsibility consistent with the degree of their practical experience. This traditional approach of teaching Medicine is laborious, tiresome and not without difficulties for both the teachers who are directly responsible for clinical teaching and for the patients. However, in this context, the simple act of asking for agreement permission to examine a sick person becomes a very special moment of human interaction. Medicine is truly learned only from patients or, to paraphrase Osler, it is advisable to say: “To teach the phenomena of disease without simulation is to sail an uncharted sea, while to teach them without patients is not to go to sea at all.”6

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REFERENCES 1. Burks DJ, Kobus AM. The legacy of altruism in health care: the promotion of empathy, prosociality and humanism. Med Educ. 2012;46(3):317-25. 2. Doukas DJ, McCullough LB, Wear S. Reforming medical education in ethics and humanities by finding common ground with Abraham Flexner. Acad Med. 2010;85(2):318-23. 3. Rosenthal S, Howard B, Schlussel YR, et al. Humanism at heart: preserving empathy in third-year medical students. Acad Med. 2011;86(3):350-8. 4. Hojat M, Louis DZ, Markham FW, et al. Physicians’ empathy and clinical outcomes for diabetic patients. Acad Med. 2011;86(3):359-64. 5. Nestel D, Groom J, Eikeland-Husebø S, O’Donnell JM. Simulation for learning and teaching procedural skills: the state of science. Simul Healthc. 2011;6 Supp:S10-3. 6. Osler W. Books and men. In: Osler W. Aequanimitas, with other addresses to medical students, nurses and practitioners of medicine. Philadelphia: Blakiston; 1904. p. 217-25. Sources of funding: None Conflict of interest: None Date of first submission: August 6, 2013 Last received: August 30, 2013 Accepted: September 4, 2013 Address for correspondence: José Baddini-Martinez Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto – Universidade de São Paulo Av. Bandeirantes, 3.900 Vila Monte Alegre — Ribeirão Preto (SP) — Brasil CEP 14048-900 Tel. (+55 16) 3602-2531 E-mail: [email protected]

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LETTER TO THE EDITOR

DOI: 10.1590/1516-3180.2014.1323808

Effects of underwater birth on the newborn Efeitos de nascimento subaquático no recém-nascido Slobodan SekulicI Department of Neurology, University Hospital, Clinical Center of Vojvodina, Novi Sad, Serbia

MD, PhD. Attending Physician and Senior Associate Scientist, Department of Neurology, University Hospital, Clinical Center of Vojvodina, Novi Sad, Serbia.

I

In a recently published comment on a systematic review published in the Cochrane Database dealing with immersion in water during labor and birth, the focus was on the benefits for pregnant women. These would include reduction of the need to use epidural/spinal analgesia, reduction of the duration of the first stage of labor, decreased need for episiotomies and higher level of satisfaction with the birth experience.1 However, the effects on the newborn relating to underwater birth also need to be taken into consideration. Reports on underwater births have suggested that specific complications may occur in newborns, due to aspiration of water, such as: respiratory distress, blood dilution, hyponatremia, convulsions, hypoxic ischemic encephalopathy and lung infection. Umbilical cord rupture could also occur.2 The concept of water birth presupposes that delivering a baby underwater will free the baby from the shock of gravity. Also, water birth should represent a more gentle transition from intrauterine to extrauterine life, and a warm bath serves as an imitation of the weightlessness experienced during the early embryonic stages.3 Conditions resembling neutral floating last up to the 20th gestational week and, during this period, the apparent weight of the fetus is 5-10% of its actual weight. During the last trimester of gestation, the apparent weight of the fetus is 60-80% of its actual weight. In other words, the fetus senses more than two-thirds of its actual weight.4 Rupture of the amniotic sac during delivery results in complete cessation of the buoyant force on the fetus and gives rise to an apparent increase in body weight of 20-40%. Underwater delivery suddenly exposes the newborn to the effects of buoyant force and puts it back into the conditions of neutral floating after several months of continuously sensing two-thirds of its actual weight. Considering that the fetus starts to have long-term memory from the 34th gestational week onwards,5 exposure to neutral floating at birth is the newborn’s first remembered encounter with this physical environment. Underwater birth therefore does not represent a more gentle transition from intrauterine to extrauterine life. Exposure of the newborn to this new environment may induce the orienting reflex, i.e. excitation of the newborn with additional stimulation of the breathing reflex. It is necessary to carry out randomized controlled trials that would determine whether underwater birth is an exotic mode of delivery that exposes the newborn or the mother to an unnecessary risk or whether it is a delivery mode associated with a reduced risk of complications, compared with classical delivery.

REFERENCES 1. Cordioli E. Immersion in water in labour and birth. Sao Paulo Med J. 2013;131(5):364. 2. Batton DG, Blackmon LR, Adamkin DH, et al. Underwater births. Pediatrics. 2005;115(5):1413-4. 3. Leboyer F. Birth without violence. New York: Alfred Knopf; 1975. 4. Sekulić SR, Lukac DD, Naumović NM. The fetus cannot exercise like an astronaut: gravity loading is necessary for the physiological development during second half of pregnancy. Med Hypotheses. 2005;64(2):221-8. 5. Dirix CE, Nijhuis JG, Jongsma HW, Hornstra G. Aspects of fetal learning and memory. Child Dev. 2009;80(4):1251-8.

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LETTER TO THE EDITOR | Sekulic S

Sources of funding: None Conflict of interest: None Date of first submission: December 11, 2013 Last received: February 22, 2014 Accepted: April 14, 2014 Address for correspondence: Slobodan Sekulic Department of Neurology, University Hospital, Clinical Center of Vojvodina, Hajduk Veljkova 1-7, 21000 Novi Sad, Serbia Tel. +381 214843841 E-mail: [email protected]

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COCHRANE HIGHLIGHTS

DOI: 10.1590/1516-3180.20141323T1

Physical training for asthma Kristin V. Carson, Madhu G. Chandratilleke, Joanna Picot, Malcom P. Brinn, Adrian J. Esterman A., Brian J. Smith The independent commentary was written by Mônica Corso Pereira ABSTRACT BACKGROUND: People with asthma may show less tolerance to exercise due to worsening asthma symptoms during exercise or other reasons such as deconditioning as a consequence of inactivity. Some may restrict activities as per medical advice or family influence and this might result in reduced physical fitness. Physical training programs aim to improve physical fitness, neuromuscular coordination and self confidence. Subjectively, many people with asthma report that they are symptomatically better when fit, but results from trials have varied and have been difficult to compare because of different designs and training protocols. Also, as exercise can induce asthma, the safety of exercise programmes needs to be considered. OBJECTIVE: To gain a better understanding of the effect of physical training on the respiratory and general health of people with asthma, from randomised trials. METHODS: Search methods: We searched the Cochrane Airways Group Specialised Register of trials up to January 2013. Selection criteria: We included randomised trials of people over eight years of age with asthma who were randomised to undertake physical training or not. Physical training had to be undertaken for at least 20 minutes, two times a week, over a minimum period of four weeks. Data collection and analysis: Two review authors independently assessed eligibility for inclusion and undertook risk of bias assessment for the included studies. MAIN RESULTS: Twenty-one studies (772 participants) were included in this review with two additional 2012 studies identified as ‘awaiting classification’. Physical training was well tolerated with no adverse effects reported. None of the studies mentioned worsening of asthma symptoms following physical training. Physical training showed marked improvement in cardiopulmonary fitness as measured by a statistically and clinically significant increase in maximum oxygen uptake (mean difference (MD) 4.92 mL/kg/min; 95% confidence interval (CI) 3.98 to 5.87; P < 0.00001; 8 studies on 267 participants); however, no statistically significant effects were observed for forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), minute ventilation at maximal exercise (VEmax) or peak expiratory flow rate (PEFR). Meta-analysis of four studies detected a statistically significant increase in maximum heart rate, and following a sensitivity analysis and removal of two studies significance was maintained (MD 3.67 bpm; 95% CI 0.90 to 3.44; P = 0.01). Although there were insufficient data to pool results due to diverse reporting tools, there was some evidence to suggest that physical training may have positive effects on healthrelated quality of life, with four of five studies producing a statistically and clinically significant benefit. AUTHORS’ CONCLUSIONS: This review demonstrated that physical training showed significant improvement in maximum oxygen uptake, though no effects were observed in other measures of pulmonary function. Physical training was well tolerated among people with asthma in the included studies and, as such, people with stable asthma should be encouraged to participate in regular exercise

training, without fear of symptom exacerbation. More research is needed to understand the mechanisms by which physical activity impacts asthma management. This is the abstract of a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2013, issue 9, Art. No. CD001116. DOI: 10.1002/14651858.CD001116.pub4 (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001116.pub4/abstract). The full text is available from: http://onlinelibrary.wiley.com/ doi/10.1002/14651858.CD001116.pub4/abstract;jsessionid=EA0BC343 85812E99C5D313683EE0D160.f03t04. The abstract is also available in the Portuguese, French and Spanish languages from: http://summaries.cochrane.org/CD001116/physicaltraining-for-asthma.

REFERENCE 1. Carson KV, Chandratilleke MG, Picot J, et al. Physical training for asthma. Cochrane Database Syst Rev. 2013;9:CD001116.

COMMENTS Asthma patients often fail to practice exercises because of limitations due to their symptoms or because they are afraid of having symptoms during the exertion. On the other hand, a sedentary lifestyle leads to a state of physical deconditioning, a situation that further reduces exercise tolerance. Obesity is a growing endemic problem and, even in Brazil, the figures are alarming. Official data from the Ministry of Health1 showed that overweight had already reached 48.5% of the Brazilian population, and that the percentage of obese individuals had increased from 11.4% in 2006 to 15.8% of the population in 2011. Asthma is more difficult to control in obese patients.2 There is not enough evidence to suggest that the management of asthma in obese patients should be different. Nevertheless, weight loss in asthmatic obese patients improves asthma control, lung function and the need for medication, and therefore weight loss should be included in the treatment plan for asthmatic obese patients.3 Regular physical exercise practice in associated with nutritional reeducation and caloric restriction in the diet are classic measures for weight reduction. Moreover, physical exercise has a positive impact on quality of life, in relation to controlling several chronic diseases and improving physical conditioning. This interesting review sought answers to two questions: 1) Is it safe to conduct physical training among asthmatic patients, i.e. is regular physical exercise practice a precipitating or aggravating factor for asthma attacks? 2) Is there any evidence of benefit (subjective or functional) to asthmatic individuals from physical exercise practice? The review showed that physical training is safe among asthmatic patients, and none of the studies included showed adverse effects or exacerbations of the disease due to physical training. Although no improvement in lung function was shown (nor would it be expected), physical training was well tolerated by the asthmatic patients included in the studies, and was shown to have a positive impact on maximal oxygen uptake, as well as a positive effect on quality of life. Mônica Corso Pereira. MD, PhD. Medical Doctor in the Department of Pulmonology and Visiting Professor of the Postgraduate Course, Department of Clinical Medicine, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), São Paulo, Brazil.

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COCHRANE HIGHLIGHTS REFERENCES 1. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Vigitel Brasil 2011: Vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico. Brasília: Ministério da Saúde 2012. Available from: http://bvsms.saude.gov.br/bvs/publicacoes/vigitel_brasil_2011_ fatores_risco_doencas_cronicas.pdf. Accessed in 2014 (Apr 11). 2. Saint-Pierre P, Bourdin A, Chanez P, Daures JP, Godar P. Are overweight asthmatics more difficult to control? Allergy. 2006;61(1):79-84. 3. Eneli IU, Skybo T, Camargo CA Jr. Weight loss and asthma: a systematic review. Thorax. 2008;63(8):671-6.

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COCHRANE HIGHLIGHTS

DOI: 10.1590/1516-3180.20141323T2

Exercise programs for people with dementia Dorothy Forbes, Emily J. Thiessen, Catherine M. Blake, Scott S. Forbes, Sean Forbes The independent commentary was written by Maysa Seabra Cendoroglo ABSTRACT BACKGROUND: This is an update of our previous 2008 review. Several recent trials and systematic reviews of the impact of exercise on people with dementia are reporting promising findings. OBJECTIVE: Primary: Do exercise programs for older people with dementia improve cognition, activities of daily living (ADLs), challenging behaviour, depression, and mortality in older people with dementia? Secondary: Do exercise programs for older people with dementia have an indirect impact on family caregivers’ burden, quality of life, and mortality? Do exercise programs for older people with dementia reduce the use of healthcare services (e.g. visits to the emergency department) by participants and their family caregivers? METHODS: Search methods: We identified trials for inclusion in the review by searching ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register, on 4 September 2011, and again on 13 August 2012. The search terms used were: ’physical activity’ OR exercise OR cycling OR swim* OR gym* OR walk* OR danc* OR yoga OR ‘tai chi’. Selection criteria: In this review, we included randomized controlled trials in which older people, diagnosed with dementia, were allocated either to exercise programs or to control groups (usual care or social contact/activities) with the aim of improving cognition, ADLs, behaviour, depression, and mortality. Secondary outcomes related to the family caregiver(s) and included caregiver burden, quality of life, mortality, and use of healthcare services. Data collection and analysis: Independently, at least two authors assessed the retrieved articles for inclusion, assessed methodological quality, and extracted data. Data were analysed for summary effects using RevMan 5.1 software. We calculated mean differences or standardized mean difference (SMD) for continuous data, and synthesized data for each outcome using a fixed-effect model, unless there was substantial heterogeneity between studies, when we used a random-effects model. We planned to explore heterogeneity in relation to severity and type of dementia, and type, frequency, and duration of exercise program. We also evaluated adverse events. MAIN RESULTS: Sixteen trials with 937 participants met the inclusion criteria. However, the required data from three trials and some of the data from a fourth trial were not published and not made available. The included trials were highly heterogeneous in terms of subtype and severity of participants’ dementia, and type, duration and frequency of exercise. Only two trials included participants living at home. Our metaanalysis suggested that exercise programs might have a significant impact on improving cognitive functioning (eight trials, 329 participants; SMD 0.55, 95% confidence interval (CI) 0.02 to 1.09). However, there was substantial heterogeneity between trials (I 2 value 80%), most of which we were unable to explain. We repeated the analysis omitting one trial, an outlier, that included only participants with moderate or severe dementia. This reduced the heterogeneity somewhat (I2 value 68%), and

produced a result that was no longer significant (seven trials, 308 participants; SMD 0.31, 95% CI -0.11 to 0.74). We found a significant effect of exercise programs on the ability of people with dementia to perform ADLs (six studies, 289 participants; SMD 0.68, 95% CI 0.08 to 1.27). However, again we observed considerable unexplained statistical heterogeneity (I2 value 77%) in this meta-analysis. This means that there is a need for caution in interpreting these findings. In further analyses, we found that the burden experienced by informal caregivers providing care in the home may be reduced when they supervise the participation of the family member with dementia in an exercise program (one study, 40 participants; MD -15.30, 95% CI -24.73 to -5.87), but we found no significant effect of exercise on challenging behaviours (one study, 110 participants; MD -0.60, 95% CI -4.22 to 3.02), or depression (six studies, 341 participants; MD -0.14, 95% CI -0.36 to 0.07). We could not examine the remaining outcomes, quality of life, mortality, and healthcare costs, as either the appropriate data were not reported, or we did not retrieve trials that examined these outcomes. AUTHORS’ CONCLUSIONS: There is promising evidence that exercise programs can have a significant impact in improving ability to perform ADLs and possibly in improving cognition in people with dementia, although some caution is advised in interpreting these findings. The programs revealed no significant effect on challenging behaviours or depression. There was little or no evidence regarding the remaining outcomes of interest. This is the abstract of a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2013, issue 12, Art. No.: CD006489. DOI: 10.1002/14651858.CD006489.pub3 (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006489.pub3/abstract;jsessi onid=EB059310003BD3AC29CC6D77710D8779.f01t02). For full citation and authors’ details see reference 1. The full text is available from: http://onlinelibrary.wiley.com/ doi/10.1002/14651858.CD006489.pub3/abstract. The abstract is also available in the Portuguese, French and Spanish languages from: http://summaries.cochrane.org/CD006489/exerciseprograms-for-people-with-dementia.

REFERENCE 1. Forbes D, Thiessen EJ, Blake CM, Forbes SC, Forbes S. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2013;12:CD006489.

COMMENTS This systematic review published by Forbes et al. is a continuation and update of the study that they published in 2008. It aimed to identify the benefits of physical exercise for elderly people with impaired cognition. The review included randomized studies with control groups. The quality of the studies was very well defined and there was an interest in selecting studies in which the intervention consisted of physical activity unassociated with other forms of treatment. In the systematic review conducted in 2008, a meta-analysis was conducted and the results were insufficient to show any evidence of benefits from exercise in relation to the primary objectives. In the study of 2013, it was observed that the subjects presented improved ability to carry out activities of daily living, possibly with improved cognition. In relation to the other primary and secondary objectives, the data were insufficient or inconclusive.

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COCHRANE HIGHLIGHTS In preclinical studies, the action of exercise has been seen to involve structural and functional changes to neurons. Exercise-related neurogenesis and neuron remodeling have been observed through increased production of brain-derived synaptic proteins (BDNF). However, neuroplasticity also results from the action of other factors involving serotonin reuptake, N-methyl-D-aspartate (NMDA) receptors and calorie and cholesterol restriction; and from manipulation of cerebral magnetic fields and electrical activity. Considering that it is possible and likely that interactions between multiple factors result in modifications to the response to the treatment used, it can be comprehended that such interactions make it difficult to identify the effect of one intervention alone. In this regard, these authors’ rigorous methodological care has placed value on their findings and partly explains the lack of evidence relating to the other objectives. Maysa Seabra Cendoroglo. Adjunct Professor in the Discipline of Geriatrics and Gerontology, Universidade Federal de São Paulo (Unifesp), São Paulo, Brazil.

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SÃO PAULO MEDICAL JOURNAL/EVIDENCE FOR HEALTH CARE Indexing and scope The 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 fields 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-effectiveness studies and systematic reviews with or without meta-analysis), narrative reviews of the literature, case reports, short communications and letters to the editor. Papers with a commercial objective will not be accepted. The Journal’s policy and procedures After receipt of the article by the Scientific Publications Sector, the authors will be provided with a protocol number. This number serves to maintain good understanding between the authors and the Scientific Publications Sector. Following this, the article will be read by the Editor, who will verify whether it is consonant with the journal’s policy and interests, i.e. whether the research or review is within the fields of health or public health. Next, the Scientific 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 after resolving such problems. When its format is acceptable, the Scientific 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 field, one associate editor (who will evaluate the article from the reader’s perspective) and one ad hoc editorial advisor (who will assess methodological aspects of the study). The authors will then receive the reviewers’ evaluation and will be asked to resolve all the problems that have been pointed out. Once the Scientific Publications Sector receives the manuscript again, the text will be sent to the scientific editor and the proofreader, who will point out problems with sentence construction, spelling, grammar, bibliographical references and other matters. The authors should then provide all further information and corrections requested and should mark in the text all the points at which modifications have been made, using different colors or electronic text marking systems, so that these modifications 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. The Scientific Publications Sector will provide a proof, including any tables and figures, for the authors to approve. No article is published without this last procedure.

Instructions for authors General guidelines: for all types of articles Texts must be submitted exclusively through the Internet, using the electronic submission system, which is available at http://www.spmj.hemeroteca.com.br. Submissions sent by e-mail or through the post will not be accepted. The manuscript must be submitted in English. Nonetheless, it must also include a summary and five key words both in Portuguese and in English. The 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 specific quality guidelines for papers reporting on clinical trials (CONSORT),2 systematic reviews and meta-analyses (PRISMA),3,4 observational studies (STROBE)5,6 and accuracy studies on diagnostic tests (STARD).7,8 The style known as the “Vancouver Style” is to be used not only for the format of the references, but also for the whole text. The 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 intraoperative devices must be described together with the manufacturer’s name and place (city and country) of manufacture in parentheses. Grants, bursaries and any other financial support for studies must be mentioned separately after 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 recommend that the item “Authorship” at http://www.icmje.org should be read to obtain clarifications 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 Medical Journal/Evidence for Health Care, but are data from other studies already published elsewhere must be accompanied by citations of the pertinent literature. Thus, statements about the incidence or

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prevalence of diseases, costs, frequency of use of certain therapies

References

and epidemiological data in general should be followed by the refer-

The list of references (in the “Vancouver style”, as indicated by the

ences for the surveys that generated this information, even if the data

International Committee of Medical Journal Editors, ICMJE) should be

come from government institutions or databases, given that these are

laid out in the final part of the article, after the conclusions and before the

data from other studies.

tables and figures. In the text, the references must be numbered accord-

Format

ing to the order of citation. The citation numbers must be inserted after

First page (cover page)

periods/full stops or commas in sentences (see examples in the preced-

The first page must contain:

ing section), and must be in superscript form (without using parentheses

1) the type of paper (original article, review or updating article,

or square brackets). References cited in the legends of tables and figures

short communication or letter to the editor); 2) the title of the paper in English and Portuguese, which must be short but informative;

must maintain sequence with the references cited in the text. In the list of references, all the authors must be listed if there are up to and including five authors; if there are six or more, the first three

3) the full name of each author (the editorial policy of the São

should be cited, followed by the expression “et al.” For books, the city

Paulo Medical Journal is that abbreviations for authors’ names

of publication and the name of the publishing house are mandatory.

must not be used; thus, names should either be sent complete

For texts published on the internet, the complete uniform resource

or with middle names omitted, for example: an author whose

locator (URL) or address is necessary (not only the main home page

full name is John Richard Smith can be presented as John

of a website or link), so that by copying the complete address into their

Smith or John Richard Smith, but not as John R. Smith; like-

computer internet browsers, the journal’s readers will be taken to the

wise, use Christopher Smith and not Chris Smith, or William

exact document cited, and not to a general website. The following are

Smith and not Bill Smith, and so on)), his/her academic titles

some examples of the most common types of references:

(abbreviated in English), in the order obtained (for example:

Article in journal

MD for medical doctor, MSc for holders of a master’s title,

- Hurt AC, Hardie K, Wilson NJ, et al. Community transmis-

PhD for holders of a doctorate or BSc for bachelor of sci-

sion of oseltamivir-resistant A(H1N1)pdm09 influenza.

ence, such as in biology), and the positions currently held

N Engl J Med. 2011;365(26):2541-2.

(for example, Doctoral Student, Attending Physician, Adjunct

Chapter of book

Professor, Associate Professor, Head of Department, etc.), in

- Miller WI, Achernabb JC, Fluck CE. The adrenal cortex and

the department and institution where he/she works, and the

its disorder. In: Sperling M. Pediatric endocrinology. 3rd ed.

city and country;

Elsevier Health Sciences; 2008. p. 444-511.

4) the place where the work was developed;

Text on the internet

5) the complete address (name of street or avenue, building

- Centers for Disease Control and Prevention. Children’s food

number, city) of the corresponding author, telephone and

environment State Indicator Report, 2011. Available from:

e-mail that can be published together with the article.

http://www.cdc.gov/obesity/downloads/ChildrensFoodEnvi-

Second page: abstract (English and Portuguese) and key words The second page must include the title and an abstract (Eng-

ronment.pdf. Accessed in 2012 (Mar 7). Last page

lish and Portuguese, maximum of 250 words each),9 structured in

The last page must contain:

five items:

1) the date and place of the event at which the paper was presented, if

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

applicable, such as congresses or dissertation or thesis presentations; 2) sources of support in the forms of finance for the project, study bursaries or funding for purchasing equipment or drugs. The protocol number for the funding must be presented; 3) description of any conflicts of interest held by the authors. We

5) conclusions.

recommend that the item “Conflicts of interest” at http://www.

The abstract (both in English and in Portuguese) should contain

icmje.org should be read to obtain clarifications regarding what

five key words. The English terms must be chosen from the Medical Subject Headings (MeSH) list of Index Medicus, which are available on

may or may not be considered to be a conflict of interest; Figures and tables

the internet (http://www.ncbi.nlm.nih.gov/sites/entrez?db=mesh).10

Images must have good resolution (minimum of 300 DPI) and be

The Portuguese terms must be chosen from the Descritores em Ciên-

recorded in “.jpg” or “.tif ” format. Do not attach images inside Micro-

cias da Saúde (DeCS), developed by Bireme, which are available on

soft PowerPoint documents. If photographs are inserted in a Micro-

the internet (http://decs.bvs.br/).11

soft Word file, the images should also be sent separately. Graphs must

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These instructions are updated periodically. We recommend that they are consulted online at: www.scielo.br/spmj

be prepared in Microsoft Excel (do not send them in image formats) and must be accompanied by the tables of data from which they have been generated. The number of illustrations must not exceed the total number of pages minus one. All figures and tables must contain legends or titles that precisely describe their content and the context or sample from which the information was obtained (i.e. what the results presented are and what the kind of sample or setting was). The legend or title sentence should be short but comprehensible without depending on reading the article. All the figures and tables should be cited in the text. São Paulo Medical Journal/Evidence for Health Care is for now published in black-and-white in its printed version. Photographs, photomicrographs, bar and line graphs and any image to be published must be prepared considering that there will be no color differentiation (any color information will be discarded). Shades of gray and printing patterns (dots, stripes and others) should be used instead, with good contrast. Original articles Clinical trials, cohort, case-control, prevalence, incidence, accuracy and cost-effectiveness studies, and systematic reviews with or without meta-analysis, are considered to be original articles. The São Paulo Medical Journal/Evidence for Health Care supports the clinical trial registration policies of the World Health Organization (WHO) and the International Committee of Medical 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 identification 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 The São Paulo Medical Journal takes the view that these guidelines not only aid in writing and organizing the content of articles in a standardized manner, thereby improving their quality and facilitating 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 considers that production of articles in accordance with these guidelines also aids in future production of systematic reviews of the literature and meta-analyses. Thus, 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 following parts: Introduction, Objective, Methods, Results, Discussion and Conclusion. The text must not exceed 5,000 words (excluding tables, figures and references), from the introduction to the end of the conclusion, and must include a structured abstract with a maximum of 250 words.9 “Structured abstract” means that the abstract must contain the following items: Context and objective, Design and setting, Method, Results and Conclusion. The structure of the document should follow the format laid out below: 1) Title and abstract: the study design and/or the way participants were allocated to interventions, for example “randomized” or “retrospective” study, should be mentioned in the title and in the abstract. The 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 scientific 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 introduction; the introduction section should be short. 3) Objective: describe briefly what the main objective or question of the study was. Clearly describe the pre-specified hypotheses. 4) Methods 4.1) 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 normal values) and the time direction (retrospective or prospective). For example: “randomized clinical trial”, “double-blind placebo-controlled clinical trial”, “cross-sectional accuracy study”, “retrospective cohort study”, “cross-sectional prevalence study” or “systematic review of clinical trials”. 4.2) Sample, participants or patients: describe the eligibility criteria 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 criteria. The numbers of patients at the beginning and end of the study (after exclusions) must be made clear. A flow diagram showing the initial recruitment, the exclusions and the Sao Paulo Med J. 2014; 132(3):I-V

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These instructions are updated periodically. We recommend that they are consulted online at: www.scielo.br/spmj

final 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 primary or tertiary; and whether in a private or in a public hospital). 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 example: “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 differences 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 after data collection (and not before), this needs to be declared. Describe the methods used to enhance the quality of measurements (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. Readers need to understand why a given number of patients was used. The planned statistical analysis, the statistical tests used and their significance levels, along with any post hoc analyses, should be presented in this section. Describe the methods 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 software 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 participants to each group (in the case of controlled trials) and who recruited the participants. 5) Results: describe the main findings. If possible, these should be accompanied by their 95% confidence intervals and the exact level of statistical significance (it is not enough to write “P < 0.05”: the exact P value should be supplied). For comparative

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Sao Paulo Med J. 2014; 132(3):I-V

studies, the confidence interval must be stated for the differences between the groups. 5.1) Participant flow diagram: describe the flow 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 flow 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 effect, adverse event or complication. 6) Discussion: provide an interpretation of the results, taking 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 published, which needs to be discussed. State whether the findings 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 practice and for further research. 7) Conclusions: specify only the conclusions that can be sustained by the results, together with their clinical significance (avoiding excessive generalization). Draw conclusions based on the objectives and hypotheses of the study. The same emphasis should be placed on studies with positive and negative 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 Collaboration’s systematic review Handbook.13 The text should not exceed 5,000 words (excluding tables, figures 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 communications are reports on the results from ongoing studies or studies that have recently been concluded for which urgent publication is important. They should be structured thus: Introduction, Objective, Methods, Results, Discussion and Conclusion, like in original articles. Individual case reports should contain: Introduction, Case Report, Discussion and Conclusion. Reports on case series constitute

These instructions are updated periodically. We recommend that they are consulted online at: www.scielo.br/spmj

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. The abstracts in short communications should be structured with: Context and objective, Design and setting, Methods, Results and Conclusion, like in original articles. The abstracts in case reports and case series should contain: Context, Case Report (with a description of the case and a pertinent discussion) and Conclusion. The São Paulo Medical Journal/Evidence for Health Care is interested 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 The 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 reviews Narrative reviews may be accepted by the São Paulo Medical Journal/Evidence for Health Care and should be structured with: Introduction, Objectives, Methods, Results, Discussion and Conclusions. The abstract must be structured with: Context and objective, Design and setting, Methods, Results and Conclusions, like in original articles. The 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. The search strategy for each database and the number of articles obtained from each database should be presented in a table. The access route to the electronic 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. The search strategies must be presented exactly as they were used during the search, including parentheses, quotation marks and Boolean operators (AND, OR, AND NOT). Letters to the editor Letters 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 submitted as letters. In the category of letters to the editor, the text has a free format, but must not exceed 500 words and five references. Documents cited 1. 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/PIIS01406736(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 nonrandomized 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/ files/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 Evidencebased 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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