Francisco José Caldeira Reis

Dornase alfa improves the health‐related quality of life among Brazilian patients with cystic fibrosis—A one‐year prospective study

Health‐related quality of life (HRQOL) measurements provide valuable information about the psychological and social impact of treatment on patients with cystic fibrosis (CF). This study evaluated the HRQOL of Brazilian patients with CF and assessed the changes in HRQOL domains over 1 year after dornase alfa (Pulmozyme) introduction.

Effect of meconium ileus on the clinical prognosis of patients with cystic fibrosis

The objective of the present study was to determine the possible prognostic factors which may explain the difference in the survival of patients with cystic fibrosis (CF) with and without meconium ileus. Over a period of 20 years, 127 patients with CF, whose diagnosis was confirmed by typical clinical characteristics and altered sweat chloride levels, were studied retrospectively. The patients were divided into two groups: group 1 consisted of patients who presented CF and meconium ileus (N = 9), and group 2 consisted of patients with CF without meconium ileus (N = 118). The characteristics studied were based on data obtained upon admission of the patients using a specific protocol. Demographic, clinical, nutritional and laboratory data were obtained. The genotype was determined in 106 patients by PCR. Survival was analyzed using the Kaplan-Meier method. The median follow-up period was 44 months. A statistically significant difference was observed between the groups studied regarding the following variables: age at diagnosis and weight and height z scores. The presence of meconium ileus was associated with an earlier diagnosis; these patients had greater deficits in height and weight at the time of diagnosis and at the end of the study. The estimated probability of survival for patients with CF without meconium ileus was 62 +/- 14% and for those with meconium ileus 32 +/- 18%. Patients with CF and meconium ileus presented a poor nutritional status at diagnosis and a lower survival rate compared to the general CF population.

Validation of the Williams ultrasound scoring system for the diagnosis of liver disease in cystic fibrosis

OBJECTIVES To describe the hepatic abnormalities revealed by ultrasound examination of cystic fibrosis (CF) patients followed at the CF Outpatient Clinic at the Federal University of Minas Gerais; to compare ultrasound data with clinical and biochemical parameters; to validate the Williams ultrasound score for the diagnosis of liver disease in CF. METHODS Seventy cystic fibrosis patients were followed prospectively and underwent clinical, biochemical and ultrasound examinations. The ultrasound findings were compared to the results of the clinical and biochemical examinations. Clinical and biochemical criteria were used as the gold standard for the validation of the Williams ultrasound score. We calculated the sensitivity, specificity, and positive and negative predictive values for the Williams score. The patients were divided into two groups: normal (score = 3) or abnormal (score > 3) ultrasound examination. RESULTS Ten patients met the clinical and/or biochemical criteria for liver disease (14.3%). All of them presented some abnormality on ultrasound examination of the liver. Abnormalities of the hepatic parenchyma, edge and periportal fibrosis were statistically more frequent in these patients. The Williams ultrasound score showed high specificity (91.7%; CI 80.9-96.9), but low sensitivity (50%; CI 20.1-79.9) for the diagnosis of liver disease. CONCLUSIONS The Williams ultrasound score was not a good screening tool when compared to the clinical and biochemical examinations. Since there are currently no adequate tests that can be used to diagnose liver disease, we recommend a sequential evaluation combining clinical, biochemical and ultrasound examinations for the diagnosis of liver disease in CF.

Survival analysis for cystic fibrosis in Minas Gerais State, Brazil.

A survival analysis was carried out on cystic fibrosis (CF) patients diagnosed and followed at the General Hospital, Federal University of Minas Gerais, Brazil. The study cohort consisted of 111 children, admitted to the Pediatric Pulmonology Section from 1 June 1970 to 31 December 1994. The survival curve and table, constructed by the Kaplan-Meier (product limit) method, show a mean survival age of 12.6 years. This life expectancy resembles the median survival age observed in developed countries by 1970. This study shows that problems relating to health system organization and unfavourable social and economic conditions in developing countries may directly affect the ultimate survival of CF patients.

Diagnostic screening of liver disease in cystic fibrosis

Objective: to determine the prevalence of clinical and biochemical abnormalities suggestive of liver disease in the population of patients with cystic fibrosis (CF) seen at the CF Outpatient Clinic of the Federal University of Minas Gerais; to describe the group of patients with liver disease and to compare it with the group without liver disease, regarding several clinical and laboratory variables. Methods: descriptive study, resultant of a prospective, and partially retrospective assessment of 106 patients with CF. Liver disease was defined by the presence of firm hepatomegaly (>2.5 cm from the right costal margin), and/or splenomegaly, and/or persistent and significant increase (>1.5 times the upper limit of normality, over six months) of at least two serum liver enzymes (alanine aminotransferase - ALT, aspartate aminotransferase - AST, alkaline phosphatase - ALP, -glutamyl transpeptidase - GGT). Results: hepatomegaly was verified in seven patients (6.6%) and splenomegaly in five (4.7%). AST activity was altered in 18.9% of the patients, ALT in 9.4%, GGT in 11.3%, and ALP in 46.2%. Significant and persistent increase in liver enzyme activities was verified in nine patients (8.5%). Ten patients with CF (9.4%) fulfill the criteria for liver disease. Other causes of liver disease were excluded. The mean age of the patients with liver disease was 7.7 years. There was absolute predominance of the male sex. All the patients are without symptoms. Conclusions: The prevalence of liver disease associated with CF was 9.4%. The frequent and transitory insignificant elevations of liver enzymes are well documented in the literature. Its significance as a predictor of liver disease has not been determined yet. However, the results of this study enhance the need for longitudinal assessment in order to define cases of liver disease in CF.

p.F508del in a heterogeneous cystic fibrosis population from Minas Gerais, Brazil

Cystic fibrosis (CF) is the most common autosomal recessive disease of the Caucasian population. Among the various CF mutations, p.F508del is the most frequent, accounting for two-thirds of the global CF chromosomes, although showing great variability among populations. We have studied 115 unrelated CF patients from a mixed population of Minas Gerais (Brazil). To evaluate part of the DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, blood DNA was obtained and PCR was performed using two pairs of primers that anneal to exons 10 and 24 of the CFTR gene. The PCR product was then submitted to automatic sequencing using the ABI PRISM 310 Genetic Analyzer. The p.F508del mutation was found in 50 (21.7%) of 230 unrelated CF alleles. Fifteen (13.0%) patients were homozygous for this mutation, while 20 (17.4%) were heterozygous; the remaining 80 (69.6%) patients did not carry the p.F508del mutation. Exon 24 sequence had no change in 75 (65.2%) patients, 21 (18.3%) had the sequence variation 4521G/A, 11 (9.6%) had a not yet described sequence variation 4407T/A and 8 (7.0%) patients had both sequence variations (4521G/A and 4407T/A). The polymorphism 4407T/A results in an amino acid modification from aspartic acid to glutamic acid, which will probably have no function effect in CFTR. This low p.F508del prevalence can be due to the variable ethnic origin of this population from Minas Gerais, which may have a high diversity of CF rare mutations.

Fatores de risco da hepatopatia da fibrose cística

OBJETIVO: Identificar os fatores de risco associados a hepatopatia da fibrose cistica. METODOS: Dos 106 pacientes acompanhados regularmente no ano de 1999, 10 preencheram os criterios clinicos, bioquimicos e/ou ultra-sonograficos para hepatopatia (9,4%). Foram obtidos dos pacientes, no protocolo do servico a admissao, fatores relacionados aos dados demograficos, genotipo, idade e manifestacoes ao diagnostico da fibrose cistica, estado nutricional e dados laboratoriais. As variaveis associadas a hepatopatia foram inicialmente identificadas pelo metodo de Kaplan-Meier. Os fatores significativos na analise univariada foram incluidos na analise multivariada, utilizando o modelo de regressao de Cox. RESULTADOS: Os fatores associados a hepatopatia na analise univariada foram: sexo masculino, idade ao diagnostico da fibrose cistica, insuficiencia pancreatica, escore z de peso a admissao, escore de Shwachman e bioquimica a admissao. Apos o ajustamento pelo modelo de Cox, duas variaveis demonstraram estar independentemente associadas ao desenvolvimento de hepatopatia: escore de Shwachman (p = 0,0057) e idade ao diagnostico da fibrose cistica (p = 0,014). CONCLUSAO:O risco de hepatopatia e maior entre os pacientes que apresentam diagnostico mais precoce e entre aqueles com pior estado clinico avaliado pelo escore de Shwachman, evidenciando que a hepatopatia parece fazer parte de uma forma mais grave da doenca. Esses pacientes merecem mais atencao quanto ao screening para hepatopatia e instituicao mais precoce do acido ursodesoxicolico na ocorrencia de alteracoes.

Brazilian guidelines for the diagnosis and treatment of cystic fibrosis

A fibrose cistica (FC) e uma doenca genetica autossomica recessiva caracterizada pela disfuncao do gene CFTR. Trata-se de uma doenca multissistemica que ocorre mais frequentemente em populacoes descendentes de caucasianos. Nas ultimas decadas, diversos avancos no diagnostico e tratamento da FC mudaram drasticamente o cenario dessa doenca, com aumento expressivo da sobrevida e qualidade de vida. Atualmente, o Brasil dispoe de um programa de ampla cobertura para a triagem neonatal de FC e centros de referencia distribuidos na maior parte desses estados para seguimento dos individuos. Antigamente confinada a faixa etaria pediatrica, tem-se observado um aumento de pacientes adultos com FC tanto pelo maior numero de diagnosticos de formas atipicas, de expressao fenotipica mais leve, assim como pelo aumento da expectativa de vida com os novos tratamentos. Entretanto, ainda se observa uma grande heterogeneidade no acesso aos metodos diagnosticos e terapeuticos para FC entre as diferentes regioes brasileiras. O objetivo dessas diretrizes foi reunir as principais evidencias cientificas que norteiam o manejo desses pacientes. Um grupo de 18 especialistas em FC elaborou 82 perguntas clinicas relevantes que foram divididas em cinco categorias: caracteristicas de um centro de referencia; diagnostico; tratamento da doenca respiratoria; tratamento gastrointestinal e nutricional; e outros aspectos. Diversos profissionais brasileiros atuantes na area da FC foram convidados a responder as perguntas formuladas pelos coordenadores. A literatura disponivel foi pesquisada na base de dados PubMed com palavras-chave, buscando-se as melhores respostas as perguntas dos autores.

362 The rebirth of the Brazilian CF Registry (REBRAFC)

Radiological tools are critical for monitoring cystic fibrosis (CF) patients’ thoracic, abdominal, rhinosinusal, and bone systems. Given the likelihood of increasing demand for ionizing techniques for research purposes, we sought to determine how clinicians use radiological tools in their centers. Methods: A 39-item questionnaire was sent to 49 pediatric and adult CF centers in July 2011. Questions were asked on frequency and indications for thoracic, abdominal, rhinosinusal, and bone imaging, as well as the radiological devices available. Results: Thirty-three of 49 (68%) centers answered the questionnaire. Among them, 36% were pediatric centers, 33% mixed, and 31% adult centers. An annual chest x-ray was done routinely in more than 95% of centers, starting at the initial stage of the disease (neonatal screening). While adult clinicians did not routinely perform chest CT, 72% of the pediatricians requested it routinely. Pediatricians declared doing the first chest CT at a mean of 4.9±1.2 years of age, and every 2 or 3 years thereafter. Respectively, 32% and 20% of pediatric and adult centers regularly indicated the cumulative doses received by patients on medical charts. MRI was used in seven out of 33 centers mainly for abdominal indications. Annual chest x-ray is part of routine follow-up for most centers; however, divergent attitudes have emerged regarding chest CT use between pediatric and adult centers. The reasons for the routine use of chest CT in pediatric patients will need further investigations. Furthermore, efforts should be made by clinicians to regularly monitored cumulative doses received by their patients, particularly in the pediatric population.

Risk factors for cystic fibrosis related liver disease

OBJECTIVE To identify the risk factors for cystic fibrosis related liver disease. METHODS Ten patients out of a total of 106 patients regularly followed-up during 1999 met the clinical, biochemical and/or ultrasound criteria for liver disease (9.4%). Using information from the admissions records at the service, we collected data on demography, genotype, age and manifestations at diagnosis of cystic fibrosis, nutritional status and laboratory findings. Variables associated with liver disease were initially identified by the Kaplan-Meier method. Those factors that were significant in the univariate analysis were included in the multivariate analysis by means of a Cox regression model. RESULTS Under univariate analysis the following factors were associated with liver disease: male sex, age at diagnosis of cystic fibrosis, pancreatic insufficiency, z score for weight at admission, Shwachman score and biochemistry at admission. After adjustment by Cox model, two variables were independently associated with liver disease: Shwachman score (p = 0.0057) and age at diagnosis of cystic fibrosis (p = 0.014). CONCLUSIONS The risk of developing liver disease is higher among patients diagnosed at an early age and those with worse clinical status as assessed by the Shwachman score, indicating that liver involvement might be part of a more severe form of the condition. These patients merit greater attention in terms of screening for liver disease and should be given treatment with ursodeoxycholic acid earlier in the event of abnormal findings.OBJECTIVE: To identify the risk factors for cystic fibrosis related liver disease. METHODS: Ten patients out of a total of 106 patients regularly followed-up during 1999 met the clinical, biochemical and/or ultrasound criteria for liver disease (9.4%). Using information from the admissions records at the service, we collected data on demography, genotype, age and manifestations at diagnosis of cystic fibrosis, nutritional status and laboratory findings. Variables associated with liver disease were initially identified by the Kaplan-Meier method. Those factors that were significant in the univariate analysis were included in the multivariate analysis by means of a Cox regression model. RESULTS: Under univariate analysis the following factors were associated with liver disease: male sex, age at diagnosis of cystic fibrosis, pancreatic insufficiency, z score for weight at admission, Shwachman score and biochemistry at admission. After adjustment by Cox model, two variables were independently associated with liver disease: Shwachman score (p = 0.0057) and age at diagnosis of cystic fibrosis (p = 0.014). CONCLUSIONS: The risk of developing liver disease is higher among patients diagnosed at an early age and those with worse clinical status as assessed by the Shwachman score, indicating that liver involvement might be part of a more severe form of the condition. These patients merit greater attention in terms of screening for liver disease and should be given treatment with ursodeoxycholic acid earlier in the event of abnormal findings.