Edna Lúcia Souza

Chlamydia trachomatis: a major agent of respiratory infections in infants from low-income families

OBJECTIVES To determine the prevalence of lower respiratory tract infection (LRTI) due to Chlamydia trachomatis in newborn infants and to describe the clinical, laboratory, and radiological characteristics of the disease. METHODS A cross-sectional study carried out over a 12-month period. All infants up to 6 months of age admitted consecutively at the Centro Pediátrico Professor Hosannah de Oliveira of the Universidade Federal da Bahia in Salvador, Brazil, and diagnosed with LRTI according to clinical and/or radiological criteria were included in the study. C. trachomatis infection was diagnosed by the enzyme-linked immunosorbent assay (ELISA) for the detection of IgM-class antibodies. The prevalence of LRTI by C. trachomatis was determined and the prevalence ratios for the infection and clinical or laboratory variables were calculated. RESULTS One hundred and fifty-one infants were submitted to serology for C. trachomatis and 15 (9.9%) tested positive. Chlamydial infection was found only in infants under 5 months of age, mainly in those aged under 2 months. Three of the infants with C. trachomatis infection were born by cesarean section. Conjunctivitis and eosinophilia had occurred in 33.3% of the cases. Chest X rays were abnormal in 92.0% of cases. There was an association between C. trachomatis infection and the duration of hospitalization exceeding 15 days (p = 0.0398) and oxygen therapy (p = 0.0484). CONCLUSIONS There was a high prevalence of C. trachomatis respiratory infection in the population studied. The infection was associated with a more severe form of the disease, emphasizing the importance of testing pregnant women for this infection to avoid infection in the newborn infant.

Perinatal tuberculosis: a diagnostic challenge.

Despite the high prevalence of tuberculosis in adults and children, the congenital and perinatal forms of tuberculosis are rare. In Brazil, there has been only one published case of congenital tuberculosis and two cases of the perinatal form of this disease. We report a case of perinatal tuberculosis presenting with pneumonia. Alcohol-acid-resistant bacilli were found in the gastric lavage. Diagnosis of this disease presentation requires a high index of suspicion.

Cystic fibrosis: Identification and frequency of mutations in a mixed population from a low-income region in Northeastern Brazil

Current evidence points to the importance of a more personalized approach that takes into account the ethnicity of a population in the diagnosis of Cystic Fibrosis (CF). Recent studies have indicated that use of gene sequencing is a reliable approach to diagnose CF. Although this approach is extremely relevant, it is costly. The rational use of health resources is highly recommended, especially in low-incomeareas.Brazil is a country of continental dimensions and with great ethnic-racial heterogeneity. The state of Bahia, located in the Northeast of Brazil, presents a population with a high degree of miscegenation due to the characteristics of its ancestry: African (47.3%), European (36.4%), and Amerindian (16.3%). The population of this state is approximately 15.2 million, most of it with low income, and only two medical centers provide clinical care for CF patients; these centers are part of the public health system, which has universal coverage in this country. Our center is a multidisciplinary clinic, located at the teaching Hospital of the Federal University of Bahia. Since January 2008, we have enrolled and prospectively followed patients with CF from 0 to 20 years of age. Between 2012 and 2017, 50 patients with confirmed CF diagnosis by two positive sweat tests were submitted to molecular analysis for screening of seven mutations by conventional methods using peripheral blood samples (polymerase chain reaction and enzymatic digestion), or by next-generation sequencing of oral mucosa samples using Illumina HiSeq platform whenever it was not possible to determine the patients’ genotype through conventional analysis. Of the patients studied, 26 (52%) were male, 48 (96%) were nonwhite, median age of 6 years. Through conventional molecular techniques, five mutations were identified, allowing us to ascertain the genotype of 25 patients. The sequencing study identified 14 new mutations (including a new variant, not yet described in the literature), expanding to 43 (86%) the number of patients with known genotype. These findings allowed us to predict that by using a 20 mutation panel, we would be able to complete diagnostic genotyping from approximately 90% of our patients. Three patients had no mutant allele identified and whereas additional four patients presented with only one mutation. Genotypes and mutation frequencies are described in Table 1. Advances in precision medicine require knowledge of the genotypic profiles of CF patients. However, the routine performance of genetic testing is not a reality for the vastmajority of CF care centers in Brazil. Data from the Brazilian Registry of Cystic Fibrosis (REBRAFC) from 2015 indicated that only 46.2% from 3857 patients were submitted to any genetic study. Thus, it expansion in use of genetic testing is warranted to better diagnose CF. To optimize diagnosis without significantly increasing cost, we predict that development of a panel of mutations more specific to each region is highly recommended, since the use of a single panel may not be equally sensitive, particularly in regions with major heterogeneity in ethnicity such as Brazil. The results of our study revealed that despite the high degree of miscegenation of the study population, with 96% non-white patients, the initial investigation of only F508del mutation determined the genotype of approximately 30% of patients. This finding corroborates with the proposal of an initial investigation searching only for F508del mutation, as suggested for patients from the Brazilian southeast. In our population, subsequent investigation for G542X and 3120 + 1G>A mutations expanded the genotype knowledge to 50% of patients. Thus, the establishment of a step wise protocol, with the research of only three mutations, can optimize the use of public health resources and increase the access to molecular diagnosis techniques. The other mutations, found only through sequencing, can be incorporated into a specific panel for this region of Brazil, reserved only for patients whose genotype could not be determined by the initial investigation. Identifying the genotypes of our patients allowed us to discover that 42% of these were eligible for precision medicine treatment: 14 (28%) patients F508del/F508del—Lumacaftor/Ivacaftor or Tezacaftor/Ivacaftor combination; 3 (6%) patients were suitable to use Ivacaftor and 3 (6%) patients for the use of the association Tezacaftor/ Ivacaftor or Ivacaftor. Furthermore, due to low availability of other diagnostic resources such as CFTR function evaluation or periodic dosing of fecal elastase to investigate pancreatic insufficiency, genotype determination has firmly contributed to improve treatment strategies for our patients.

Hepatobiliary disease in children and adolescents with cystic fibrosis

OBJECTIVES The aims of the study were to determine the frequency of hepatobiliary disease in patients with cystic fibrosis and to describe the sociodemographic, clinical, and laboratory profile of these patients. METHODS This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with cystic fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted and sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies were registered. RESULTS Hepatobiliary disease was diagnosed in 16.4% of the patients and occurred as an initial manifestation of cystic fibrosis in 55.6% of these cases. The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of cystic fibrosis in 88.9% of the children. All patients with hepatobiliary disease were considered non-white, with a predominance of females (77.8%) and median (IQR) of 54 (27-91) months. Compared with the group without hepatobiliary disease, children with liver disease had a higher frequency of severe mutations identified in the CFTR gene (77.8% vs. 39.6%, p=0.033) and severe pancreatic insufficiency (88.9% vs. 31.6%, p=0.007). CONCLUSION The frequency of hepatobiliary disease was high, with a very early diagnosis of the disease and its complications in the studied series. A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the CFTR gene. It is emphasized that cystic fibrosis is an important differential diagnosis of liver diseases in childhood.

Incidence and treatment of methicillin-resistant S. aureus infection in cystic fibrosis patients: a cohort study

In Brazil the knowledge about methicillin-resistant Staphylococcus aureus infection in cystic fibrosis patients is scarce. This study aimed to determine the incidence of respiratory tract colonization and the identification rates after a standardized treatment. A retrospective cohort was performed highlighting the history of respiratory colonizations between January 2008 and June 2015. Patients under the age of 21 years with cystic fibrosis confirmed by sweat test or genetic study receiving care at the outpatient clinics of a Teaching Hospital were included. The treatment consisted of trimethoprim/sulfamethoxazole, rifampicin, nasal mupirocin and chlorhexidine 2%. The mean follow-up period was of 22.2 months and those with ≥3 negative cultures were considered free of methicillin-resistant Staphylococcus aureus. Forty-two patients were included. Methicillin-resistant Staphylococcus aureus was identified in six patients. Most patients had methicillin-sensitive S. aureus isolation prior to methicillin-resistant Staphylococcus aureus. Five children used the standardized treatment, none presented side effects. Only one child had a new isolation of methicillin-resistant Staphylococcus aureus during follow-up (after 20 months). The incidence of methicillin-resistant Staphylococcus aureus infection was high and occurred in young patients. The therapeutic regimen was effective, safe and being a good option to treat methicillin-resistant Staphylococcus aureus infection.

Description of rare mutations and a novel variant in Brazilian patients with Cystic Fibrosis: a case series from a referral center in the Bahia State

Knowledge of the genetic profile of Cystic Fibrosis (CF) contributes to a better understanding of the genotype/phenotype relationship, particularly in mixed populations such as in Brazil. To describe clinical data of CF patients with rare or not yet observed CFTR gene mutations in Brazil. It was a case series of CF patients followed-up at a referral center. Clinical and laboratory data were obtained through medical records. Molecular analysis of the mutations was performed by conventional methods and/or by next-generation sequencing. Ten patients were studied, seven had five pathogenic mutations without previous description in Brazil (Q1100P, Y109C, A107P, E1409K and K162E), one of which has not yet been reported in patients with CF (A107P). Among the seven patients, three (two siblings) had the second mutant allele of rare occurrence among Brazilians patients (G1069R and 2307insA). Three other patients also had at least one rare variant (V201M, S466X and G1069R). The age of the CF diagnosis ranged from 1 to 190 months in the ten cases and the main clinical manifestations were respiratory symptoms and difficulty in gaining weight. All but one patient presented clinical and/or laboratory data compatible with pancreatic insufficiency. The identification of rare or not yet described CFTR mutations in patients with CF in Brazil highlights the high genetic heterogeneity in this population. Knowledge of the genotypic profile of Brazilian CF patients can contribute to the development of specific mutation panels for the genetic investigation targeting each region of the country, as well as helping to understand the complex genotype/phenotype relationship, especially in mixed populations.

Manifestações clínicas da mutação F508del: uma série de casos de pacientes com fibrose cística

Introducao: a Fibrose Cistica (FC) e a doenca autossomica recessiva mais comum e letal na populacao de origem caucasoide. Causada por mutacoes no gene que codifica a proteina CFTR, no qual ja existem mais de 2.000 mutacoes identificadas, sendo a mutacao F508del a mais frequente. Esta doenca apresenta-se de forma multissistemica com quadro clinico altamente variado e com consideravel diversidade na gravidade e na progressao da doenca. Alguns estudos correlacionam os sintomas ao genotipo dos pacientes. Objetivo: descrever o genotipo e apresentacao clinica dos pacientes homozigotos ou heterozigotos para esta mutacao F508del. Metodologia: foi realizada a descricao de uma serie de casos de pacientes diagnosticados com FC que apresentam a mutacao F508del, acompanhados pelo Ambulatorio Multidisciplinar de FC do Complexo Hospitalar Universitario Prof. Edgard Santos do Estado da Bahia. Resultados: Dez (45,4%) criancas eram homozigotos para a mutacao e 12/22 (54,5%) heterozigotos. As principais manifestacoes clinicas que levaram ao diagnostico foram: insuficiencia pancreatica (95,4%), sintomas respiratorios (85,2%), dificuldade em ganhar peso (88,5%), esteatorreia (73,3%), e ritmo intestinal alterado (53,8%). A idade de inicio dos sintomas (mediana 0,16 anos) e do diagnostico (mediana 0,58 anos) foram precoces, refletindo a gravidade da doenca. Conclusoes: Conclui-se que as caracteristicas clinicas e laboratoriais dos pacientes descritos foram semelhantes aos relatados na literatura e destacam a associacao entre insuficiencia pancreatica e o genotipo dos pacientes, enfatizando a importância do estudo genetico na determinacao do prognostico dos pacientes, em especial em populacoes altamente miscigenadas, como no Brasil.

Celiac Disease and Cystic Fibrosis: Challenges to Differential Diagnosis

Abstract Cystic fibrosis and celiac disease were considered a single clinical entity for many years. Differentiation between the diseases occurred some time in the 1930s of the 20th Century. Both diseases may present the intestinal malabsorption syndrome and similar clinical manifestations that contribute to difficulties with clinical distinction. We describe a report of two patients with initial diagnosis of cystic fibrosis, who were subsequently diagnosed with celiac disease. These case reports emphasize the possibility of false positivity being shown in the sweat test in CD, which may result in delayed diagnosis and inadequate management of this disease.

7 Frequency of five CFTR gene mutations in miscegenated cystic fibrosis population of the Brazilian Northeast

Introduction There are more than 1,900 known mutations in the CFTR gene. In the state of Bahia, in the northeastern area of Brazil, there are high rates of miscegenation, principally white/black miscegenation. The knowledge about genetics of cystic fibrosis (CF) in this population is scarce. Objective To determine the prevalence of five CFTR gene mutations in cystic fibrosis patients being assisted at Professor Edgard Santos Teaching Hospital in Salvador, Brazil. Methods It was a cross-sectional study involving 47 patients of 0–20 years of age with cystic fibrosis. The molecular analysis for DF508, G542X, G551D, R553X and 3120+1G→A mutations was performed by standard methods. Results The median age of the patients was 5.6 years at the time of diagnosis. The allele frequency of DF508 and G542X mutations was 23.9% (21/88) and 2.7 (2/74), respectively. So far the mutations G551D, R553X and 3120+1G→A have been studied in 21 patients. Three patients had the splicing mutation 3120+1G→A and the other mutations were not observed. Conclusion The diagnosis of the disease was late. The frequency of the DF508 mutation was lower than that one found in Caucasian populations, but the frequency of G542X mutation was similar to the one observed in this population. The 3120+1G→A mutation was found in three patients.

Experiência de Alunos de Graduação em Medicina com a Estratégia AIDPI

SOUZA, E.L.S., et al. Experiência de Alunos de Graduação em Medicina com a Estratégia AIDPI. In: CUNHA, A. J. L. A., BENGUIGUI, Y., and SILVA, M. A. S. F., orgs. Atenção integrada às doenças prevalentes na infância: implantação e avaliação no Brasil [online]. Rio de Janeiro: Editora FIOCRUZ, 2006, pp. 243-267. ISBN: 978-85-7541-604-4. Available from: doi: 10.7476/9788575416044.0015. Also available in ePUB from: http://books.scielo.org/id/v3d7g/epub/cunha-9788575416044.epub.