José Dirceu Ribeiro

Fibrose cística em um centro de referência no Brasil: características clínicas e laboratoriais de 104 pacientes e sua associação com o genótipo e a gravidade da doença

OBJECTIVE To identify the clinical, laboratory and radiographic characteristics of the cystic fibrosis patients under care at Universidade Estadual de Campinas (UNICAMP) in the last decade of the twentieth century, and to investigate the association of these characteristics with genotype and severity of the disease as measured by the Shwachman score. METHODS Descriptive, retrospective and cross-sectional study of the patients assisted at UNICAMP hospitals Cystic Fibrosis Clinic from July 1990 to July 2000. RESULTS One hundred and four patients were studied; 53.8% male; 93.3% Caucasian; 89.4% presented with respiratory symptoms; 59.6% presented with digestive symptoms; 5.8% had meconium ileus; 4.8% had diabetes. The mean age at onset of symptoms was 3 months, and the mean age at diagnosis was 2 years and 4 months. At diagnosis, 69.9 and 56.6% of the patients had weight and height below 10th percentile, respectively; in 10.6%, sweat chloride was < 60 mEq/l. Staphylococcus aureus was found in 80.2%, Pseudomonas aeruginosa in 76%, and Burkholderia cepacia in 5.2%. DeltaF508 homozygosis was observed in 18.75%, whereas 62.50% of the patients were DeltaF508 heterozygous. A moderate/severe Shwachman score was found in 15.7%. Eighteen patients died in that period (17.3%). The mean age at death was 7 years and 8 months; median survival after diagnosis was 18 years and 4 months. Patients who have at least one DeltaF508 mutation have more frequent alterations in fecal fat levels when compared to patients who do not have this mutation (p < 0.05). There were no differences in any parameter between DeltaF508 homozygous and heterozygous patients. CONCLUSIONS The clinical and laboratory characteristics of the 104 patients studied were similar to the characteristics described for patients in other countries. Exceptions are the higher age at diagnosis and lower survival. Our results support the recommendation for early diagnosis and the need for more treatment opportunities in the population of cystic fibrosis patients.OBJECTIVE: To identify the clinical, laboratory and radiographic characteristics of the cystic fibrosis patients under care at Universidade Estadual de Campinas (UNICAMP) in the last decade of the twentieth century, and to investigate the association of these characteristics with genotype and severity of the disease as measured by the Shwachman score. METHODS: Descriptive, retrospective and cross-sectional study of the patients assisted at UNICAMP hospitals Cystic Fibrosis Clinic from July 1990 to July 2000. RESULTS: One hundred and four patients were studied; 53.8% male; 93.3% Caucasian; 89.4% presented with respiratory symptoms; 59.6% presented with digestive symptoms; 5.8% had meconium ileus ; 4.8% had diabetes. The mean age at onset of symptoms was 3 months, and the mean age at diagnosis was 2 years and 4 months. At diagnosis, 69.9 and 56.6% of the patients had weight and height below 10th percentile, respectively; in 10.6%, sweat chloride was < 60 mEq/l. Staphylococcus aureus was found in 80.2%, Pseudomonas aeruginosa in 76.0%, and Burkholderia cepacia in 5.2%. DF508 homozygosis was observed in 18.75%, whereas 62.50% of the patients were DF508 heterozygous. A moderate/severe Shwachman score was found in 15.7%. Eighteen patients died in that period (17.3%). The mean age at death was 7 years and 8 months; median survival after diagnosis was 18 years and 4 months. Patients who have at least one DF508 mutation have more frequent alterations in fecal fat levels when compared to patients who do not have this mutation (p < 0.05). There were no differences in any parameter between DF508 homozygous and heterozygous patients. CONCLUSIONS: The clinical and laboratory characteristics of the 104 patients studied were similar to the characteristics described for patients in other countries. Exceptions are the higher age at diagnosis and lower survival. Our results support the recommendation for early diagnosis and the need for more treatment opportunities in the population of cystic fibrosis patients.

Association of TGF-beta1, CD14, IL-4, IL-4R and ADAM33 gene polymorphisms with asthma severity in children and adolescents

OBJECTIVE To verify the association of transforming growth factor-beta1(TGF-beta1) (C-509T and T869C), CD14 (C-159T), IL-4 (C-590T), IL-4R (ILe50Val) and ADAM33 (S_2) gene polymorphisms with asthma severity in a sample of patients with mild, moderate and severe persistent atopic asthma. METHODS A clinical, laboratory, prospective study was performed in patients with persistent atopic asthma, compared to a control group at Hospital Universitário da Universidade Estadual de Campinas between 2006 and 2007. Analysis of the TGF-beta1 T869C gene polymorphism was performed using the technique polymerase chain reaction (PCR) + amplification refractory mutation system (ARMS). TGF-beta1 C-509T, CD14 C-159T, IL-4 C-590T, IL-4Ra ILe50Val, and ADAM33 S2 gene polymorphisms were detected by PCR and restriction enzyme. RESULTS This study included 88 patients with persistent atopic asthma (27 mild, 23 moderate and 38 severe) and 202 healthy blood donors. As to T869C polymorphism (TGF-beta1), there was an association between the CC genotype and patients with severe asthma. There was no association in polymorphisms C-509T (TGF-beta1), C-590T (IL-4) and S_2 (ADAM33). When distribution of C-159T polymorphism genotype frequency (CD14) in severe asthma was compared with the control group, there was a significant result with the TT genotype. There was significant association of the Val/Val genotype (IL-4R) with mild asthma. CONCLUSION Our results indicate that T869C (TGF-beta1), C-159T (CD14) and Val/Val (IL-4R) polymorphisms might be involved in modulation of asthma severity.

Controvérsias na fibrose cística: do pediatra ao especialista

Objetivos: nos ultimos 70 anos, a fibrose cistica emergiu da obscuridade para o reconhecimento como a mais importante doenca hereditaria, potencialmente letal, incidente na raca branca. Embora seja uma doenca genetica, na qual o defeito basico acomete celulas de varios orgaos, nem todos os individuos expressam respostas clinicas na mesma intensidade. Varias manifestacoes clinicas, principalmente pulmonares e digestivas, podem ocorrer durante a vida dos pacientes fibrocisticos. O objetivo deste artigo e propiciar ao pediatra geral uma visao atualizada dos principais assuntos referentes a fibrose cistica. Fontes dos dados: revisao sistematica e atualizada em fonte de dados oficial (Medline). Sintese dos dados: foram revisados 79 artigos sobre fibrose cistica, de periodicos internacionais, colocando, de modo atual e critico, os principais eventos relacionados com a incidencia, a fisiopatogenia, as manifestacoes clinicas, o diagnostico e o tratamento da fibrose cistica. Conclusoes: apesar de nao existir cura para essa doenca, muitos conhecimentos novos sobre a etiologia e a fisiopatologia, adquiridos nas duas ultimas decadas, propiciaram uma nova abordagem para o tratamento da fibrose cistica. A compreensao dos mecanismos basicos da doenca pulmonar, bem como das manifestacoes digestivas na fibrose cistica, decorrente dos conhecimentos de pesquisas recentes, tem sido a chave para o aumento da sobrevida e a melhora da qualidade de vida dos pacientes.

Associação dos polimorfismos dos genes TGF-beta1, CD14, IL-4, IL-4R e ADAM33 com a gravidade da asma em crianças e adolescentes

OBJETIVO: Verificar, em uma amostra de pacientes com asma atopica persistente leve, moderada e grave, a associacao entre os polimorfismos dos genes fator de crescimento transformante-b1 (TGF-b1) (C-509T e T869C), CD14 (C-159T), IL-4 (C-590T), IL-4R (ILe50Val) e ADAM33 (S_2) com a gravidade da asma. METODOS: Realizou-se um estudo clinico laboratorial prospectivo em pacientes com asma atopica persistente, comparados a um grupo controle no Hospital Universitario da Universidade Estadual de Campinas nos anos de 2006 e 2007. A analise do polimorfismo T869C do gene TGF-b1 foi realizada pela tecnica de reacao em cadeia da polimerase (PCR) + sistema de amplificacao refrataria de mutacao (ARMS). Os outros polimorfismos, C-509T do gene TGF-b1, C-159T do gene CD14, C-590T da IL-4, ILe50Val da IL-4Ra e S2 do gene ADAM33, foram detectados por PCR e enzima de restricao. RESULTADOS: Foram incluidos 88 pacientes com asma atopica persistente (27 leves, 23 moderados e 38 graves) e 202 individuos saudaveis, doadores de sangue. Em relacao ao polimorfismo T869C (TGF-b1), observou-se uma associacao entre o genotipo CC e os pacientes com asma grave. Nenhuma associacao foi encontrada com os polimorfismos C-509T (TGF-b1), C-590T (IL4) e S_2 (ADAM33). Quando se comparou a distribuicao da frequencia genotipica do polimorfismo C-159T (CD14) na asma grave com o grupo controle, foi observado um resultado significativo com o genotipo TT. Houve associacao significativa do genotipo Val/Val (IL-4R) com a asma leve. CONCLUSAO: Nossos resultados indicam que os polimorfismos T869C (TGF-b1), C-159T (CD14) e Val/Val (IL-4R) podem estar envolvidos na modulacao da gravidade da asma.

Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors

BackgroundLower respiratory tract infection (LRTI) is a major cause of pediatric morbidity and mortality, especially among non-affluent communities. In this study we determine the impact of respiratory viruses and how viral co-detections/infections can affect clinical LRTI severity in children in a hospital setting.MethodsPatients younger than 3 years of age admitted to a tertiary hospital in Brazil during the months of high prevalence of respiratory viruses had samples collected from nasopharyngeal aspiration. These samples were tested for 13 different respiratory viruses through real-time PCR (rt-PCR). Patients were followed during hospitalization, and clinical data and population characteristics were collected during that period and at discharge to evaluate severity markers, especially length of hospital stay and oxygen use. Univariate regression analyses identified potential risk factors and multivariate logistic regressions were used to determine the impact of specific viral detections as well as viral co-detections in relation to clinical outcomes.ResultsWe analyzed 260 episodes of LRTI with a viral detection rate of 85% (n = 222). Co-detection was observed in 65% of all virus-positive episodes. The most prevalent virus was Respiratory Syncytial Virus (RSV) (54%), followed by Human Metapneumovirus (hMPV) (32%) and Human Rhinovirus (HRV) (21%). In the multivariate models, infants with co-detection of HRV + RSV stayed 4.5 extra days (p = 0.004), when compared to infants without the co-detection. The same trends were observed for the outcome of days of supplemental oxygen use.ConclusionsAlthough RSV remains as the main cause of LRTI in infants our study indicates an increase in the length of hospital stay and oxygen use in infants with HRV detected by RT-PCR compared to those without HRV. Moreover, one can speculate that when HRV is detected simultaneously with RSV there is an additive effect that may be reflected in more severe clinical outcome. Also, our study identified a significant number of children infected by recently identified viruses, such as hMPV and Human Bocavirus (HBov), and this is a novel finding for poor communities from developing countries.

Measurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis

Background Cystic Fibrosis (CF) is caused by ∼1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl−) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement thus causing diagnostic dilemmas, especially for non-classic cases. Methodology/Principal Findings To further establish measurement of CFTR function as a sensitive and robust biomarker for diagnosis and prognosis of CF, we herein assessed cholinergic and cAMP-CFTR-mediated Cl− secretion in 524 freshly excised rectal biopsies from 118 individuals, including patients with confirmed CF clinical diagnosis (n = 51), individuals with clinical CF suspicion (n = 49) and age-matched non-CF controls (n = 18). Conclusive measurements were obtained for 96% of cases. Patients with “Classic CF”, presenting earlier onset of symptoms, pancreatic insufficiency, severe lung disease and low Shwachman-Kulczycki scores were found to lack CFTR-mediated Cl− secretion (<5%). Individuals with milder CF disease presented residual CFTR-mediated Cl− secretion (10–57%) and non-CF controls show CFTR-mediated Cl− secretion ≥30–35% and data evidenced good correlations with various clinical parameters. Finally, comparison of these values with those in “CF suspicion” individuals allowed to confirm CF in 16/49 individuals (33%) and exclude it in 28/49 (57%). Statistical discriminant analyses showed that colonic measurements of CFTR-mediated Cl− secretion are the best discriminator among Classic/Non-Classic CF and non-CF groups. Conclusions/Significance Determination of CFTR-mediated Cl− secretion in rectal biopsies is demonstrated here to be a sensitive, reproducible and robust predictive biomarker for the diagnosis and prognosis of CF. The method also has very high potential for (pre-)clinical trials of CFTR-modulator therapies.

Respiração bucal e anteriorização da cabeça: efeitos na biomecânica respiratória e na capacidade de exercício em crianças

OBJECTIVE To evaluate submaximal exercise tolerance and respiratory muscle strength in relation to forward head posture (FHP) and respiratory mode in children, comparing mouth-breathing (MB) children with nasal-breathing (NB) children. METHODS This was a controlled, analytical cross-sectional study involving children in the 8-12 year age bracket with a clinical otorhinolaryngology diagnosis of MB, recruited between October of 2010 and January of 2011 from the Mouth Breather Clinic at the State University of Campinas Hospital de Clínicas, located in the city of Campinas, Brazil. The exclusion criteria were obesity, asthma, chronic respiratory diseases, heart disease, and neurological or orthopedic disorders. All of the participants underwent postural assessment and the six-minute walk test (6MWT), together with determination of MIP and MEP. RESULTS Of the 92 children in the study, 30 presented with MB and 62 presented with NB. In the MB group, the differences between those with moderate or severe FHP and those with normal head posture, in terms of the mean MIP, MEP and six-minute walk distance (6MWD), were not significant (p = 0.079, p = 0.622, and p = 0.957, respectively). In the NB group, the mean values of MIP and MEP were higher in the children with moderate FHP than in those with normal head posture (p = 0.003 and p = 0.004, respectively). The mean MIP, MEP, and 6MWD were lower in the MB group than in the NB group. Values of MIP and MEP were highest in the children with moderate FHP. CONCLUSIONS Respiratory biomechanics and exercise capacity were negatively affected by MB. The presence of moderate FHP acted as a compensatory mechanism in order to improve respiratory muscle function.OBJECTIVE: To evaluate submaximal exercise tolerance and respiratory muscle strength in relation to forward head posture (FHP) and respiratory mode in children, comparing mouth-breathing (MB) children with nasal-breathing (NB) children. METHODS: This was a controlled, analytical cross-sectional study involving children in the 8-12 year age bracket with a clinical otorhinolaryngology diagnosis of MB, recruited between October of 2010 and January of 2011 from the Mouth Breather Clinic at the State University of Campinas Hospital de Clinicas, located in the city of Campinas, Brazil. The exclusion criteria were obesity, asthma, chronic respiratory diseases, heart disease, and neurological or orthopedic disorders. All of the participants underwent postural assessment and the six-minute walk test (6MWT), together with determination of MIP and MEP. RESULTS: Of the 92 children in the study, 30 presented with MB and 62 presented with NB. In the MB group, the differences between those with moderate or severe FHP and those with normal head posture, in terms of the mean MIP, MEP and six-minute walk distance (6MWD), were not significant (p = 0.079, p = 0.622, and p = 0.957, respectively). In the NB group, the mean values of MIP and MEP were higher in the children with moderate FHP than in those with normal head posture (p = 0.003 and p = 0.004, respectively). The mean MIP, MEP, and 6MWD were lower in the MB group than in the NB group. Values of MIP and MEP were highest in the children with moderate FHP. CONCLUSIONS: Respiratory biomechanics and exercise capacity were negatively affected by MB. The presence of moderate FHP acted as a compensatory mechanism in order to improve respiratory muscle function.

Fatores maternos e neonatais na incidência de displasia broncopulmonar em recém-nascidos de muito baixo peso

OBJECTIVE: To determine the incidence of bronchopulmonary dysplasia, to identify maternal and neonatal factors associated with the disease, and to determine the correlation between bronchopulmonary dysplasia and the progress of newborns. METHODS: Data were prospectively collected on 153 infants born in Campinas (state of Sao Paulo, Brazil) from September 2000 to April 2002 weighing less than 1,500 g and treated at the University Hospital. The ratio of incidence rates with 95% CI, Breslow-Cox regression, Students t test, linear regression and the Fishers exact test were utilized. RESULTS: Among the 124 babies who survived until 28 days of age, 33 (26.6%) developed bronchopulmonary dysplasia. Birthweight < 1,000 g (5.6; 95% CI 3.0, 10.4) and gestational age < 30 weeks (4.0; 95% CI 2.1, 7.2) were correlated with increased incidence of bronchopulmonary dysplasia. Breslow-Cox regression showed that other factors including gender, Apgar score, hyaline membrane disease, antenatal steroid therapy, pregnancy-induced hypertension, delivery route and maternal age were not associated with bronchopulmonary dysplasia. Mean duration of hospitalization and ventilator therapy in newborns with and without bronchopulmonary dysplasia was 78.8 days (SD = 26.67) vs. 43.0 days (SD = 14.49) (p < 0.01) and 27.2 days (SD = 21.26) vs. 3.7 days (SD = 3.02) (p < 0.01), respectively. Mean weight gain per day was lower in newborns with bronchopulmonary dysplasia (p < 0.01). Mortality in newborns with bronchopulmonary dysplasia was 21% (p < 0.00005). CONCLUSION: Gestational age and birthweight were inversely proportional to incidence of bronchopulmonary dysplasia. After the onset of bronchopulmonary dysplasia, newborns with the disorder required longer periods of ventilator therapy and hospitalization, and presented inadequate weight gain and higher mortality rates than newborns without bronchopulmonary dysplasia.

Are immunoglobulin E levels associated with early wheezing? A prospective study in Brazilian infants.

The relationship between wheezing or asthma and serum immunoglobulin (Ig)E levels in early life is unclear. The aim of this study was to follow-up the IgE immune response in infants that did, or did not, develop recurrent wheezing during their first year of life. One-hundred and two randomised term neonates were included, in which IgE levels were quantified in cord blood samples, at 3, 6, 9 and 12 months of age. Specific IgE levels for food and inhalant allergens and the skin-prick test for inhalant allergens were also assessed at 6 and 12 months. During clinical follow-up, 32 (31%) infants presented with two or more wheezing episodes, while 70 (69%) had no wheezing. Total IgE levels were significantly higher up to 12 months in wheezing infants when compared to nonwheezing group. At 12 months, the specific IgE levels to cows milk, egg white and mites were higher in infants with recurrent wheezing. There was no influence of family history for atopy on IgE levels. The skin-prick tests were positive in 14% and 23% in wheezing infants at 6 and 12 months, respectively. These results indicate an early allergic sensitisation in wheezing infants, suggesting an altered immunoregulatory T-cell role in immunoglobulin E production.

Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis

BackgroundThe most common cystic fibrosis (CF) manifestation is the progressive chronic obstructive pulmonary disease caused by deficiency, dysfunction, or absence of the CFTR (Cystic Fibrosis Transmembrane Regulator) protein on the apical surface of the cells in the respiratory tract. The use of bronchodilators (BD), and inhaled corticosteroids (IC) have been suggested for the management of airway inflammation in CF. The effectiveness of BD and IC have been verified, proven in laboratory and in the clinical treatment for asthma patients. However, in CF, the effectiveness of these drugs is controversial. The extent of asthma’s response to BD depends on the presence of polymorphisms in the ADRB2 gene. In contrast, in CF, little is known about the response to the BD and the association of CF´s severity with the different polymorphisms in ADRB2 gene. In this context, our objective was to verify whether the Arg16Gly and Glu27Gln polymorphisms in ADRB2 gene are associated with severity and with the bronchodilator response in CF patients.MethodCross-sectional study of 122 CF patients subjected to analysis of mutations in the CFTR gene, polymorphisms in ADRB2 gene, along with clinical and laboratorial characteristics of severity.ResultThe Arg16Gly polymorphism in ADRB2 gene was associated with pancreatic insufficiency(p:0.009), Bhalla score(p:0.039), forced expiratory volume in the first second[FEV1(%)](p:0.003), forced expiratory flow between 25 and 75% of the forced vital capacity-FVC[FEF25-75(%)](p:0.008) and lower age at the first isolation of the Pseudomonas aeruginosa(p:0.012). The response to the BD spirometry was associated with clinical severity markers, FEV1(%)(p:0.011) and FEF25-75(%)(p:0.019), for the Arg16Gly polymorphism in the ADRB2 gene. The haplotype analysis showed association with the FEV1/FVC marker from the spirometry test, before and after using the BD, with higher values in the group with Gly/Gly and Glu/Glu, respectively, for the Arg16Gly and Gln27Glu polymorphisms. The analysis by MDR2.0 software, showed association with FEF25-75%; the response to Arg16Gly was respondent by 17.35% and Gln27Glu by 6.8% in variation found.ConclusionThere was an association between the Arg16Gly and Gln27Glu polymorphisms in ADRB2 gene with CF´s severity and bronchodilator response.