C-reactive protein/albumin ratio is associated with lung function among children/adolescents with cystic fibrosis: a three-year longitudinal study

ABSTRACT BACKGROUND: Chronic lung infections, inflammation and depletion of nutritional status are considered to be prognostic indicators of morbidity in patients with cystic fibrosis. The aim of this study was to investigate the association between inflammatory markers and lung function, nutritional status and morbidity among children/adolescents with cystic fibrosis. DESIGN AND SETTINGS: Prospective three-year longitudinal study conducted in an outpatient clinic in southern Brazil. METHODS: Children/adolescents aged 1-15 years with cystic fibrosis were enrolled. Nutritional status was determined from weight-to-length and body mass index-to-age z-scores and was classified as acceptable, at risk or nutritional failure. Tumor necrosis factor-α, interleukin-1β, myeloperoxidase, C-reactive protein and C-reactive protein/albumin ratio were analyzed. Lung function was evaluated based on the forced expiratory volume in the first second and morbidity according to the number of hospitalizations for pulmonary exacerbation and infections by Pseudomonas aeruginosa. Lung function, nutritional status and morbidity were the outcomes. Odds ratios and 95% confidence intervals were to evaluate the effect of baseline inflammatory markers on the clinical outcomes after three years of follow-up and p-values < 0.05 were considered significant. RESULTS: We evaluated 38 children/adolescents with cystic fibrosis: 55% female; median age (with interquartile range), 3.75 years (2.71-7.00). Children/adolescents with high C-reactive protein/albumin ratio at baseline had odds of 18 (P = 0.018) of presenting forced expiratory volume in the first second ≤ 70% after three years. The other inflammatory markers were not associated with the outcomes. CONCLUSION: C-reactive protein/albumin ratio was associated with forced expiratory volume in the first second ≤ 70% after three years.

Association between hypovitaminosis D and frequency of pulmonary exacerbations in children and adolescents with cystic fibrosis / Associação entre hipovitaminose D e frequência de exacerbações pulmonares em crianças e adolescentes com fibrose cística

Abstract Objective We evaluated the association between vitamin D levels and nutritional status, pulmonary function and pulmonary exacerbations in children and adolescents with cystic fibrosis. Methods 25-hydroxyvitamin D (25(OH)D) levels of 37 children and adolescents were retrospectively evaluated. Pulmonary function, body mass index, height for age, and pulmonary exacerbations episodes were associated with vitamin D levels divided into two groups: sufficient (≥30ng/mL) and hypovitaminosis (<30ng/mL). Results Hypovitaminosis D (25(OH)D <30ng/mL) was observed in 54% of subjects. The mean level of 25(OH)D was 30.53±12.14ng/mL. Pulmonary function and nutritional status were not associated with vitamin D levels. Pulmonary exacerbations over a 2-year period (p=0.007) and the period from measurement up to the end of the follow-up period (p=0.002) were significantly associated with vitamin D levels. Conclusion Hypovitaminosis D was associated with higher rates of pulmonary exacerbations in this sample of children and adolescents with cystic fibrosis. Hypovitaminosis D should be further studied as a marker of disease severity in cystic fibrosis. Further prospective and randomized studies are necessary to investigate causality of this association.

RESUMO Objetivo Avaliar a associação entre níveis de vitamina D e estado nutricional, função pulmonar e exacerbações pulmonares em crianças e adolescentes com fibrose cística. Métodos Os níveis de 25-hidroxivitamina D (25(OH)D) de 37 crianças e adolescentes foram avaliados retrospectivamente. Função pulmonar, índice de massa corporal, altura para a idade, e episódios de exacerbações pulmonares foram associados aos níveis de vitamina D divididos em dois grupos: suficiente (≥30ng/mL) e hipovitaminose (<30ng/mL). Resultados Hipovitaminose D (25(OH)D <30ng/mL) foi observada em 54% dos pacientes. O nível médio de 25(OH)D foi de 30,53±12,14ng/mL. A função pulmonar e o estado nutricional não foram associados aos níveis de vitamina D. As exacerbações pulmonares durante um período de 2 anos (p = 0,007) e do período de medição até o final do período de seguimento (p=0,002) foram significativamente associadas aos níveis de vitamina D. Conclusão A hipovitaminose D esteve associada a maiores taxas de exacerbações pulmonares nesta amostra de crianças e adolescentes com fibrose cística. A hipovitaminose D deve ser mais estudada como marcador da gravidade da doença na fibrose cística. Outros estudos prospectivos e randomizados são necessários para investigar a relação causal desta associação.

O impacto da fibrose cística no perfil imunológico de pacientes pediátricos / The impact of cystic fibrosis on the immunologic profile of pediatric patients

OBJETIVO: Comparar o estado imunológico de 44 pacientes pediátricos com fibrose cística (FC)a umgrupo-controle formado por 16 indivíduos saudáveis. MÉTODOS: Foram selecionados para o estudo pacientes com FC com idade entre 3 e 12 anos, apresentando um escore clínico moderado e bom. Foram avaliados a glutationa eritrocitária, a produção de espécies reativas de oxigênio, citocinas (TNF-α, IFN-γ, IL-8, IL-6, IL-10) em culturas de células mononucleares do sangue periférico em condições espontâneas e estimuladas por BCG ou PHA, a concentração sérica de TGF-β2, IgA, IgG, IgM, IgE e IgA salivar. RESULTADOS :A produção espontânea de TNF-α, IL-6 e IL-10, a produção de IL-6 estimulada por PHA e TGF-β2, IgA e IgG séricas aumentaram em amostras de pacientes com FC. Indivíduos saudáveis tiveram uma produção mais elevada de TNF-α em resposta a BCG. CONCLUSÃO: Apesar de os pacientes com FC parecerem clinicamente estáveis, os resultados de seus exames de sangue periférico mostraram que houve um impacto sobre o sistema imunológico.

OBJECTIVE: To compare the immunologic state of 44 pediatric patients with cystic fibrosis (CF) with a control group consisting of 16 healthy individuals. METHODS: CF patients aged 3 to 12 years with moderate to good clinical score were selected for the study. Erythrocytic glutathione, production of reactive oxygen species, cytokines (TNF-α, IFN-γ, IL-8, IL-6, IL-10) in peripheral blood mononuclear cells cultures under spontaneous and BCG- or PHA-stimulated conditions, serum concentrations of TGF-β2, IgA, IgG, IgM, IgE, and salivary IgA were evaluated. RESULTS: The spontaneous production of TNF-α, IL-6, and IL-10, the PHA-stimulated production of IL-6, and the serum TGF-β2, IgA, and IgG were increased in samples from CF patients. Healthy subjects had a higher production of TNF-α in response to BCG. CONCLUSION: Although CF patients appearedclinically stable, the results of their peripheral blood examinations demonstrated an impact on the immune system.

Frequency of 8 CFTR gene mutations in cystic fibrosis patients in Minas Gerais, Brazil, diagnosed by neonatal screening

The nature and frequency of cystic fibrosis mutations in Brazil is not uniform due to the highly varied ethnic composition of the population. The average frequency of the F508del mutation has been reported to be 48.6 percent. Other common mutations in Brazil are G542X, R1162X, and N1303K. The aim of this study was to analyze the frequency of 8 mutations (F508del, G542X, R1162X, N1303K, W1282X, G85E, 3120+1G>A, and 711+1G>T) in a sample of 111 newborn patients with cystic fibrosis diagnosed by the Cystic Fibrosis Neonatal Screening Program of Minas Gerais State. The mutations were tested by allele-specific oligonucleotide PCR with specially designed primers. An allele frequency of 48.2 percent was observed for the F508del mutation, and allele frequencies of 5.41, 4.50, 4.05, and 3.60 percent were found for the R1162X, G542X, 3120+1G>A, and G85E mutations, respectively. The genotypes obtained were in Hardy-Weinberg equilibrium. These data demonstrate that the 8-mutation panel studied here has extensive coverage (68 percent) for the cystic fibrosis mutations in Minas Gerais. These data improve our knowledge of cystic fibrosis in Brazil, particularly in this region. In addition, this investigation contributed to the establishment of a sensitive and population-specific mutation panel, which can be helpful for molecular diagnosis of cystic fibrosis.

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 percent) of 230 unrelated CF alleles. Fifteen (13.0 percent) patients were homozygous for this mutation, while 20 (17.4 percent) were heterozygous; the remaining 80 (69.6 percent) patients did not carry the p.F508del mutation. Exon 24 sequence had no change in 75 (65.2 percent) patients, 21 (18.3 percent) had the sequence variation 4521G/A, 11 (9.6 percent) had a not yet described sequence variation 4407T/A and 8 (7.0 percent) 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.