Quantification of Phenotypic Variability of Lung Disease in Children with Cystic Fibrosis.

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.

Gene modifiers of cystic fibrosis lung disease: A systematic review.

BACKGROUND: Lung disease is the major source of morbidity and mortality in cystic fibrosis (CF), with large variability in severity between patients. Although accurate prediction of lung disease severity would be extremely useful, no robust methods exist. Twin and sibling studies have highlighted the importance of non-cystic fibrosis transmembrane conductance regulator (CFTR) genes in determining lung disease severity but how these impact on the severity in CF remains unclear. METHODS: A systematic review was undertaken to answer the question "In patients with CF which non-CFTR genes modify the severity of lung disease?" The method for this systematic review was based upon the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" statement, with a narrative synthesis of results planned. RESULTS: A total of 1168 articles were screened for inclusion, with 275 articles undergoing detailed assessment for inclusion. One hundred and forty articles were included. Early studies focused on candidate genes, whereas more recent studies utilized genome-wide approaches and also examined epigenetic mechanisms, gene expression, and therapeutic response. DISCUSSION: A large body of evidence regarding non-CFTR gene modifiers of lung disease severity has been generated, examining a wide array of genes. Limitations to existing studies include heterogeneity in outcome measures used, limited replication, and relative lack of clinical impact. Future work examining non-CFTR gene modifiers will have to overcome these limitations if gene modifiers are to have a meaningful role in the care of patients with CF.

Impact of Intermediate Cystic Fibrosis Classification on Parents' Perceptions of Child Vulnerability and Protectiveness.

This cross-sectional, mixed-method study examined factors associated with parent perceptions of child vulnerability and protectiveness in three groups: cystic fibrosis (CF-group, n = 40), intermediate CF classification (I-group, n = 20), and healthy (H-group, n = 50). A composite indicator structural equation (CISE) using Bayesian estimation tested two mediational models: psychological and biological. Significant results ( p < .05) from the psychological model showed I-group and CF-group parents perceived their children to be more vulnerable than H-group parents but reported lower levels of protectiveness than H-group parents. Perceptions of vulnerability mediated protectiveness for CF- and I-groups. The biological model showed I-group children had significantly less severe genotype and phenotype, and lower sweat chloride levels than the CF-group; I-group parents had lower expectations about children developing CF symptoms. Both models showed negative associations between children's ages and protectiveness. Psychological factors explained perceptions of child vulnerability and protectiveness; biological factors explained protectiveness. Parent perceptions of vulnerability and protectiveness are separate, independent constructs.

Efeitos da fibrose cística sobre o microbioma bucal e o proteoma salivar / Effects of cystic fibrosis on oral microbiome and salivary proteome

A Fibrose Cística (FC) é uma doença genética de elevada prevalência global e que causa função anormal das glândulas exócrinas. As alterações nas funções das glândulas salivares podem impactar a saúde bucal que por sua vez podem influenciar a saúde geral. A boca pode representar um reservatório microbiano de potenciais patógenos e colonizadores das vias aéreas, causando infecções crônicas pulmonares. O objetivo deste estudo foi avaliar os impactos da FC na cavidade bucal, saliva e microbioma bucal. Foram incluídos no estudo 50 pacientes com diagnóstico de FC com idades de 3 a 20 anos, divididos em 2 grupos de acordo com o grau de severidade da doença determinado pelo escore de Shwachman-Kulczycki: G1 (baixa severidade) e G2 (alta severidade). Foi também incluído grupo controle pareado ao grupo de estudo quanto ao gênero e idade (G3, n=50). A presença de lesões de cárie foi avaliada. O impacto da FC sobre a saúde bucal foi avaliado por questionário preenchido pelos pais ou responsáveis. Amostra de saliva estimulada foi coletada de todos os pacientes. O microbioma bucal foi avaliado por Human Oral Microbe Identification using Next Generation Sequencing (HOMINGS) e metodologias de cultivo, para análise da microbiota potencialmente oportunista e cariogênica. Realizouse ainda a análise proteômica da saliva e quantificação de imunoglobulinas salivares. Os resultados foram analisados e, de acordo com a distribuição dos dados e avaliação desejada, foram aplicados os testes estatísticos apropriados, sendo adotado o nível de significância de 5%. O questionário aplicado apontou que os pais consideraram que a saúde bucal não impacta negativamente a saúde geral dos seus filhos em todos os grupos estudados Os grupos de pacientes com FC apresentaram menores índices de Ceo-d, CPO-D, taxa de fluxo salivar e pH inicial em relação ao grupo controle. As contagens de estafilococos e leveduras foram significativamente mais elevadas nos grupos FC. Todos os isolados fúngicos foram suscetíveis aos antifúngicos testados. Alta incidência de resistência foi observada dentre as cepas bacterianas. Os níveis de IgA foram mais altos nos grupos com FC em relação ao controle. Pseudomonas aeruginosa foi detectada apenas nos grupos com FC. A análise proteômica identificou 7 potenciais biomarcadores para a fibrose cística. Conclui-se que o monitoramento do microbioma oral de pacientes com fibrose cística pode ser uma ferramenta importante na prevenção da colonização pulmonar por potenciais patógenos. O estudo de biomarcadores salivares pode contribuir para o desenvolvimento de novos métodos de diagnóstico alternativos ao teste do suor para a fibrose cística(AU)

Cystic Fibrosis (CF) is a genetic disease with high global prevalence that causes abnormal function of the exocrine glands. The functional alterations of salivary glands and saliva can impact the oral health and influence general health. Oral cavity may represent a microbial reservoir of potential pathogens that can colonize the airways and cause chronic pulmonary infections. The aim of this study is to evaluate the impact of cystic fibrosis on the oral cavity, saliva and oral microbiome. Fifty CF patients aged from 3 to 20 years were divided into two groups according to the disease severity determined by the Shwachman-Kulczycki score: G1 (low severity) and G2 (high severity). Also, age and gender paired control group was included in the study (G3, n = 50). The occurrence of caries was evaluated. The impact of CF on oral health was evaluated by a questionnaire filled by parents or responsible person. Stimulated whole saliva (WS) samples were collected from all patients. The oral microbiome was analyzed by Human Oral Microbe Identification using Next Generation Sequencing (HOMINGS) and by microbiological culture methodologies to evaluate the potential opportunistic and cariogenic microbiota. The proteomic analysis of saliva and quantification of salivary immunoglobulins were carried out. Statistical analysis was performed according to the normality of the data at a significance level of 5%. The applied questionnaire pointed out that oral health did not impact systemic health negatively, according to the parents in all groups. The groups of patients with CF had lower rates of dmft, DMFT, salivary flow rate and initial pH in comparison to the control group. The counts of staphylococcal and yeast from CF groups were significant higher than the controls. All fungal isolates were susceptible to the antifungal agents. Higher incidence of bacterial resistance was observed. The IgA levels were higher in both CF groups than in the control group. Pseudomonas aeruginosa were detected only in the CF groups. The proteomic analysis identified 7 potential biomarkers for cystic fibrosis. The effects of CF in saliva and oral microbiome must be considered to establishment of therapeutic and preventives multidisciplinary protocols aiming overall health and quality of life of these patients. In conclusion, monitoring the oral microbiome of CF patients may be an important tool in the prevention of pulmonary colonization by potential pathogens. The study of salivary biomarkers may contribute to the development of new diagnostics methods alternative to sweat test for CF(AU)

From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.

Refining the continuum of CFTR-associated disorders in the era of newborn screening.

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.

Similar performance of Brasfield and Wisconsin scoring systems in young children with cystic fibrosis.

BACKGROUND: To assess the severity of lung disease in cystic fibrosis (CF), scoring systems based on chest radiographs (CXRs), CT and MRI have been used extensively, although primarily in research settings rather than for clinical purposes. It has recently been shown that those based on CXRs (primarily the Brasfield and Wisconsin systems) are as sensitive and valid as those based on CT. The reproducibility and correlation of both systems to pulmonary function tests (PFTs) were recently investigated and were found to be statistically identical. However, the relative performance of these systems has not been specifically assessed in children younger than 5 years old with mild lung disease, a critical age range in which PFTs is rarely performed. OBJECTIVE: To investigate and compare the performance of the Brasfield and Wisconsin systems in children 0-5 years old with predominantly mild lung disease. MATERIALS AND METHODS: Fifty-five patients 0-5 years old with 105 CXRs were included in the study. Given that the goal was to compare system performance in mild disease, only the first two CXRs from each patient were included (all but five patients had two images). When only one image was available in the target age range, it only was included. Agreement between the Brasfield and Wisconsin systems was assessed using a 2X2 contingency table assuming binary classification of CF lung disease using CXR scoring systems (mild vs. non-mild). In the absence of PFTs or another external gold standard for comparison, the Wisconsin system was used as an arbitrary gold standard against which the Brasfield was compared. Correlation between the two systems was assessed via a concordance correlation coefficient (CCC) for repeated measures. RESULTS: Scores were rated as mild or non-mild based on published numerical cutoffs for each system. The systems agreed on 89/105 (85%) and disagreed on 16/105 (15%) of the CXRs. Agreement between the two systems was statistically significant (P < 0.001). Relative sensitivity and specificity of the Brasfield system (which since using the Wisconsin as the gold standard reflects relative agreement rather than absolute performance of the Brasfield) was also fairly high (85% and 84%, respectively). Relatively high correlation between the two systems was also estimated (r = 0.72). CONCLUSION: The current study, powered to find at least a mild correlation between the two systems, confirms the Brasfield and Wisconsin systems are in agreement when assessing CF lung disease even in patients younger than 5 years of age with predominantly mild disease.

Aproximación diagnóstica a las enfermedades pulmonares difusas / Diagnostic approach to diffuse pulmonary diseases

Las enfermedades pulmonares difusas representan un grupo de enfermedades que comparten un mismo criterio radiológico, existiendo más de 200 entidades que se presentan como tal. La clínica es fundamental para aproximar el diagnóstico etiológico que muchas veces resulta complejo. Tos y disnea progresiva son los síntomas clínicos característicos de estas enfermedades y se acompañan de la radiografía de tórax con opacidades difusas como método radiológico inicial. El estudio en general es multi- disciplinario incluyendo patrones radiológicos de la tomografía axial de tórax, estudio de función pulmonar, lavado bronquioal- veolar y biopsia pulmonar en algunos casos.

The diffuse lung diseases are a group of conditions that share common radiological criteria. There are over 200 causes. The clinic skill is essential to approximate the etiologic diagnosis, often complicated. Cough and progressive dyspnea are the clinical features of these diseases and are accompanied by chest radiography with diffuse opacities as the initial radiological method. The study is generally multidisciplinary and including radiological patterns in computer tomography of the chest, lung function study, bronchoalveolar lavage and lung biopsy in some cases.

Correlation between Bhalla score and spirometry in children and adolescents with cystic fibrosis.

OBJECTIVE: To correlate the findings of high resolution computed tomography of the chest based on the Bhalla score with the clinical data and spirometry in children and adolescents with cystic fibrosis, and to study the concordance between two radiologists for the Bhalla score and its categories. METHODS: We evaluated the medical records of 23 patients from the outpatient clinic. The items evaluated included age, weight, height, height/age Z-score, weight/age Z-score, body mass index (BMI), O2 saturation, spirometry and Bhalla score. RESULTS: The patients had a mean age of 17.4 years ± 5.7 years, with fifteen females and eight males. There was good correlation between Bhalla score and spirometry (FVC-r =0.718, p<0.001; FEV1-r=0.830, p<0.001; FEF25-75%-r =0.786, p<0.001; FEV1/FVC-r=0.714, p<0.001). It was also noted that some patients with FEF25-75%> 70% already had changes in their final Bhalla score. In the analysis of the concordance between the examiners a Kappa coefficient of 0.81 (p <0.001) was found, and an intraclass correlation coefficient of 0.98. CONCLUSION: A good correlation between Bhalla scores with spirometry confirmed its usefulness in evaluating and monitoring patients with cystic fibrosis, given it can be used both in patients who are unable to perform spirometry as well as for a pooled analysis of the two examinations since the HRCT scans show early changes in patients with normal function tests.

Correlation between Bhalla score and spirometry in children and adolescents with Cystic Fibrosis / Correlação entre escore de Bhalla e espirometria em crianças e adolescentes com fibrose cística

Objective: to correlate the findings of high resolution computed tomography of the chest based on the Bhalla score with the clinical data and spirometry in children and adolescents with cystic fibrosis, and to study the concordance between two radiologists for the Bhalla score and its categories. Methods: we evaluated the medical records of 23 patients from the outpatient clinic. The items evaluated included age, weight, height, height/age Z-score, weight/age Z-score, body mass index (BMI), O2 saturation, spirometry and Bhalla score. Results: the patients had a mean age of 17.4 years ± 5.7 years, with fifteen females and eight males. There was good correlation between Bhalla score and spirometry (FVC-r =0.718, p<0.001; FEV1-r=0.830, p<0.001; FEF25-75%-r =0.786, p<0.001; FEV1/FVC-r=0.714, p<0.001). It was also noted that some patients with FEF25-75%> 70% already had changes in their final Bhalla score. In the analysis of the concordance between the examiners a Kappa coefficient of 0.81 (p <0.001) was found, and an intraclass correlation coefficient of 0.98. Conclusion: a good correlation between Bhalla scores with spirometry confirmed its usefulness in evaluating and monitoring patients with cystic fibrosis, given it can be used both in patients who are unable to perform spirometry as well as for a pooled analysis of the two examinations since the HRCT scans show early changes in patients with normal function tests. .

Objetivo: correlacionar os achados da tomografia computadorizada de alta resolução (TCAR) do tórax, com base no escore de Bhalla, com os dados clínicos e a espirometria em crianças e adolescentes com fibrose cística (FC), além de estudar a concordância entre dois médicos radiologistas para o escore de Bhalla e suas categorias. Métodos: foram avaliados os prontuários e os exames de 23 pacientes do ambulatório. Os itens avaliados foram idade, peso, altura, escore Z altura/idade, escore Z peso/ idade, índice de massa corpórea (IMC), saturação de O2, espirometria e escore de Bhalla. Resultados: os pacientes avaliados tinham média de idade de 17,4±5,7 anos, sendo 15 do sexo feminino e 8 do sexo masculino. Houve boa correlação entre o escore de Bhalla e a espirometria (CVF-r = 0,718, p < 0,001; VEF1-r = 0,830, p < 0,001; FEF 25-75%-r = 0,786, p < 0,001; VEF1/ CVF-r = 0,714, p < 0,001). Nota-se, ainda, que alguns pacientes com FEF 25-75% > 70% já apresentavam alterações na nota final do escore de Bhalla. Na análise da concordância entre os examinadores, foi encontrado coeficiente kappa de 0,81 (p < 0,001) e coeficiente de correlação intraclasse de 0,98. Conclusão: a boa correlação do escore de Bhalla com as provas de função pulmonar confirma a sua utilidade na avaliação e no acompanhamento dos pacientes com FC, podendo ser utilizado tanto para pacientes que são incapazes de realizar a espirometria quanto para uma análise em conjunto dos dois exames, uma vez que a TCAR mostra alterações precoces em pacientes com espirometrias normais. .

Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis.

OBJECTIVE: To evaluate the diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suspected of having mild or atypical cystic fibrosis (CF). METHODS: This was a cross-sectional study involving adolescents and adults aged > 14 years. Volunteers underwent clinical, laboratory, and radiological evaluation, as well as spirometry, sputum microbiology, liver ultrasound, sweat tests, and molecular analysis of the CFTR gene. We then divided the patients into three groups by the number of mutations identified (none, one, and two or more) and compared those groups in terms of their characteristics. RESULTS: We evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation. The mean age of the patients was 32.5 ± 13.6 years, and females predominated (75.7%). The molecular analysis contributed to the definitive diagnosis of CF in 3 patients (8.1%), all of whom had at least two mutations. There were 7 patients (18.9%) with only one mutation and 26 patients (70.3%) with no mutations. None of the clinical characteristics evaluated was found to be associated with the genetic diagnosis. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H, and p.T351S. CONCLUSIONS: The molecular analysis of the CFTR gene coding region showed a limited contribution to the diagnostic investigation of patients suspected of having mild or atypical CF. In addition, there were no associations between the clinical characteristics and the genetic diagnosis.

Contribuição da análise molecular do gene regulador da condutância transmembrana na fibrose cística na investigação diagnóstica de pacientes com suspeita de fibrose cística leve ou doença atípica / Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis

OBJETIVO: Avaliar a contribuição da análise molecular do gene cystic fibrosis transmembrane conductance regulator (CFTR, regulador da condutância transmembrana na fibrose cística) na investigação diagnóstica da fibrose cística em pacientes com suspeita de fibrose cística (FC) leve ou atípica. Métodos: Estudo transversal em adolescentes e adultos (idade > 14 anos). Os voluntários foram submetidos à avaliação clínica, laboratorial e radiológica; espirometria, microbiologia do escarro, ecografia hepática, teste do suor e análise molecular do gene CFTR. Compararam-se as características dos pacientes divididos em três grupos, segundo o número de mutações identificadas (duas ou mais, uma e nenhuma). Resultados: Foram avaliados 37 pacientes com achados fenotípicos de FC, com ou sem confirmação pelo teste do suor. Houve predomínio do sexo feminino (75,7%), e a média de idade dos participantes foi de 32,5 ± 13,6 anos. A análise molecular contribuiu para o diagnóstico de FC em 3 casos (8,1%), todos esses com pelo menos duas mutações. Houve a identificação de uma e nenhuma mutação, respectivamente, em 7 (18,9%) e 26 pacientes (70,3%). Nenhuma característica clínica estudada se associou com o diagnóstico genético. A mutação p.F508del foi a mais comum, encontrada em 5 pacientes. A associação de p.V232D e p.F508del foi encontrada em 2 pacientes. Outras mutações encontradas foram p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H e p.T351S. Conclusões: A análise molecular da região codificadora do gene CFTR apresentou uma contribuição limitada para a investigação diagnóstica desses pacientes com suspeita de FC leve ou atípica. Além disso, não houve associações entre as características clínicas e o diagnóstico genético.

OBJECTIVE: To evaluate the diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suspected of having mild or atypical cystic fibrosis (CF). METHODS: This was a cross-sectional study involving adolescents and adults aged > 14 years. Volunteers underwent clinical, laboratory, and radiological evaluation, as well as spirometry, sputum microbiology, liver ultrasound, sweat tests, and molecular analysis of the CFTR gene. We then divided the patients into three groups by the number of mutations identified (none, one, and two or more) and compared those groups in terms of their characteristics. RESULTS: We evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation. The mean age of the patients was 32.5 ± 13.6 years, and females predominated (75.7%). The molecular analysis contributed to the definitive diagnosis of CF in 3 patients (8.1%), all of whom had at least two mutations. There were 7 patients (18.9%) with only one mutation and 26 patients (70.3%) with no mutations. None of the clinical characteristics evaluated was found to be associated with the genetic diagnosis. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H, and p.T351S. CONCLUSIONS: The molecular analysis of the CFTR gene coding region showed a limited contribution to the diagnostic investigation of patients suspected of having mild or atypical CF. In addition, there were no associations between the clinical characteristics and the genetic diagnosis.

Eradication therapy for Pseudomonas aeruginosa colonization episodes in cystic fibrosis patients not chronically colonized by P. aeruginosa.

Pseudomonas aeruginosa (Pa) is one of the most common and clinically important pathogens in patients with cystic fibrosis (CF). Chronic Pa colonization in CF patients is associated with increased morbidity and mortality. Pa strains causing early infection are usually antibiotic sensitive and have low bacterial density in the airways. As a result, the treatment strategy has shifted from suppressive therapy in patients chronically colonized by Pa to attempts at early eradication therapy as soon as Pa is detected. In the literature, different treatment regimens have been studied. However, the optimal treatment regimen and duration of treatment are not yet determined. In this article, an overview on the natural history of early Pa colonization and the history of eradication treatment is given. Moreover, the results of the different eradication treatment trials and directions for future research are discussed.

[Genetics and modifier genes, atypical and rare forms]. / Génétique et gènes modificateurs, formes atypiques et rares.

Cystic fibrosis (CF) is defined as the most common life shortening genetic disorder in the Caucasian populations. The cloning of the gene responsible for the disease - the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene - twenty years ago has greatly improved our knowledge of the pathophysiology of CF. That disease is characterized by a highly phenotypic variability and the CFTR mutations cannot explain all the variability observed in the disease severity. The possible influence of the environment and modifier genes has therefore been evocated. Several genetic variants coding for genes involved in the physiopathology of the disease have been studied, like genes involve in the immunity and the inflammatory response. Some of these genes have indeed been shown to influence the disease severity. A new approach has also been developed, analyzing the whole genome. This review summarizes the genetic basis of CF in its classical and atypical forms, as well as the work performed in the field of modifier genes.

[Cystic fibrosis in images: the Bhalla scoring system for computed tomography in paediatric patients]. / Fibrosis quística en imágenes. Clasificación de Bhalla para la tomografía computarizada en pacientes pediátricos.

To monitor the course of lung damage in patients with cystic fibrosis (CF) using the different chest X-ray and high resolution computed tomography (HRCT) scoring systems that have been developed. The HRCT technique is more sensitive than chest radiography to evaluate the anatomy. However, in paediatric patients, the use of CT should be kept to a minimum, and guidelines for radiation protection and dose reduction should be applied. One of the most used classification systems for HRCT is the one proposed by Bhalla in 1991, which helps in the assessment of the severity and course of the disease in these patients depending on the different imaging findings. We present various examples of these criteria for HRCT, observed while reviewing a group of 48 paediatric patients.

Nutrición en el niño con fibrosis quística / Nutrition in children with cystic fibrosis

La fibrosis quística (FQ), es la enfermedad hereditaria más frecuente en la raza blanca. Uno de los objetivos de la intervención nutricional, es lograr el crecimiento y desarrollo adecuados para la edad. Dentro de las funciones del nutricionista, está reflejar investigación reciente, guías clínicas y consensos actualizados. Las técnicas antropométricas para la evaluación del niño con FQ ya están descritas en la literatura. Se considera una situación de prevención, los primeros 12 meses después de haberse realizado el diagnóstico de FQ. Varios son los factores de alarma, entre los que se encuentra el no aumento el peso. En la consulta nutricional se debe evaluar el estado de nutrición de forma periódica para detectar precozmente cambios en su estado y establecer las medidas de prevención y terapéuticas adecuadas.

Cystic fibrosis (CF) is the mot common inherited disease among caucasians. One of the goals of nutritional intervention is to achieve growth and ageappropriate development. The functions of the nutritionist is to reflect recent research, current clinical guidelines and consensus. Anthropometric techniques for the evaluation of children with CF are described in the literatura. It is considered a prevention situation, the first 12 months after the diagnosis of CF.

Requerimientos nutricionales en el niño con fibrosis quística / Nutritional requirements in children with cystic fibrosis

El gasto de energía incrementado en el paciente con FQ se debe a la insuficiencia pancreática, malabsorción de nutrimentos e inflamación. Una adecuada alimentación favorece la síntesis proteica. Los carbohidratos, deben representar el 45 al 50% de la energía total recomendada. Los lípidos, deben representar del 34-40% de la energía total recomendada. Los pacientes con FQ, tienen fibra deficiente. El Consenso Europeo favorece el uso profiláctico de vitaminas que se han descrito como frecuentemente deficientes. Los pacientes con FQ están a riesgo de tener hiponatremia. La deficiencia de hierro es común en FQ por la infección crónica, la inadecuada ingesta de alimentos, la malabsorción de este micronutrimento, y las hemorragias, entre otros. La deficiencia de zinc, puede deberse a la formación de complejos con lípidos y fósforo en caso de existir esteatorrea.

Increased energy expenditure in patients with cystic fibrosis (CF) is due to pancreatic insufficiency, malbsorption of nutrients and inflammation. Adequate nutrition promotes protein synthesis. Carbohydrates should represent 45 to 50% of recommended total energy. Lipids, should represent 34-40% of recommended total energy. CF patients have poor fiber. The European Consensus favors the prophylactic use of vitamins that are often described as por. Patients with CF are at risk for hypnatremia. Iron deficiency is common in CF and chronic infection, inadequate food intake, malabsorption on this micronutrient, and bleeding, among others.

Recommendations for the classification of diseases as CFTR-related disorders.

Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.

Terapia enzimática en alteraciones del páncreas exocrino / Enzyme therapy in exocrine pancreatic disorders

La insuficiencia pancreática (IP) exocrina se manifiesta cuando el páncreas ha perdido alrededor del 98% de sus glándulas. La fibrosis quística (FQ) es la causa más común de IP en los niños, entre el 85% y 90% de ellos requerirá tratamiento con enzimas pancreáticas. La monitorización de la eficacia debe realizarse fundamentalmente observando la respuesta nutricional del paciente y la consistencia de la deposiciones. Se debe reconocer que la respuesta inadecuada al tratamiento en la mayoría de los casos está relacionada con la baja adherencia o la inadecuada toma de las enzimas.

Pancreatic insufficiency (PI) occurs when the exocrine páncreas has lost about 98% of their glands. Cystic fibrosis (CF) is the most common cause of PI in children, between 85% and 90% of them require treatment with pancreatic enzymes. The monitoring of efficacy should primarily be looking at the patient's nutritional response and consistency of stools. If should be recognized tha the inadequate response to treatment in most cases is related to poor adherence or inadequate making enzymes.

Correlación clínica- para-clínica en un escolar con hipertensión porta de etiología a esclarecer / Clinical-paraclinical in a school with portal hypertension to determine

La hipertensión porta (HTP) es el resultado del incremento de la presión dentro del sistema venoso porta. Se presenta con poca frecuencia en el paciente pediátrico pero es una de las mayores causas de morbilidad y mortalidad en el niño con enfermedad hepática. La mayoría de los pacientes con http presentan un estado hiperdinámico, lo cual aumenta el flujo venoso porta y mantiene la hipertensión. Puede ser secundaria a obstrucción a nivel prehepático, intrahepático o extrahehepático.

Portal hypertension (PH) is the result of increased pressure within the portal venous system. It occurs infrequently in the pediatric patient but it is a major cause of morbidity and mortality in children with liver disease. Most patients with PH have a hyperdynamic state, which increases venous flow and portal hypertension remains. May be secondary to obstruction at prehepatic, intrahepatic or extrahehepatic.