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.

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.

[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.

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.

Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

Methylene blue as an electrochemical indicator for DF508 cystic fibrosis mutation detection.

Cystic fibrosis is one of the most common life-shortening, childhood-onset inherited diseases. Among the 1,000 known cystic fibrosis-related mutations, DF508 is the most common, with a frequency varying between 50% and 70% according to geographical areas and population typology. In this work, we report the use of methylene blue as an electrochemical reporting agent in the discrimination of synthetic PCR analogue of the DF508 cystic fibrosis mutation (Mut) from the wild type (Wt). At optimum experimental condition, a discrimination factor between mutant and wild type of approximately 1.5-fold was found. The proposed assay was quantitative and linear in the range of 10-100 nM, exhibiting a limit of detection of 2.64 nM. Electrochemical studies at variable ionic strength conditions allowed further elucidation of the mechanism of the methylene blue (MB)-DNA interaction. To the best of our knowledge, this is the first report of detection of hybridisation solely via guanine-specific MB-DNA interaction simultaneously in MB solution, independent of electrostatic interaction as demonstrated in the ionic strength study. The introduction of formamide in the hybridization buffer, to improve discrimination, was also investigated. Finally, mutant wild type discrimination was demonstrated, at 10 nM concentration, with the use of a multi-sensor setup.

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.

Genetic modifiers of lung disease in cystic fibrosis.

BACKGROUND: Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis. METHODS: We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1. RESULTS: In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02). CONCLUSIONS: Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.

Ontology-based knowledge base model construction-OntoKBCF.

Semantic web technologies are used in the construction of a bio-health knowledge base model, which, when coupled with an Electronic Health Record (EHR), is to be used by clinicians. Specifically, this ontology provides the basis for a domain knowledge resource that attempts to bridge biological and clinical information. The prototype is focused on a Cystic Fibrosis exemplar, and the content of the model includes: Cochrane reviews; a time-oriented description; gene therapy; and the most common cystic fibrosis gene mutations. The facts within the model range from nucleo-base mutation and amino acid change to clinical phenotype. The knowledge is represented by layers from the micro level to the macro level. Here, emphasis is placed upon the details between levels (i.e., the vertical axis) and these are made available to bridge the knowledge from different levels. The description of gender, age, mutation and clinical manifestations are clues for matching points within an EHR system. OWL is the ontology representation language used and the output from Protégé-OWL is a XML-based file format, which facilitates further application and communication.

[Cystic fibrosis: how to use pulmonary function tests]. / Mucoviscidose: du bon usage des explorations fonctionnelles respiratoires.

INTRODUCTION: Neonatal screening for cystic fibrosis (CF) leads to early dedicated specialist care for all patients. BACKGROUND: Pulmonary function tests (PFT) are mandatory for routine monitoring of CF patients. The aim of this article is to review the current guidelines for PFTs in CF, particularly the type of test, the age and the clinical status of the patient. VIEWPOINT: The regular use of spirometry is generally accepted. Many other tests are used but their clinical value in the routine follow-up of CF patients remains to be established. CONCLUSION: Further efforts should be made to evaluate the value of PFTs in CF, particularly in very young children.

Clinical scoring systems in cystic fibrosis.

The first cystic fibrosis (CF) scoring system was published in 1958. Since then, many other scoring systems were developed. Clinical parameters, details about statistical evaluations, and recent strategic uses of scores were identified. Several similar scores aiming to assess chronic illness severity (Shwachman-Kulczycki score and a modification, Cooperman, Berneze-score and the NIH score) have not been evaluated and are out of date, given the changing natural history of CF. Of the current scoring systems, the modified Shwachman score by Doershuk is perhaps most reliable for describing follow-up studies. Scores designed for acute changes and short-term evaluation were also developed. The modified Huang score may be useful in the prognostic evaluation of patients with end-stage disease. It could also be used for discrimination of adult patients with differing disease severity and for longitudinal evaluation. Scores assessing pulmonary exacerbations could help provide consensus among clinicians regarding the need for intervention. Most of these scores require further evaluation. Although scores could provide an objective measure of disease severity, progression, need for and response to interventions, including value in selecting patients for lung transplantation and as an outcome measure for research studies, no scoring system can fulfill all these objectives. Nevertheless, there is a need for the development of a modern day longitudinal score that is sensitive, valid and reproducible, to reflect the milder disease status of patients.

Reproducibility of a scoring system for computed tomography scanning in cystic fibrosis.

INTRODUCTION: Computerized tomography (CT) scanning shows promise as an outcome surrogate for cystic fibrosis (CF) lung disease progression. The scoring system used to convert the CT image to numeric data is an essential determinant of the performance of CT scanning. METHODS: Three radiologists independently scored 16 high-resolution CT scans performed on children in the Wisconsin CF Neonatal Screening Project. The test scans were selected to provide a broad range of disease severity. The scoring system provided subscores for the presence and severity of 5 findings of CF lung disease. The sum of the subscores provided a total score. The CT scans were then read again by each of the radiologists at least 11 months later. Using Mixed Effects Linear Model Analysis, the sources of error (scan-to-scan variation, interrater variance, and intrarater variance) were calculated. RESULTS: For the total score, the scan-to-scan variation was 14.48, interrater variance was 0.28, and intrarater variance was 0.45, with an overall reproducibility of 95%. The square root of scan-to-scan variance, a measure of sensitivity, was 3.81. Evaluation of the subscores showed higher reproducibility for bronchiectasis and hyperinflation (95% and 88%, respectively). The bronchiectasis score was more sensitive than the air-trapping score (1.46 vs. 0.89). DISCUSSION: This system was developed to provide a reproducible method that could be used to evaluate the lobar location, severity, and extent of a broad spectrum of CT features of CF lung disease, especially in children. This study demonstrates that the overall score is both sensitive to variation in the severity of lung disease and reproducible.

[Exhaled nitric oxide: a new biomarker for respiratory pathologies]. / Le monoxyde d'azote exhalé: un nouveau biomarqueur des pathologies respiratoires.

There has been a growing interest for exhaled biomarkers. We review studies examining NO as a potential marker of airway inflammation, enabling noninvasive repeated monitoring of airway inflammation. The measurement technique has been standardized. We have determined the local normal levels for the Liège region. The exhaled NO level is elevated in asthma, and can predict asthma exacerbation. Exhaled NO has a value for the diagnosis of cystic fibrosis and primary ciliary dyskinesia.

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.

The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic pulmonary infection with acute pulmonary exacerbations (APEs) requiring IV antibiotic treatment. We report on a blinded comparative trial of IV meropenem (40 mg/kg to 2 g q8h) or ceftazidime (5 mg/kg to 2 g q8h), each of which was administered with IV tobramycin (at a serum peak of > or = 8 microg/mL and a trough of < 2 microg/mL), as treatment for CF patients with APEs. METHODS: Patients who were > or = 5 years of age who were infected with ceftazidime-susceptible Pseudomonas aeruginosa were stratified by lung function and randomized to treatment with meropenem/tobramycin or ceftazidime/tobramycin. Patients infected with Burkholderia cepacia complex or ceftazidime-resistant P aeruginosa were assigned to receive open-label meropenem/tobramycin. Clinical response was assessed by spirometry to determine the change in percent predicted FEV1 and by a clinical acute change score (ACS). RESULTS: One hundred two patients were randomized to meropenem/tobramycin (n = 50) or ceftazidime/tobramycin (n = 52). Nineteen patients received open-label meropenem/tobramycin. FEV1 was improved at the end of treatment (EOT) with meropenem/tobramycin (mean [+/- SD] increase, 38.8 +/- 52.3%) and with ceftazidime/tobramycin (mean increase, 29.4 +/- 35.1%; p < 0.0001 vs baseline values). The proportion of patients with > or = 15% relative increase from baseline FEV1 (satisfactory response) at day 7 was 62% for the meropenem/tobramycin group and 44% for the ceftazidime/tobramycin group (p = 0.04). The median time to FEV1 response was 4 days for meropenem/tobramycin therapy vs 6 days for ceftazidime/tobramycin therapy. Similarly, FEV1 improved in the open-label group (mean increase, 12.5 +/- 25.7%; p = 0.05). ACS improved in all three groups at EOT (p < 0.0001 vs baseline values). CONCLUSIONS: Therapy with both meropenem/tobramycin and ceftazidime/tobramycin improved pulmonary and clinical status and reduced sputum bacterial burden in CF patients with APEs. A larger proportion of patients receiving meropenem/tobramycin therapy demonstrated a satisfactory FEV1 response at day 7. Resistant P aeruginosa emerged infrequently during treatment with both regimens.

Randomized, double-blind, placebo-controlled, dose-escalating study of aerosolized interferon gamma-1b in patients with mild to moderate cystic fibrosis lung disease.

Interferon gamma-1b (IFN-gamma1b) is a pleiotropic cytokine with immunomodulatory activities that could decrease bacterial burden, inflammation, and obstruction in patients with CF. Patients with CF (> or =12 years old, FEV1 > or =40% predicted) were randomly assigned to sequential dose cohorts inhaling 500 microg IFN-gamma1b, 1,000 microg IFN-gamma1b, or placebo by Respirgard II nebulizer thrice weekly for 12 weeks. Sputum bacterial density and spirometry were measured. Safety, antibiotic use, hospitalization, and sputum neutrophils, elastase, DNA, IL-8, and myeloperoxidase were also evaluated. Sixty-six patients (mean age, 24 years, with mean baseline FEV1 of 74 +/- 20 (SD) percent predicted) were studied. One patient had bronchospasm after the first dose of IFN-gamma1b; the overall withdrawal rate was 15% (5 in the placebo group, 2 in the 500-microg IFN-gamma1b group, and 3 in the 1,000 microg IFN-gamma1b group). The 500-microg IFN-gamma1b dose was well-tolerated, but the 1,000-mug dose cohort, who had a higher baseline bacterial density than placebo patients (mean difference, 1.2 log(10) CFU/g sputum, 95% confidence interval (CI), 0.1,2.8, P=0.04), had 24% more hospitalizations for exacerbation than placebo patients (95% CI, 2,45%, P=0.05). There was a 0.12-l difference between the 500-microg IFN-gamma1b and placebo groups with respect to the 12-week change in FEV1 (active group minus placebo group, 95% CI, -0.03,0.26, P=0.11), as compared to a 0.01-l difference between the 1,000-microg IFN-gamma1b and placebo groups (95% CI, -0.16,0.17, P=0.96). No effects of IFN-gamma1b were seen in sputum bacterial density or inflammatory biomarkers at 12 weeks. Aerosolized IFN-gamma1b did not improve pulmonary function, reduce sputum bacterial density, or affect inflammatory sputum markers in patients with mild-moderate lung disease.

Wisconsin cystic fibrosis chest radiograph scoring system.

A new clinical scoring system for patients with cystic fibrosis is needed because of recent advances in diagnosis and treatment which have changed the course of this disease. Chest radiograph scoring is the best objective measure of pulmonary disease for longitudinal studies beginning with infants; however, based on pilot studies, previous scoring systems are not sensitive enough in discriminating between degrees of mild lung disease. Therefore, a new radiographic scoring system was developed with the goal of achieving both sensitivity and reproducibility. This objective was pursued by applying multiattribute utility theory, using a panel of interpreters with expertise in cystic fibrosis radiology, and employing mathematical modeling techniques to weight the various components. The system was developed and validated in three phases including comparison to the Brasfield method of quantitative radiology. The data demonstrate that the new system can be applied reliably and conveniently to generate reproducible scores of pulmonary disease severity. Evaluation of the scores by four independent raters using chest radiographs from 61 patients at an average age of 8.37 years revealed good agreement with a .714 Kendall coefficient of concordance. Assessment of serial changes over time was performed using a group of 176 chest radiographs from 25 patients ranging from 4 weeks to 6 years old; this showed that the Wisconsin system generates score differences that are greater in magnitude with disease progression compared with the Brasfield method. Therefore, the new method is more sensitive to progression of mild disease and should be superior to prior radiographic scoring systems for evaluating therapies designed to modify the early course of disease. The Wisconsin system is designed to be useful in longitudinal clinical studies involving young children with cystic fibrosis and is capable to detecting progression from normality to mild lung disease.

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV-2c/KM19 B haplotype.

We have reinvestigated a classification of clinical heterogeneity among cystic fibrosis (CF) patients that we previously reported and investigated the possible relationship of the identified CF subgroups to haplotypes around the CF gene and to HLA-DR haplotypes. Age-corrected values for sweat electrolytes, rate of progression of lung disease as assessed by Brasfield chest x-ray scores, and severity of pancreatic insufficiency as assessed by daily supplemented enzyme dosage were obtained for 55, 59, and 59 patients, respectively. XV-2c and KM19 RFLPs were determined by hybridization to TaqI and PstI digests of human genomic DNA, respectively, and analysis of mutations by PCR amplification followed by allele-specific oligo-deoxynucleotide hybridization was performed for 29 patients. HLA-DR restriction fragment length polymorphisms (RFLPs) were determined by hybridization of cDNA beta 1 and genomic DQ alpha probes to TaqI digests of human genomic DNA. The results show that the previous subdivision on the basis of age-corrected levels of sweat electrolytes, as well as measures of severity of lung disease and pancreatic disease, is valid. In addition, the C and D haplotypes are associated with lower age-corrected sweat sodium level. No significant relationship between CF haplotypes and the other two disease variables or between HLA-DR haplotypes and any of the clinical variables was found.

Hidden depletion of fat-free mass and bone mineral density in adults with cystic fibrosis.

BACKGROUND: Weight loss is associated with reduced survival in patients with cystic fibrosis (CF). OBJECTIVE: We hypothesized that some adult patients with a normal body mass index (BMI) have evidence of hidden fat-free mass (FFM) and bone mineral density (BMD) depletion that is linked to more severe disease. DESIGN: Fat mass (FM), FFM, and BMD were determined by dual-energy x-ray absorptiometry (DXA) and by bioelectric impedance in 56 adults in clinically stable condition and 20 age-matched healthy subjects. FM index and FFM index (FFMI) [kilograms per meter squared] of the right arm, leg, and trunk (ratio to height squared) were calculated. Lung function, including the maximum inspiratory pressure (MIP) and sustained MIP (SMIP), physical activity, serum C-reactive protein (CRP) and the number of exacerbations in the previous year were recorded. RESULTS: Patients had a lower total FFM than healthy subjects (p < 0.01), while FM was similar. Of the 56 patients, 30 patients had a normal BMI, of which 12 patients had a low FFM (hidden loss) by DXA. The right arm, leg, and trunk FFMI and BMD at hip sites were less in these patients than in those with a normal BMI and normal FFM (all p < 0.01). This group had a lower FEV(1), SMIP, more frequent exacerbations, and greater circulating CRP (all p < 0.05). CONCLUSIONS: In adults with CF, apparent or hidden loss of FFM, rather than weight loss, was related to overall disease severity. Hidden depletion of FFM was associated with increased loss of BMD and systemic inflammatory activity.