Young adults with cystic fibrosis have altered trabecular microstructure by ITS-based morphological analysis.

UNLABELLED: Young adults with cystic fibrosis have compromised plate-like trabecular microstructure, altered axial alignment of trabeculae, and reduced connectivity between trabeculae that may contribute to the reduced bone strength and increased fracture risk observed in this patient population. INTRODUCTION: The risk of fracture is increased in patients with cystic fibrosis (CF). Individual trabecular segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography (HR-pQCT) images segments trabecular bone into individual plates and rods of different alignment and connectivity, which are important determinants of trabecular bone strength. We sought to determine whether alterations in ITS variables are present in patients with CF and may help explain their increased fracture risk. METHODS: Thirty patients with CF ages 18-40 years underwent DXA scans of the hip and spine and HR-pQCT scans of the radius and tibia with further assessment of trabecular microstructure by ITS. These CF patients were compared with 60 healthy controls matched for age (±2 years), race, and gender. RESULTS: Plate volume fraction, thickness, and density as well as plate-plate and plate-rod connectivity were reduced, and axial alignment of trabeculae was lower in subjects with CF at both the radius and the tibia (p < 0.05 for all). At the radius, adjustment for BMI eliminated most of these differences. At the tibia, however, reductions in plate volume fraction and number, axially aligned trabeculae, and plate-plate connectivity remained significant after adjustment for BMI alone and for BMI and aBMD (p < 0.05 for all). CONCLUSIONS: Young adults with CF have compromised plate-like and axially aligned trabecular morphology and reduced connectivity between trabeculae. ITS analysis provides unique information about bone integrity, and these trabecular deficits may help explain the increased fracture risk in adults with CF not accounted for by BMD and/or traditional bone microarchitecture measurements.

Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium.

A phase I clinical trial was conducted in which recombinant adenovirus containing the cystic fibrosis trans-membrane regulator (CFTR) (Ad2/CFTR) was administered by bronchoscopic instillation or aerosolization to the lungs of cystic fibrosis (CF) patients. In this paper, we evaluate the efficiency of Ad2/CFTR-mediated transduction of bronchial airway cells. The ability of an Ad2/CFTR vector to transduce airway cells was first evaluated in patients to whom the vector was administered by bronchoscopic instillation. Cells at the administration site were collected 2 days after treatment by bronchoscopic brushing. Ad2-specific CFTR DNA was detected in four of five individuals by PCR, and Ad2-specific CFTR RNA was detected in three of five individuals by RT-PCR. Ad2/CFTR-mediated transduction of airway epithelial cells was then determined in CF individuals receiving this vector by aerosol inhalation. Ad2-specific CFTR DNA was detected in 13 of 13 individuals 2 days after aerosolization, and in 3 of 5 individuals 7 days after aerosolization. Ad2-specific RNA was detected in 4 of 13 individuals on day 2, but was not detected in the 5 individuals tested on day 7. The percentage of airway epithelial cells containing nuclear-localized vector DNA was < or =2.4% as determined by fluorescence in situ hybridization (FISH). However, in some cases, a high percentage of nonepithelial mononuclear cells or squamous metaplastic epithelial cells was infected with the adenoviral vector. In conclusion, aerosol administration is a feasible means to distribute adenoviral vectors throughout the conducting airways, but improvements in adenovirus-mediated transduction of airway epithelial cells are necessary before gene therapy for CF will be effective.

Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications.

Cystic fibrosis (CF), an autosomal recessive disorder resulting from mutations in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene, is the most common lethal genetic illness in the Caucasian population. Gene transfer to airway epithelium, using adenoviruses containing normal CFTR cDNA, leads to transient production of CFTR mRNA and, in some studies, to correction of the airway epithelial ion transport defect caused by dysfunctional CFTR. Inflammatory responses to the adenoviral vector have been reported, particularly at high viral titers. We evaluated the effects of adenovirus-mediated CFTR gene transfer to airway epithelium in 36 subjects with CF (34 individuals, 2 of whom received two separate doses of vector), 20 by lobar instillation and 16 by aerosol administration. Doses ranged from 8 x 10(6) to 2.5 x 10(10) infective units (IU), in 0.5-log increments. After lobar administration of low doses there were occasional reports of cough, low-grade temperature, and myalgias. At the highest lobar dose (2.5 x 10(9) IU) two of three patients had transient myalgias, fever, and increased sputum production with obvious infiltrates on CT scan. After aerosol administration there were no significant systemic symptoms until the 2.5 x 10(10) IU dose, when both patients experienced myalgias and fever that resolved within 24 hr. There were no infiltrates seen on chest CT scans in any of the patients in the aerosol administration group. There were no consistent changes in pulmonary function tests or any significant rise in serum IgG or neutralizing antibodies in patients from either group. Serum, sputum, and nasal cytokines, measured before and after vector administration, showed no correlation with adenoviral dose. Gene transfer to lung cells was inefficient and expression was transient. Cells infected with the vector included mononuclear inflammatory cells as well as cuboidal and columnar epithelial cells. In summary, we found no consistent immune response, no evidence of viral shedding, and no consistent change in pulmonary function in response to adenovirus-mediated CFTR gene transfer. At higher doses there was a mild, nonspecific inflammatory response, as evidenced by fevers and myalgias. Overall, vector administration was tolerated but transfer of CFTR cDNA was inefficient and transgene expression was transient for the doses and method of administration used here.

Adolescents with cystic fibrosis: family reports of adolescent health-related quality of life and forced expiratory volume in one second.

PURPOSE: To assess the relationship between adolescent and parent reports of adolescent health-related quality of life (HRQL) and between adolescent pulmonary function (forced expiratory volume in 1 second as percent of predicted) and reporter perceptions of adolescent health. METHODS: Twenty-four adolescents with cystic fibrosis (CF), their mothers, and their fathers completed the Child Health Questionnaire during routine CF clinic visits at 2 urban hospitals. Patients were between the ages of 11 and 18 years (mean age: 14.2 years) and were predominantly male (75%). The best measure of forced expiratory volume in 1 second as percent of predicted for the year of the study was also collected for each adolescent. RESULTS: Adolescent pulmonary function was related to the perceived adolescent physical health scales. It was not, however, associated to perceptions of adolescent emotional, social, or behavioral HRQL by any of the 3 family reporters. Associations were found between adolescent pulmonary function and self-reports of general health (0.73), role/social limitations-physical (0.47), and bodily pain (0.42). Adolescent pulmonary function was related to mother reports of adolescent general health (0.73), role/social limitations-physical (0.73), bodily pain (0.55), and physical functioning (0.70). Father perceptions of adolescent health were associated to adolescent pulmonary function on general health (0.54), role/social limitations-physical (0.60), and physical functioning (0.64). Associations between adolescent and parent perceptions of adolescent HRQL were also health scale-specific. Mother and child reports of adolescent HRQL were related on adolescent behavior problems (0.71) and role/social limitations attributable to behavior (0.48), role/social limitations attributable to physical (0.62), bodily pain (0.69), physical functioning (0.69), family activities (0.45), and general health (0.66). Associations were found between father and adolescent reports on perceived adolescent behavior problems (0.66); self-esteem (0.65); and role/social limitations attributable to physical (0.49), general health (0.61), and perceived mental health (0.48). CONCLUSIONS: Results demonstrate the need to include multiple informants and comprehensive, multidimensional measures of HRQL, in addition to pulmonary function, when assessing health in adolescents with CF.

Increased circulating levels of plasma ATP in cystic fibrosis patients.

Recent studies have shown that the cystic fibrosis transmembrane conductance regulator (CFTR), an ATP-binding cassette (ABC) transporter whose mutations are responsible for cystic fibrosis (CF), permeates ATP. However, little information is available concerning extracellular ATP concentrations in CF patients. Thus, the goal of this preliminary study was to determine the circulating levels of plasma ATP in CF patients. Circulating levels of plasma ATP were determined by the luciferin-luciferase assay in both CF patients and healthy volunteer control subjects. The two groups were compared using an analysis of variance. CF genotype and age, which ranged from 7 to 56 years, were also used to compare data by single-blind analysis. With comparable sample numbers, CF patients had statistically higher levels of circulating ATP (34%, P<0.01) when compared by analysis of covariance with the age of the subjects as the cofactor. The CF patients bearing the DeltaF508 genotype had a 54% (n=33, P<0.01) higher plasma ATP concentration compared to controls, while patients bearing other CF genotypes were similar to controls (n=10, P<0.4). We conclude that CF patients have higher circulating levels of ATP when compared to controls. Increased levels of plasma ATP, which is an important autocrine/paracrine hormone in many cell types, may be associated with chronic manifestations of the disease.

Parent and child mealtime behavior in families of children with cystic fibrosis.

OBJECTIVES: We investigated the hypothesis that children with cystic fibrosis (CF) and their parents would show more maladaptive behaviors during dinner than children without CF and their parents. STUDY DESIGN: Children with CF (n = 32) and their parents were compared with 29 children without CF and their parents on the rate and frequency of parent-child behaviors during a typical dinner in the families' homes by using multivariate analyses of variance. RESULTS: When the rate of behavior, controlling for meal length, was examined, no differences were found between groups. However, parents of children with CF were found to differ from parents of control subjects in the frequency of direct and indirect commands (P <.05), coaxes (P <.01), physical prompts (P <.01), and feeding their child (P <.05). Children with CF were found to engage in more talk, spend more time away from the table, refuse food, and exhibit more noncompliance toward commands to eat than control children (P <.05 for all child variables). When behaviors were examined as a function of meal phase, parents of children with and without CF both showed an increase in commands (P <.01), coaxes (P <.05), feeds (P <.01), and physical prompts (P <.01) in the second half of the meal as compared with the first. Children with CF and the control children showed an increase in behaviors incompatible with eating during the second half of the meal compared with the first (P <.01). When faster eaters were compared with slower eaters, faster eaters consumed a higher percentage of the recommended daily allowance of energy (P <.01) than slower eaters and showed a trend to be at higher weight percentiles for age and sex (P =.08) regardless of group (CF or control). CONCLUSIONS: Children with CF and their parents do not differ from children without CF and their parents in the rate of behaviors exhibited or types of strategies used to encourage eating. However, children with CF and their parents engage in these behaviors more frequently. Our data do not support typical parenting behaviors as effective in meeting the CF dietary requirements. Additional support in the form of child behavior management training may be needed to assist parents in meeting their child's caloric requirements.

Descriptive analysis of eating behavior in school-age children with cystic fibrosis and healthy control children.

STUDY OBJECTIVE: To investigate calorie intake, behavioral eating styles, and parent perception of eating behavior of school-age children with cystic fibrosis (CF) compared with healthy peers. DESIGN: A two-group comparison study. SETTING: A clinical sample of 28 school-age children with CF and a community sample of 28 healthy peers matched for age (6 to 12 years) and socioeconomic status. MEASUREMENTS AND MAIN RESULTS: The children with CF consumed more calories per day (2175 cal/d) than the control children (1875 cal/d) and achieved a significantly higher recommended daily allowance (RDA) of energy (128% of the RDA) than the control children (91.61% of the RDA). Fifty-four percent of the CF sample were achieving the CF dietary recommendations of 120% of the RDA. Despite this energy intake, the CF sample was significantly below the control sample on weight (24.56 vs 31.23 kg), height (125.48 vs 133.06 cm), and z score for weight (-0.811 vs 0.528) and height (-0.797 vs 0.371). On measures of behavioral eating style, the CF sample had significantly longer meals (23.90 min) than the control sample (17.34 min) and had a significantly slower pace of eating (43.27% 10-second intervals with bites) than the control sample (51.29% 10-second intervals with bites) but did not differ significantly on the number of calories consumed during dinner. On a measure of parent report of mealtime behaviors, parents of the children with CF rated mealtime behavior problems of "dawdles" and "refuses food" as more intense (mean, 3. 46) than did the parents of control children (mean, 2.67). For the CF sample, a significant correlation was found between the parent intensity ratings of problem behavior in general and meal duration (r = .48), and a significant negative correlation was found between the parent intensity ratings of problem mealtime behaviors and the percentage of intervals with bites (pace of meal) (r = -.533). CONCLUSIONS: Although the school-age children with CF were consuming more calories per day than their healthy peers, and more than 50% of the children in the CF sample were at or above the CF dietary recommendations, the children in the CF sample were significantly below the control children on measures of weight and height. The behavioral data suggest that increased caloric intake is not without cost, because the CF sample spent an additional 7 minutes per day at dinner and ate their meals at a slower pace than their healthy peers. These data were associated with higher intensity ratings of mealtime behaviors by parents of children with CF. These findings point to the need for individualized assessment of energy needs for school-age children with CF and comprehensive programs that teach parents behavioral strategies to motivate their children to meet these higher energy requirements in an adaptive manner.

Follicular bronchitis in the pediatric population.

Five patients in a pediatric population were identified with idiopathic follicular bronchitis (IFB) by open lung biopsy and their case records were reviewed. All were tachypneic and had a chronic cough by 6 weeks of age. The physical examination was characterized by diffuse fine crackles in four patients and by coarse rhonchi in one. The chest radiographs in all demonstrated a diffuse interstitial pattern. None had a collagen vascular or an autoimmune disease demonstrable. Response to corticosteroid therapy was minimal. Associated or coincidental esophageal reflux was treated surgically in two. No viral or bacterial agents were isolated in the sputum or the biopsy specimens. Patients have been followed up for 2 to 15 years; the conditions of all patients improved at about 2 to 4 years of age. The older patients have residual mild obstructive lung disease. To our knowledge, this is the first reported series of IFB in the pediatric population.

Combined immunodeficiency associated with xeroderma pigmentosum.

We report a 15-month-old boy with xeroderma pigmentosum, a history of repeated infections, and immune deficiency who developed a fatal pneumonia with parainfluenza type 1. Immunologic evaluation revealed a severe combined immunodeficiency with hypoglobulinemia, C3 deficiency, anergic response to skin testing, and an abnormal lymphocytic response to mitogens. We suggest that patients with xeroderma pigmentosum be evaluated carefully for immune deficiencies, should repeated infections occur.

Does lithium carbonate affect the ion transport abnormality in cystic fibrosis?

Lithium is known to affect several aspects of cellular regulation which may be related to ion channel function in epithelial cells. To determine whether the ion transport abnormality in cystic fibrosis (CF) is affected by lithium with resultant changes in clinical status, 36 CF patients, 12-37 years old, were enrolled in a 14 week, double-blind, placebo-controlled trial. Eighteen patients were randomly assigned to receive lithium carbonate for 10 weeks. At the end of therapy their average serum lithium concentration was 0.56 +/- 0.06 mmol (SEM) per liter. Their sweat chloride concentration fell from 92.1 +/- 4.8 mmol per liter to 87.4 +/- 4.0 mmol per liter after 10 weeks of therapy (P = 0.07) and rose to 94.4 +/- 3.5 mmol per liter 4 weeks after end of therapy (P less than 0.001 compared to results at end of therapy). Their forced vital capacity (FVC) fell from 72 +/- 5.3% of predicted to 66 +/- 5.1% of predicted after 4 weeks of therapy (P less than 0.01), and their forced expiratory volume in one second (FEV1) fell from 56 +/- 5.5% of predicted to 51 +/- 5.5% of predicted after 4 weeks of therapy (P less than 0.01). In a non-blind assessment, performed 19 weeks after the end of therapy, their FVC and FEV1 had risen and were not significantly different from baseline. Sweat chloride, FVC, and FEV1 remained unchanged in the placebo group throughout the period of study.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral abductor paresis masquerading as asthma.

Rare upper airway lesions may be mistaken for asthma. A 16-year-old Hispanic male athlete presented to our allergy clinic with a 4-month history of wheezing and snoring with hoarseness and progressive fatigue on exertion or during sleep. His mother taped periods of harsh stridor and sleep apnea. There was no family history of vocal cord abnormalities. A year before the onset of symptoms, he suffered injury to his oral cavity with a loss of consciousness during a wrestling match. He denied dysphagia or dysphonia. He failed to respond to bronchodilators, cromolyn, or prednisone therapy during 4 weeks. On referral to our clinic, his physical examination and tape recording were characterized by harsh inspiratory stridor. His pulmonary function tests were significant for peak flow depressed out of proportion to FEV1 with reduced FVC, no response to bronchodilator, and flattened inspiratory loop unresponsive to cough or panting. Fluoroscopy and endoscopy of the upper airway was consistent with "marked bilateral limitation of vocal cord abduction." Sleep study demonstrated desaturation with CO2s in the 60s during sleep. He was started on continuous positive airway pressure, 10 cm at night, with no desaturation or sleep disturbance on follow-up.

Kartagener's syndrome. A blinded, controlled study of cilia ultrastructure.

We investigated respiratory mucosa cilia ultrastructure in patients homozygous for the gene for Kartagener's syndrome (KS) and patients apparently phenotypic for KS who had bronchiectasis and sinusitis but without situs inversus. Parents, as obligate carriers of the recessive KS gene, were also evaluated among other control groups. The four patients with KS had significantly fewer cilia outer dynein arms than normal subjects or parents of patients with KS. Two of five patients apparently phenotypic for KS demonstrated distinctive ultrastructural changes. No other subjects demonstrated explicit ultrastructural abnormalities. Internal control specimens showed that the number of outer dynein arms was consistent within a subject compared with variation between subjects. The outer dynein arm serves as a dependable ultrastructural marker. Carriers of KS do not demonstrate distinctive morphologic cilia abnormalities. Not every patient with chronic bronchiectasis and sinusitis demonstrates abnormal cilia ultrastructure.

Role of clotting factor(s) in the etiology of lung disease related to ciliostasis.

Mucociliary experiments conducted in vitro using avian tracheal rings show that serum from both normal and cystic fibrosis patients will cause ciliostasis in airways. The evidence suggests that endogenous mucus is not inhibitory to cilia and that inhibition observed with serum is due to blood clotting factors (probably fibrin), since a variety of anticoagulants and fibrin-destroying substances will either prevent or reverse the inhibitory effects of serum. Because fibrin and serum are normally found in the lung, we propose that an early event in the pathogenesis of many lung diseases (e.g., asthma, some forms of emphysema, cystic fibrosis), is an increase in the level of clotting factors in the respiratory tract. Based on these results, we provide a rationale for investigating the usefulness of a number of pharmacologic agents in the treatment of diseases related to mucostasis.

Altered membrane sodium transport in Bartter's syndrome.

To explore the possibility that Bartter's syndrome is the manifestation of an inherited abnormality of sodium transport, we have measured various parameters of sodium transport in erythrocytes from patients with Bartter's syndrome, their siblings, and their parents. Sodium transport in six of the eight patients with Bartter's syndrome differed significantly from that in the other two patients. On the basis of this difference, the patients were divided into two groups (type I and type II). In the six type I patients, fractional sodium outflux (0.38+/-0.05/hr [SD]) was significantly less than normal (0.50+/-0.07) and erythrocyte sodium concentration (9.48+/-0.84 mmoles/liter cells per hr) was significantly greater than normal (5.24+/-0.66). In the two type II patients, none of the measured parameters of sodium transport differed significantly from normal. Erythrocyte sodium transport in the relatives of three type I patients was altered in a way similar to that in the type I patients and was significantly different from that in the relatives of a type II patient. These findings indicate the presence of inherited alterations of erythrocyte sodium transport in certain patients with Bartter's syndrome.

Abnormal membrane sodium transport in Liddle's syndrome.

We have documented the presence of abnormal sodium transport in Liddle's syndrome by measuring sodium concentration, sodium influx, and fractional sodium outflux in vitro in erythrocytes from normal subjects, two patients with Liddle's syndrome, and one patient with primary hyperaldosteronism. Sodium influx and fractional sodium outflux, but not sodium concentration, were significantly increased in patients with Liddle's syndrome. Sodium outflux in a patient with primary hyperaldosteronism did not differ significantly from normal. These alterations of sodium transport in erythrocytes from patients with Liddle's syndrome were not attributable to circulating levels of aldosterone, renin, angiotensin, or serum potassium. Furthermore, changes in aldosterone secretory rate and levels of circulating renin produced by varying dietary sodium intake, did not alter sodium influx or fractional sodium outflux in either patients with Liddle's syndrome or normal subjects. The response of fractional sodium outflux and sodium influx to ouabain, ethacrynic acid, and to changes in the cation composition of the incubation medium suggests that the increased sodium fluxes in Liddle's syndrome do not result solely from a quantitative increase in those components of sodium transport which occur in normal human erythrocytes. Instead, at least a portion of the increased erythrocyte sodium transport in Liddle's syndrome represents a component of sodium transport which does not occur in normal human erythrocytes.