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Biomedical subjects

F J Accurso

Publications and source records attributed to F J Accurso.

At least 19 recordsLinked to original sources
PubMed2004

Linkage of neutrophil serine proteases and decreased surfactant protein-A (SP-A) levels in inflammatory lung disease.

BACKGROUND: In patients with cystic fibrosis (CF) neutrophils are recruited in excess to the airways yet pathogens are not cleared and the patients suffer from chronic infections. Recent studies have shown a deficiency in airway fluids from patients with CF and other inflammatory pulmonary conditions of surfactant protein A (SP-A), a pattern recognition molecule that facilitates uptake of microbes by macrophages and neutrophils. METHODS: In vitro simulations were used to test the hypothesis that decreased SP-A levels in CF might be the result of degradation by neutrophil serine proteases. RESULTS: Very low levels of the neutrophil granule serine proteases cathepsin G, elastase, and proteinase-3 rapidly degraded pure SP-A when tested in buffered saline. The order of potency was cathepsin G>elastase>proteinase-3. The addition of cathepsin G or elastase to normal bronchoalveolar lavage (BAL) fluid caused a dose dependent degradation of endogenous native SP-A. Cathepsin G and elastase were present in the BAL fluid from many patients with CF. Simple incubation of protease positive BAL fluid from patients with CF caused a time dependent degradation of added SP-A or, where present, endogenous SP-A. The degradation of SP-A by protease(s) in BAL fluid of patients with CF was abrogated by diisopropylfluorophosphate and monocyte/neutrophil elastase inhibitor. CONCLUSIONS: The findings strongly suggest that the neutrophil serine proteases cathepsin G and/or elastase and/or proteinase-3 contribute to degradation of SP-A and thereby diminish innate pulmonary antimicrobial defence.

Adolescent↗
PubMed2002

Longitudinal investigation of energy expenditure in infants with cystic fibrosis.

OBJECTIVE: To determine when energy expenditure becomes elevated in infants with cystic fibrosis (CF). DESIGN: Longitudinal studies of total energy expenditure (TEE) using doubly labeled water were conducted in infants identified with CF by newborn screening through the first year of life. SETTING: Hospital and community based studies in Denver, Colorado, USA and Cambridge, UK. RESULTS: Eight of the 12 infants enrolled had begun enzyme therapy but were clinically asymptomatic. Four of the 12 infants were heterozygous for the delta F508 mutation, however no difference was seen in TEE from the remaining homozygous infants. TEE was compared to control cohorts at 2, 6 and 12 months of age. There was no difference from the control groups in TEE/kg fat free mass (FFM)/day at 2 months. However, by 6 months of age TEE/kg FFM/day in infants with CF exceeded that of age-matched controls by 25% (P<0.001). This elevation in TEE continued at 12 months of age exceeding that of controls by 30% (P<0.05). CONCLUSIONS: These results indicate that infants with CF have increased energy needs by 6 months of age and that early diagnosis alone does not prevent the development of increased caloric requirements. These findings emphasize the need for close nutritional monitoring to prevent suboptimal growth during infancy in this population. SPONSORSHIP: This research was supported by grant number 5 MO1 RR00069, General Clinical Research Centers Program, National Center for Research Resources, NIH.

Anthropometry↗
PubMed2001

Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction.

A noninvasive method to characterize inflammation and infection in the airways of nonexpectorating children with cystic fibrosis (CF) is needed for clinical and research purposes. Accordingly, we performed sputum inductions by administering 3% saline to 11 healthy control children and 20 children with CF, composed of 7 sputum producers (capable of spontaneously expectorating sputum) and 13 nonproducers. Induced sputum weights were comparable in each group, whereas the amount of induced sputum collected from the CF producers was over 10-fold higher than the spontaneously expectorated samples. We found a significant increase in indices of airway inflammation, including total cell counts, absolute neutrophil counts, interleukin-8 (IL-8) levels, and neutrophil elastase activity in the CF subjects compared with the healthy control subjects. These same indices in the induced sputum specimens from CF producers were significantly correlated with levels in the matched expectorated sputum specimens. Sputum total protein concentration was elevated in the CF groups, whereas urea and albumin levels were not significantly different. Salivary analysis, performed separately, revealed higher levels of IL-8 and total protein in the CF groups. Airway infection, as assessed by quantitative counts of CF-related bacterial pathogens, was also higher in the CF subjects. The same bacterial pathogens, in similar colony counts, were isolated from both the induced and expectorated sputum samples from the CF producers. We conclude that airway inflammation and infection, assessed through sputum induction, are significantly increased in children with CF as compared with healthy children. Furthermore, induced sputum samples are similar to spontaneously expectorated samples in describing both inflammation and infection in the CF airway.

Child↗
PubMed2001

Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: a pilot study.

Inhaled corticosteroids are commonly used in cystic fibrosis (CF), but there are few studies evaluating their safety in young children. We, therefore, prospectively administered beclomethasone diproprionate (BDP) to 12 clinically stable young children with CF to examine the safety of this therapy with respect to adrenal suppression and airway infection. To determine potential mechanisms of corticosteroid action in CF, we also examined airway markers of inflammation before and after inhaled steroid treatment. BDP 210 microg twice a day was given via spacer for 2 months. Twelve-hour serum and urine cortisols and response to low-dose synthetic ACTH cortisol stimulation were assessed. Bronchoalveolar lavage fluid (BALF) was examined pre- and posttreatment with BDP by quantitative bacteriology and indices of airway inflammation, including levels of total neutrophils, neutrophil elastase-alpha-1 antiprotease complexes (NEAP), CA 19-9 mucin-associated antigen, interleukin-8 (IL-8), and macrophage IL-8 mRNA. Following 2 months of treatment, serum and urine cortisol levels were unchanged. Response to low-dose ACTH cortisol stimulation was not significantly decreased at 30 min. Posttreatment BALF bacterial density was not statistically different from pretreatment; however, one patient who was initially culture negative became culture-positive with Hemophilus influenzae. BALF total neutrophil counts, corrected for epithelial lining fluid dilution, were decreased to approximately one third of pretreatment values (P = 0.03). NEAP and CA 19-9 mucin-associated antigen demonstrated similar decreases. BALF IL-8 levels and macrophage IL-8 mRNA levels were not statistically changed. These findings suggest that treatment with BDP 420 microg per day for 2 months in young children with CF does not affect urine and blood cortisol, causes no decrease in adrenal reserve, and does not result in a clinically significant increase in airway infection. In addition, the fall in bronchoalveolar lavage fluid inflammatory markers following BDP suggests possible modulation of neutrophil influx into the CF airway and provides justification for further studies of inhaled corticosteroids in CF.

Administration, Inhalation↗
PubMed2001

Comparison of high-frequency chest wall oscillation and oscillating positive expiratory pressure in the home management of cystic fibrosis: a pilot study.

Enhanced airway clearance is thought to result in better-maintained pulmonary function in cystic fibrosis (CF). Postural drainage, percussion, and vibration (PDPV) have been the primary airway clearance technique (ACT) employed in CF for over 40 years. Two new airway clearance modalities are high-frequency chest wall oscillation (HFCWO) and oscillating positive expiratory pressure (OPEP). This pilot study was undertaken to evaluate the efficacy of these techniques during home use, assess patient satisfaction with them as compared to PDPV, and assess the feasibility of performing a definitive comparative trial. The prospective, randomized, multicenter crossover trial was conducted at three urban academic CF Care Centers. Twenty-nine CF patients, 9-39 years of age, participated. Subjects performed 4 weeks each of HFCWO and OPEP following 2-week lead-in/washout periods. Spirometry, lung volumes, National Institutes of Health and Petty Scores, and a satisfaction survey were performed at baseline and after each treatment period. An ACT preference survey was completed at the conclusion of the study. Twenty-four subjects completed both therapies. There were no statistically significant differences between therapies for spirometry, lung volumes, or clinical scores. No significant safety issues arose during the study period. Compliance between therapies was similar. Significant differences among therapies existed in patient satisfaction. Given a choice of therapy, 50% of subjects chose HFCWO, 37% OPEP, and 13% PDPV. This study suggests that HFCWO and OPEP are safe and as effective as patients' routine therapies when used for airway clearance in a home setting. Patient satisfaction and preference differ among ACTs and should be considered when prescribing home therapy. A definitive, multi-center, comparative study evaluating long-term efficacy of these techniques is feasible.

Adolescent↗
PubMed2000

Abnormalities in zinc homeostasis in young infants with cystic fibrosis.

Low plasma zinc concentrations have been reported in approximately 30% of young infants with cystic fibrosis identified by newborn screening. The objective of this study was to examine zinc homeostasis in this population by application of stable isotope methodology. Fifteen infants with cystic fibrosis (9 male, 6 female; 7 breast-fed, 8 formula-fed) were studied at a mean (+/-SD) age of 1.8 +/- 0.7 mo. On d 1, 70Zn was administered intravenously, and 67Zn was quantitatively administered with all human milk/formula feeds during the day. Three days later, a 3-d metabolic period was initiated, during which time intake was measured and complete urine and fecal collections were obtained. Fractional zinc absorption, total absorbed zinc, endogenous fecal zinc, and net absorbed zinc were measured; fecal fat excretion was also determined. Fractional absorption was significantly higher for the breast-fed infants (0.40 +/- 0.21) compared with the formula-fed group (0.13 +/- 0.06) (p = 0.01), but with the significantly higher dietary zinc intake of the formula-fed group, total absorbed zinc was higher for those receiving formula (p = 0.01). In 1 infants with complete zinc metabolic data, excretion of endogenous zinc was twofold greater for the formula-fed infants (p < 0.05); net absorption (mg zinc/d) was negative for both feeding groups: -0.04 +/- 0.52 for breast-fed; -0.28 +/- 0.57 for formula-fed. Endogenous fecal zinc losses correlated with fecal fat excretion (r = 0.89, n = 9, p = 0.001), suggesting interference with normal conservation of endogenously secreted zinc. These findings indicate impaired zinc homeostasis in this population and suggest an explanation for the observations of suboptimal zinc status in many young infants with cystic fibrosis prior to diagnosis and treatment.

Administration, Oral↗
PubMed1999

Infant lung function after inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn.

Our objectives were to determine whether the use of inhaled nitric oxide (iNO) for severe persistent pulmonary hypertension of the newborn (PPHN) causes impaired lung function during infancy. We therefore performed a prospective study of lung function in 22 infants after neonatal intensive care unit (NICU) discharge who had been treated for severe persistent pulmonary hypertension of the newborn (PPHN) with (n = 15) or without (n = 7) iNO, and compared these findings in lung function to those of healthy control infants (n = 18). Five infants with interstitial lung disease (ILD) were included to assure that the pulmonary function tests (PFT) were sensitive enough to detect abnormalities of lung function in this age group. We measured passive respiratory mechanics and functional residual capacity (FRC) using a commercially available system. All data were expressed as means and standard deviation. Statistical analysis was performed by analysis of variance (ANOVA). A Bonferroni multiple comparisons test was used for variables that showed overall group differences. Twenty-two infants were studied during follow-up 4-12 months after NICU discharge. None of the infants were actuely ill, and only one infant was on 0.25 L of oxygen per minute at the time of study. We found no differences in lung function between the treatment groups (iNO + mechanical ventilation (MV), or MV alone), or between either treatment group and healthy control infants of the same age. We were able to detect significant differences in functional residual capacity adjusted for weight or height, and compliance of the respiratory system adjusted for weight or lung volume in the ILD infants compared to the healthy controls or infants who had PPHN, indicating that these PFTs were sensitive enough to determine abnormal lung function in this age group. We conclude that inhaled nitric oxide therapy for the treatment of severe PPHN does not alter lung function as determined by lung volume and passive respiratory mechanics measurements during early infancy.

Administration, Inhalation↗
PubMed1999

Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen.

OBJECTIVE: To prospectively evaluate the biochemical status of vitamins A, D, and E in children with cystic fibrosis (CF). SUBJECTS: A total of 127 infants identified by the Colorado CF newborn screening program. DESIGN: Vitamin status (serum retinol, 25-hydroxy vitamin D, ratio of alpha-tocopherol/total lipids) and serum albumin were assessed at diagnosis (4 to 8 weeks), ages 6 months, 12 months, and yearly thereafter, to age 10 years. RESULTS: Deficiency of 1 or more vitamins was present in 44 (45.8%) of 96 patients at age 4 to 8 weeks as follows: vitamin A 29.0%, vitamin D 22.5%, and vitamin E 22.8%. Of these patients with initial deficiency, the percent that was deficient at 1 or more subsequent time points, despite supplementation, was vitamin A 11.1%, vitamin D 12.5%, and vitamin E 57.1%. Of the initial patients with vitamin sufficiency, the percent who became deficient at any time during the 10-year period was as follows: vitamin A 4.5%, vitamin D 14.4%, and vitamin E 11.8%. The percent of patients deficient for 1 or more vitamins ranged from 4% to 45% for any given year. CONCLUSIONS: Despite supplementation with standard multivitamins and pancreatic enzymes, the sporadic occurrence of fat-soluble vitamin deficiency and persistent deficiency is relatively common. Frequent and serial monitoring of the serum concentrations of these vitamins is therefore essential in children with CF.

Child↗
PubMed1998

Low plasma zinc concentrations in young infants with cystic fibrosis.

OBJECTIVES: The purpose of this study was to examine the zinc status of young infants with cystic fibrosis before and after the initiation of pancreatic enzyme therapy. STUDY DESIGN: Cross-sectional data were obtained for infants with cystic fibrosis identified by newborn screening. Plasma zinc concentrations were measured and analyzed according to enzyme use at the time of the blood draw. On a subgroup of infants, zinc concentrations were determined again after several weeks with enzyme therapy. RESULTS: Mean (+/-SD) plasma zinc concentration for the infants studied before the initiation of enzyme therapy was 10.4 +/- 2.2 micromol/L (68.3 +/- 14.7 microgram/dL) (n = 48), which was significantly lower than the mean for those receiving enzymes for >/=2 weeks, 11.8 +/- 2. 3 micromol/L (77.1 +/- 14.9 microgram/dL) (n = 15) (P =.03). For the group not yet receiving enzymes, 29% of infants had zinc concentrations in the deficient range. Data were available before and after enzyme therapy for 30 infants and indicated a mean increase of 1.64 +/- 3.0 micromol/L (10.7 +/- 19.3 microgram/dL) (P =. 005). CONCLUSIONS: These data suggest that many of the infants were zinc deficient at the time of diagnosis. We conclude that zinc should be included among the specific micronutrients given consideration in the management of cystic fibrosis, particularly in infants.

Cross-Sectional Studies↗
PubMed1998

Enteral nutrition for patients with cystic fibrosis: comparison of a semi-elemental and nonelemental formula.

OBJECTIVE: To determine whether differences in tolerance and absorption of fat and nitrogen exist between a semi-elemental nutritional formula without enzyme replacement and a nonelemental formula with enzyme replacement. STUDY DESIGN: Sixteen patients (eight girls and eight boys) with cystic fibrosis, 4 to 20 years of age (12+/-1.3, mean +/- SEM), who were pancreatic insufficient completed two 6-day regimens of nocturnal continuous enteral feedings offered in random order. Forty-four percent of the total daily energy was consumed as enteral tube feedings, and the remaining oral dietary intake remained constant throughout the study. Seventy-two-hour fecal collections from each study period were analyzed for total fat, long-chain fatty acids (LCFAs), medium-chain fatty acids (MCFAs), and nitrogen. RESULTS: Fat absorption was 80.2%+/-2.9% and 82.3%+/-3.1% (p = 0.58) for the semi-elemental and nonelemental formulas, respectively. Similarly, the coefficient of absorption of LCFAs was 69.5%+/-4.5% and 79.6%+/-3.4% (p = 0.30) for the semi-elemental and nonelemental formulas. Malabsorption of MCFAs contributed minimally to total fat malabsorption. There was no difference between formulas for MCFA or for nitrogen absorption, 83.7%+/-1.9% and 87.4%+/-1.4%, p = 0.48. All patients tolerated all feedings, and weight gained was 1.8+/-0.3 kg with no difference in weight gain between the trials. CONCLUSION: A nonelemental formula, with enzyme replacement, is absorbed as well as a predigested formula in patients with CF who are pancreatic insufficient.

Adolescent↗
PubMed1997

Early pulmonary disease in cystic fibrosis.

In cystic fibrosis, airway infection and inflammation lead to chronic progressive lung disease. The pathogenesis of cystic fibrosis is still not completely understood, but increasing evidence indicates that the disease process occurs in young patients. Treatment of respiratory symptoms in young patients, although not well studied, is commonly accepted and includes the full range of treatments used in older patients-secretion clearance techniques, bronchodilators, anti-inflammatory agents, and antibiotics by oral, inhaled, and systemic routes. It is not clear, however, whether early treatment can delay or prevent progressive lung disease in these patients. Outcome measures, including determination of infant lung function, imaging techniques, and direct lower airway sampling through bronchoalveolar lavage are under development and will allow large, multicenter interventional trials in young children. These studies will be aimed at delaying the initiation of lung disease and slowing disease progression.

Bronchoalveolar Lavage↗
PubMed1996

Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis.

Airway inflammation in children younger than 5 yr of age is difficult to assess, particularly in patients with cystic fibrosis (CF). Furthermore, determining responses to therapies is often subjective in infants, especially those with CF. To determine whether airway DNA levels could be used as an index of airway inflammation, we measured DNA levels in bronchoalveolar lavage fluid (BALF), using a Hoechst dye-binding assay. BALF DNA levels and neutrophils from 16 infants with CF were compared with levels obtained from seven older CF patients and nine control children who underwent bronchoalveolar lavage for evaluation of other pulmonary diseases. BALF DNA was increased in both infants (3.2 +/- 0.7 microg/ml) and older patients with CF (5.4 +/- 0.9 microg/ml) compared with the controls (0.7 +/- 0.2 microg/ml) (mean +/- SEM). BALF DNA levels were not significantly different between infants and older patients with CF. BALF neutrophil counts in CF patients were significantly higher than in controls. Furthermore, BALF DNA levels and total neutrophil counts in infants with CF correlated positively with one another. We conclude that: (1) DNA levels were easily quantifiable in BALF of young children; (2) DNA levels in BALF from CF patients were greater than in a group of children with other pulmonary diseases, and that in some infants with CF, BALF DNA levels were equivalent to those of much older patients with CF; (3) DNA levels in BALF correlate with BALF neutrophil number, an index of inflammation; and (4) some infants with CF have increased levels of DNA in BALF, which may justify a clinical trial of aerosolized rhDNase in this population.

Adult↗
PubMed1995

Normal energy expenditure in the infant with presymptomatic cystic fibrosis.

To investigate whether a fundamental lesion in energy metabolism is a feature of cystic fibrosis, we measured total energy expenditure using the doubly labeled water technique in 19 infants with presymptomatic cystic fibrosis (0.8 to 6.6 months of age) identified through newborn screening. Total energy expenditure data collected in a cohort of healthy infants by the same method were used for comparison. Energy balance studies were additionally performed in 10 of the infants with cystic fibrosis. Total energy expenditure levels in infants with cystic fibrosis, expressed as either kilocalories per day or kilocalories per kilogram of fat free mass per day, did not differ from control levels. When expressed on the basis of body weight (in kilocalories per kilogram per day), expenditure levels in infants with cystic fibrosis were greater (p < 0.05) than control levels. No differences in expenditure were observed between those infants who were homozygous (n = 10) for the delta F508 mutation and the heterozygous infants (n = 7), regardless of how expenditure was expressed. Assessment of energy balance indicated that infants with cystic fibrosis grow at a normal rate for metabolizable energy intakes similar to those reported for healthy infants. We conclude that there are no differences in energy expenditure between infants with presymptomatic cystic fibrosis and healthy infants, once differences in body composition are taken into account. This finding indicates that the primary cystic fibrosis defect is not an energy-requiring one.

Anthropometry↗
PubMed1995

Early pulmonary inflammation in infants with cystic fibrosis.

The mechanisms underlying the initiation of lung disease and early respiratory morbidity in cystic fibrosis (CF) are poorly understood. By identifying infants with CF through a statewide neonatal screening program, we investigated whether airway inflammation was present in these infants, with the goal of furthering our understanding of the early events in this lung disease. Bronchoalveolar lavage fluid (BALF) from 16 infants with CF (mean age, 6 mo) and 11 disease control infants (mean age, 12 mo) was examined for the following inflammatory parameters: (1) neutrophil count; (2) activity of free neutrophil elastase; (3) elastase/alpha 1-antiprotease inhibitor complexes; and (4) the level of interleukin-8 (IL-8). We also quantified the spontaneous level of expression of IL-8 mRNA transcripts by airway macrophages. Each index of airway inflammation was increased in the BALF of infants with CF as compared with control infants. In addition, both the number of neutrophils and IL-8 levels were increased in infants with CF who had negative cultures (n = 7) for common bacterial CF-related pathogens, as well as for common respiratory viruses and fungi at the time of bronchoalveolar lavage (BAL). These findings suggest that airway inflammation is already present in infants with CF who are as young as 4 wks. Furthermore, although many different cell types (e.g., epithelial cells) may express IL-8, airway macrophages appear to be a source of this chemokine, and may thus play a prominent role in early neutrophil influx into the lung.

Base Sequence↗
PubMed1995

Short-term effects of postural drainage with clapping vs autogenic drainage on oxygen saturation and sputum recovery in patients with cystic fibrosis.

To compare the short-term effects of postural drainage with clapping (PD) and autogenic drainage (AD) on oxygen saturation, pulmonary function, and sputum recovery, we studied ten patients with cystic fibrosis (CF) randomly treated with PD or AD on separate days. Pulse oximetry was monitored and sputum was collected during and for 1 h following each treatment. Pulmonary function was measured before and then 1, 15, and 60 min after each treatment. There was no significant difference in the amount of sputum recovered with AD (14.0 +/- 3.5 g) vs PD (10.4 +/- 3.0 g) and no significant differences in pulmonary function occurred. Oxygen saturation during PD fell from 93.3 +/- 0.7% to 91.2 +/- 0.8% (p < 0.01) and required 15 min following treatment to return to baseline. Oxygen saturation did not fall during AD and increased to 94.5 +/- 0.7% by 1 h following treatment (baseline, 93.3 +/- 0.8%; p < 0.01). We conclude that AD is less likely to produce oxygen desaturation and may be better tolerated by patients with CF, while producing similar benefits in sputum clearance.

Adolescent↗