Safety of bronchoalveolar lavage in young children with cystic fibrosis.

OBJECTIVE: Our aim was to determine the safety of BAL in young children <6 years with CF. METHODS: As part of a multi-center study of BAL-directed therapy, children with CF < 6 years had one or more BALs between September 1999 and December 2005. Adverse events were recorded intraoperatively and for 24 hr thereafter. Clinical characteristics before BAL, findings at bronchoscopy and BAL results were assessed as risk factors for adverse events. RESULTS: 333 BALs were conducted in 107 (56 males) children, median age 23.5 (range 1.6-67.5) months, including 170 (51%) for pulmonary exacerbation. 29 BALs (8.7%) were followed by fever >or=38.5 degrees C and 10 (3%) had clinically significant episodes (five intraoperative hemoglobin desaturations to <90% requiring intervention, one tachyarrhythmia, two needing post-operative supplemental oxygen, one hospitalization for stridor). Two contaminated bronchoscopes were detected. 180 minor adverse events were recorded in 174 (52%) BAL procedures (137 altered cough, 41 fever <38.5 degrees C). Low percentage BAL return (P = 0.002) and focal bronchitis (P = 0.02) were associated with clinically significant deterioration. Multivariable analysis identified Streptococcus pneumoniae (OR 22.3; 95% confidence interval (CI); 6.9,72), Pseudomonas aeruginosa (OR 2.4; 95% CI 1.0, 5.8), respiratory signs (OR 5.0; 95% CI 1.7, 14.6) and focal bronchitis (OR 5.9; 95% CI 1.2, 29.8) as independent risk factors for post-bronchoscopy fever >or=38.5 degrees C. CONCLUSIONS: Adverse events are common with BAL in young CF children, but are usually transient and well tolerated. Parents should be counseled that signs of a pre-existing lower respiratory infection are associated with increased risk of post-BAL fever.

Novel neutrophil-derived proteins in bronchoalveolar lavage fluid indicate an exaggerated inflammatory response in pediatric cystic fibrosis patients.

BACKGROUND: Airway inflammation in cystic fibrosis (CF) is exaggerated and characterized by neutrophil-mediated tissue destruction, but its genesis and mechanisms remain poorly understood. To further define the pulmonary inflammatory response, we conducted a proteome-based screen of bronchoalveolar lavage fluid (BALF) collected from young children with and without CF experiencing endobronchial infection. METHODS: We collected BALF samples from 45 children younger than 5 years and grouped them according to the presence of respiratory pathogens: > or = 1 x 10(5) colony-forming units (CFU)/mL BALF (18 and 12 samples with and without CF, respectively) and <1 x 10(5) CFU/mL (23 and 15 samples). BALF proteins were analyzed with SELDI-TOF mass spectrometry (MS) and H4 ProteinChips. Proteins were identified and characterized using trypsin digestion, tandem MS, Fourier transform ion cyclotron resonance MS, immunoblotting, and ELISA. RESULTS: The SELDI-TOF MS BALF profiles contained 53 unique, reliably detected proteins. Peak intensities of 24 proteins differed significantly between the CF and non-CF samples. They included the neutrophil proteins, alpha-defensin 1 and 2, S100A8, S100A9, and S100A12, as well as novel forms of S100A8 and S100A12 with equivalent C-terminal deletions. Peak intensities of these neutrophil proteins and immunoreactive concentrations of selected examples were significantly higher in CF than non-CF samples. CONCLUSIONS: Small neutrophil-derived BALF proteins, including novel C-terminal truncated forms of S100A proteins, are easily detected with SELDI-TOF MS. Concentrations of these molecules are abnormally high in early CF lung disease. The data provide new insights into CF lung disease and identify novel proteins strongly associated with CF airway inflammation.

Vitamin A levels in patients with CF are influenced by the inflammatory response.

BACKGROUND: Serum vitamin A, normally depressed in inflammatory conditions, is frequently low in people with CF. Vitamin A is important in respiratory epithelial regeneration and repair. We hypothesised that serum vitamin A would be associated with inflammation and disease severity. METHODS: Serum vitamin A (as retinol), C-reactive protein (CRP), vitamin E, 25-hydroxy vitamin D (25OHD), 1,25-dihydroxy vitamin D (1,25(OH)(2)D), weight, and lumbar spine bone mineral density (LSBMD) were measured in 138 subjects with CF (5-56 years) and 138 control subjects (5-48 years). FEV(1), presence of CF liver disease (CFLD) and hospital admissions were recorded in those with CF. RESULTS: Serum vitamin A level was lower in CF subjects than in controls (mean, 95% CI: 1.29, 1.0-1.37 vs. 1.80, 1.7-1.87 micromol/l, p < 0.0001), and inversely correlated with CRP (r(s) = -0.37, p < 0.0001). CF subjects with low vitamin A (45%) level had poorer FEV(1), weight z-score, LSBMD z-score, and higher CRP compared with those with normal levels. In the CF group CRP, vitamin E, 1,25(OH)(2)D, presence of CFLD, admissions, and age were associated with vitamin A level. CONCLUSIONS: Serum vitamin A is negatively associated with CRP in subjects with CF, consistent with normal population studies. It is important to distinguish between low serum vitamin A associated with the inflammatory response and that due to poor nutritional stores. The role of vitamin A in CF warrants further study, in the contexts both of chronic recurrent inflammatory disease and acute pulmonary exacerbation.

Abnormalities of the PTH-vitamin D axis and bone turnover markers in children, adolescents and adults with cystic fibrosis: comparison with healthy controls.

Abnormalities of calcium and vitamin D metabolism in cystic fibrosis (CF) are well documented. We tested the hypothesis that alterations in calcium metabolism are related to vitamin D deficiency, and that bone resorption is increased relative to accretion in patients with CF. Calcitropic hormones, electrolytes, osteocalcin (OC) and bone alkaline phosphatase (BAP), (markers of bone mineralisation), urinary deoxypyridinoline [total (t) Dpd, a marker of bone resorption] and lumbar spine bone mineral density (LS BMD), expressed as a z-score, were measured in 149 (81 M) CF and 141 (61 M) control children aged 5.3-10.99 years, adolescents aged 11-17.99 years and adults aged 18-55.9 years. Data were analysed by multiple regression to adjust for age. In patients, FEV(1)% predicted and CRP (as disease severity markers), genotype and pancreatic status (PS) were recorded. The distribution of PTH differed between groups ( P<0.0001), with CF levels both below and above the control range. 25OH vitamin D (25OHD) was not different in control and CF subjects ( P=0.06). Active hormonal vitamin D (1,25(OH)(2)D) was lower in the CF group ( P<0.0001), not explained by 25OHD or disease severity, as was serum magnesium ( P<0.0001). OC was decreased in CF adults ( P=0.004), and tDpd increased in CF adolescents ( P=0.003) and adults ( P=0.03). The ratio of OC to tDpd (a measure of bone coupling) was similar in CF and control children, but decreased in CF adolescents ( P=0.04) and adults ( P=0.02), suggesting decreased overall bone accrual in CF adolescents and uncoupling of bone balance in adults. 1,25(OH)2D was weakly correlated with OC in CF children ( r=0.43, P=0.01), and with tDpd in CF and control adolescents ( r=0.33, P=0.05 and r=0.36, P=0.02, respectively); thus there was limited evidence of association of calcitropic hormones, which had an abnormal pattern in all age groups, with bone turnover. There was no association between calcitropic hormones or bone turnover markers and LS BMD z-score. Despite vitamin D sufficiency, abnormalities of calcium metabolism and bone turnover markers were still apparent and bone accretion was decreased relative to resorption in the CF adolescent and adult groups. These changes were not fully explained by disease severity or genotype, but are consistent with reports of decreased BMD and unique bone histomorphometry in older subjects with CF.