Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature.

OBJECTIVE: To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm. STUDY DESIGN: A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009. RESULTS: Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930). CONCLUSIONS: Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.

Urine protein biomarkers for the diagnosis and prognosis of necrotizing enterocolitis in infants.

OBJECTIVES: To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC). STUDY DESIGN: Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation. RESULTS: A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC. CONCLUSIONS: We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.

Current treatment options for invasive aspergillosis.

Invasive pulmonary aspergillosis is a major cause of morbidity and mortality in immunocompromised patients, particularly those with hematological malignancies in the setting of profound neutropenia and/or hematopoietic stem cell transplant recipients. The optimal therapy for invasive aspergillosis relies on the restoration of leukocyte counts and effective antifungal treatment initiated at the earliest stage of infection. Several alternative antifungal compounds are currently available. A rational approach should take into account not only the degree of certainty of infection (as codified by the EORTC/MSG classification), but also previous exposure to other antifungals, the pharmacokinetic and pharmacodynamic characteristics of the antifungals employed and the clinical characteristics of the patient.

Increasing severity of pectus excavatum is associated with reduced pulmonary function.

OBJECTIVE: To determine whether pulmonary function decreases as a function of severity of pectus excavatum, and whether reduced function is restrictive or obstructive in nature in a large multicenter study. STUDY DESIGN: We evaluated preoperative spirometry data in 310 patients and lung volumes in 218 patients aged 6 to 21 years at 11 North American centers. We modeled the impact of the severity of deformity (based on the Haller index) on pulmonary function. RESULTS: The percentages of patients with abnormal forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced expiratory flow from 25% exhalation to 75% exhalation, and total lung capacity findings increased with increasing Haller index score. Less than 2% of patients demonstrated an obstructive pattern (FEV(1)/FVC <67%), and 14.5% demonstrated a restrictive pattern (FVC and FEV(1) <80% predicted; FEV(1)/FVC >80%). Patients with a Haller index of 7 are >4 times more likely to have an FVC of ≤80% than those with a Haller index of 4, and are also 4 times more likely to exhibit a restrictive pulmonary pattern. CONCLUSIONS: Among patients presenting for surgical repair of pectus excavatum, those with more severe deformities have a much higher likelihood of decreased pulmonary function with a restrictive pulmonary pattern.

Risk factors for intestinal failure in infants with necrotizing enterocolitis: a Glaser Pediatric Research Network study.

OBJECTIVE: To determine risk factors for intestinal failure (IF) in infants undergoing surgery for necrotizing enterocolitis (NEC). STUDY DESIGN: Infants were enrolled in a multicenter prospective cohort study. IF was defined as the requirement for parenteral nutrition for >or= 90 days. Logistic regression was used to identify predictors of IF. RESULTS: Among 473 patients enrolled, 129 had surgery and had adequate follow-up data, and of these patients, 54 (42%) developed IF. Of the 265 patients who did not require surgery, 6 (2%) developed IF (OR 31.1, 95% CI, 12.9 - 75.1, P < .001). Multivariate analysis identified the following risk factors for IF: use of parenteral antibiotics on the day of NEC diagnosis (OR = 16.61, P = .022); birth weight < 750 grams, (OR = 9.09, P < .001); requirement for mechanical ventilation on the day of NEC diagnosis (OR = 6.16, P = .009); exposure to enteral feeding before NEC diagnosis (OR=4.05, P = .048); and percentage of small bowel resected (OR = 1.85 per 10 percentage point greater resection, P = .031). CONCLUSION: The incidence of IF among infants undergoing surgical treatment for NEC is high. Variables characteristic of severe NEC (low birth weight, antibiotic use, ventilator use, and greater extent of bowel resection) were associated with the development of IF.

Spirometer-triggered high-resolution computed tomography and pulmonary function measurements during an acute exacerbation in patients with cystic fibrosis.

OBJECTIVE: To evaluate a high-resolution computed tomography (HRCT) scoring system, clinical parameters, and pulmonary function measurements in patients with cystic fibrosis (CF) before and after therapy for a pulmonary exacerbation. STUDY DESIGN: Patients (n = 17) were evaluated by spirometer-triggered HRCT imaging, clinical parameters, and pulmonary function tests (PFTs) before and after treatment. HRCT scans were reviewed by 3 radiologists using a modified Bhalla scoring system. RESULTS: Bronchiectasis, bronchial wall thickening, and air trapping were identified in all subjects on initial evaluation. The initial total HRCT score correlated significantly with the Brasfield score (r = -.91, P <.001) and several PFT measures. After treatment, there were improvements in the acute change clinical score (ACCS) (P <.001), most pulmonary function measurements, and total HRCT score (P <.05). Bronchiectasis, bronchial wall thickening, and air trapping did not significantly change. Mucus plugging subcomponent HRCT score, slow vital capacity (SVC), forced expiratory volume in 1 second (FEV(1)), and forced vital capacity (FVC) (percent predicted) and reversible and total HRCT scores were most sensitive to change by effect size analysis. CONCLUSIONS: Improvements occurred with treatment in total and reversible HRCT scores, PFTs, and ACCS. Total and reversible HRCT scores and percent predicted SVC, FEV1, and FVC were the most sensitive to change. The greatest change was seen in the mucus plugging subcomponent HRCT score.

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis.

UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. STUDY DESIGN: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. RESULTS: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. CONCLUSION: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.

Bone acquisition and loss in children and adults with cystic fibrosis: a longitudinal study.

OBJECTIVES: To determine patterns of bone mineral acquisition in children and young adults with cystic fibrosis (CF) and to identify clinical and laboratory correlates of change in bone mineral density (BMD). STUDY DESIGN: Bone mineral and clinical status were assessed in 41 patients with CF (26 female, aged 9 to 50 years) at baseline and 1.5 years later. Bone mineral content of the lumber spine, femoral neck, and whole body was determined by dual-energy x-ray absorptiometry and expressed as BMD and bone mineral apparent density (BMAD). Changes in weight, height, pubertal status, glucocorticoid use, physical activity, disease severity, and biochemical markers of bone turnover were examined for associations with changes BMD and BMAD. RESULTS: Mean BMD Z-scores (adjusted for age and sex) were reduced at the spine, hip, and whole body at baseline in both adults and youths, and decreased further at all sites among youths at follow-up (-0.4 at spine, p < 0.05; -0.3 at hip, p < 0.10; -0.5 for whole body, p < 0.0005). These data indicate failure to gain bone mineral at the expected rate. BMAD was also reduced at follow-up, suggesting that the observed osteopenia could not be explained by small bone size. Bone loss at multiple sites was observed in four youths and two adults. In general glucocorticoid use, change in body mass, physical activity, and disease severity were the most significant correlates for change in BMD and in BMD Z-score. CONCLUSIONS: Osteopenia in CF generally reflects inadequate gains in bone mineral, although bone loss may occur, particularly in patients requiring glucoc therapy. Late gains in bone mineral may accompany weight gain and pubertal development, but the catch-up appears to be incomplete.

Deficiency of IgG4 in children: association of isolated IgG4 deficiency with recurrent respiratory tract infection.

To study the relationship between serum IgG subclass deficiency and clinical host defense impairment, we reviewed the clinical and immunologic features of 123 patients with a history of recurrent infection who had been examined for immunodeficiency in our laboratory (group 1). We then compared immunoglobulin isotype levels with those in sera from 127 age-matched control subjects without recurrent infection from whom blood had been drawn for evaluation of atopy (group 2). There was a significantly higher prevalence of IgG4 deficiencies among patients with recurrent infections (17% vs 7%; p less than 0.02), solely because of a higher prevalence of isolated IgG4 deficiency (n = 9; 7.3%) than in atopic control subjects (n = 1; 0.8%; p less than 0.05); there was a comparable prevalence of multiple isotype deficiencies that included low levels of IgG4 (9.8% and 6.3%, respectively). All nine group 1 patients with isolated IgG4 deficiency had severe recurrent respiratory tract infections requiring multiple hospitalizations; in addition, five were atopic, five had asthma, and one had chronic diahrrea. Antibody responses to bacterial polysaccharide antigens were normal for age in all patients with isolated IgG4 deficiency; two had defective antibody responses to protein antigens. Isolated IgG4 deficiency appears to be associated with impaired respiratory tract defenses and may occur in the absence of an easily definable antibody deficiency state. This association suggests a physiologic defense role for mucosal IgG4.

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis.

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.

Allergy to semisynthetic penicillins in cystic fibrosis.

Allergic reactions to anti-Pseudomonal penicillin derivatives are an increasing problem in therapy of cystic fibrosis lung disease. We evaluated 15 patients, ages 12 to 37 years, with documented allergic reactions to carbenicillin, ticarcillin, or piperacillin. Intradermal skin test reactions were positive for benzylpenicillin in seven patients, penicilloyl-polylysine in one, and ticarcillin or piperacillin in eight, for a total of 11 of 11 tested. Results of radioallergosorbent testing to penicilloyl conjugates were positive in eight of 14 patients and equivocal in four others. Overall, skin tests or RAST results were positive in 13 of 15 patients. All patients were desensitized with a semisynthetic penicillin by continuous serial intravenous infusion of 10-fold dose increments, beginning with 10(-6) of the therapeutic dose. Desensitization was successful in 25 of 26 instances. After intravenously administered therapy, maintenance of desensitization with dicloxacillin orally was unsuccessful in four of six patients. We conclude that (1) allergy to semisynthetic penicillins in cystic fibrosis usually is IgE mediated; (2) such allergy can be evaluated by skin testing; (3) it can be safely and in most cases successfully treated by intravenous desensitization; and (4) allergic patients should be desensitized on each subsequent admission for intravenously administered therapy.

125I-Clq-binding and specific antibodies as indicators of pulmonary disease activity in cystic fibrosis.

We studied the incidence and levels of circulating immune complexes by the 125I-Clq-binding assay in patients with cystic fibrosis in relation to clinical respiratory status and specific IgG and IgE antibodies to Pseudomonas aeruginosa. Staphylococcus aureus, Aspergillus fumigatus, and Candida albicans. Overall prevalence of CIC was 43%, but 86% of serially studied patients had evidence of CIC at some time. Patients with acute respiratory exacerbations and deteriorating pulmonary function had a higher incidence of CIC (76%) as compared to stable patients (36%, P less than 0.01), as well as significantly higher levels of CIC. Acute exacerbations were also associated with significant increases in IgG antibody to Pseudomonas (P less than 0.005) but not in other antibodies. CIC did not correlate with Pseudomonas-specific IgG nor with any other specific antibody studied. A variety of age-related differences in specific antibody levels were seen. The episodic appearance of CIC is common in CF and is usually associated with exacerbation of lung disease.