Warren Rosenfeld

Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IGIV

The Food and Drug Administration recently approved the use of palivizumab (palē-vizhū-mäb), an intramuscularly administered monoclonal antibody preparation. Recommendations for its use are based on a large, randomized study demonstrating a 55% reduction in the risk of hospitalization attributable to respiratory syncytial virus (RSV) infections in high-risk pediatric patients. Infants and children with chronic lung disease (CLD), formerly designated bronchopulmonary dysplasia, as well as prematurely born infants without CLD experienced a reduced number of hospitalizations while receiving palivizumab compared with a placebo. Both palivizumab and respiratory syncytial virus immune globulin intravenous (RSV-IGIV) are available for protecting high-risk children against serious complications from RSV infections. Palivizumab is preferred for most high-risk children because of ease of administration (intramuscular), lack of interference with measles–mumps–rubella vaccine and varicella vaccine, and lack of complications associated with intravenous administration of human immune globulin products. RSV-IGIV, however, provides additional protection against other respiratory viral illnesses and may be preferred for selected high-risk children including those receiving replacement intravenous immune globulin because of underlying immune deficiency or human immuno-deficiency virus infection. For premature infants about to be discharged from hospitals during the RSV season, physicians could consider administering RSV-IGIV for the first month of prophylaxis. Most of the guidelines from the American Academy of Pediatrics for the selection of infants and children to receive RSV-prophylaxis remain unchanged. Palivizumab has been shown to provide benefit for infants who were 32 to 35 weeks of gestation at birth. RSV-IGIV is contraindicated and palivizumab is not recommended for children with cyanotic congenital heart disease. The number of patients with adverse events judged to be related to palivizumab was similar to that of the placebo group (11% vs 10%, respectively); discontinuation of injections for adverse events related to palivizumab was rare.

Long-term follow-up of premature infants treated with prophylactic, intratracheal recombinant human CuZn superoxide dismutase.

OBJECTIVE:To examine the long-term effects of treatment with recombinant human CuZn superoxide dismutase (rhSOD) in infants enrolled previously in two placebo-controlled trials.STUDY DESIGN:Records for 46 (88%) infants were examined, with 19 infants having received either single or multiple intratracheal (i.t.) doses of placebo, 12 having received a single i.t. dose of rhSOD, and 15 having received multiple i.t. doses of rhSOD. Mean age at follow-up was 28 months corrected age. Records were examined for neurologic dysfunction, developmental delay, and any significant medical disorders.RESULTS:Four placebo infants (21%) had evidence of neurodevelopmental abnormalities and four infants developed asthma. Four single-dose rhSOD infants (33%) had neurodevelopmental abnormalities and two infants developed asthma. One multiple-dose rhSOD infant had evidence ofneurodevelopmental abnormalities and one developed asthma. No other differences were found between the placebo and rhSOD groups.CONCLUSION: Preliminary data suggest that rhSOD is safe and not associated with any long-term adverse effects. Further results will depend on the results of multicenter trials of rhSOD in preterm infants.

Pharmacologic interactions of exogenous lung surfactant and recombinant human Cu/Zn superoxide dismutase

ABSTRACT: The effect of exogenous surfactant on the pharmacokinetics of intratracheally administered recombinant human superoxide dismutase (rhSOD) was studied. Five groups of rats received the following intratracheally: 1 mL/kg of saline; 5 or 25 mg/kg of rhSOD; or 4 mL/kg of exogenous surfactant followed in 30 min by 5 or 25 mg/ kg of rhSOD. Animals were killed at 24,48, and 72 h, and serum, bronchoalveolar lavage, and lung tissue were analyzed for rhSOD. rhSOD was not detected in the lungs of saline-treated animals or in serum from any animal. At 24 h, lung-tissue rhSOD was higher in rats treated with surfactant and rhSOD versus rhSOD alone (5 mg/kg: 6.8 ± 2.5 versus 0 μg/whole lung, p < 0.05; 25 mg/kg: 29.9 ± 9.6 versus 0.1 ± 0.1 μg/whole lung, p < 0.05). Bronchoalveolar lavage fluid levels correlated well with lung tissue concentrations. By 48 h, lung tissue rhSOD concentrations were insignificant in all groups. rhSOD was still present in lavage fluid from rats treated with surfactant and rhSOD. No rhSOD was detected at 72 h. In separate in vitro experiments, physical and biological drug-drug interaction studies were performed. When radiolabeled rhSOD was combined with exogenous surfactant and centrifuged at 10000 × g for 30 min, 81.3 ± 2.5% of rhSOD was found in the supernatant versus 18.7 ± 2.5% in the surfactant pellet. Serial washing of the surfactant pellet removed virtually all remaining rhSOD. This finding suggests that the rhSOD and surfactant were only weakly associated. Combining rhSOD and exogenous surfactant did not alter the activity of either agent. Data suggest that exogenous surfactant prolongs the t½ of rhSOD in the lung. This finding may be important in determining future rhSOD administration strategies in preterm infants with respiratory distress syndrome who receive exogenous surfactant replacement therapy.

Reduction of Retinopathy of Prematurity in Extremely Low Gestational Age Newborns Treated with Recombinant Human Cu/Zn Superoxide Dismutase

Background: Reactive oxygen species have been implicated in the pathogenesis of retinopathy of prematurity (ROP). Extremely low gestational age (GA) newborns (ELGANs) have the highest risk of ROP and might benefit most from treatment with antioxidants. Objectives: To determine whether recombinant human Cu/Zn superoxide dismutase (rhSOD) decreases the incidence or severity of ROP in ELGANs. Methods: A previous multicenter trial of intratracheal rhSOD for prevention of bronchopulmonary dysplasia randomized 302 preterm infants to receive intratracheal rhSOD or placebo at birth and every 48 h for 1 month. An analysis of the incidence and severity of ROP was performed in ELGANs. Results: The risk of ROP increased with decreasing GA. Within the entire cohort, no significant differences in ROP were found in the placebo versus rhSOD groups. Subgroup analysis on infants born at <26 weeks (n = 72) revealed a 22% reduction in ROP from 85% (placebo) to 66% (rhSOD) (p = 0.06). In subjects born at <25 weeks (n = 24), ROP was reduced by 53% from 85% (placebo) to 40% (rhSOD) (p = 0.03). ROP severity above stage 2 was found in 42% of placebo-treated infants but only 25% of rhSOD-treated subjects with ROP. Conclusions: This post hoc analysis suggests that rhSOD reduces the risk of developing ROP in ELGANs, although further studies are required to confirm this observation.

Ischemic injury to newborn rabbit ileum: Protective role of human superoxide dismutase

The effectiveness of human superoxide dismutase (hSOD) in the prevention of reperfusion injury was evaluated in a rabbit ileal loop model. Weanling white New Zealand rabbits, 6 weeks of age and weighing 500 to 1,000 g, were used. Intraluminal administration of SOD (5 mg/kg) was studied in 12 animals with each animal serving as its own control. In an additional 12 animals, parenteral SOD in a dose of 5 mg/kg in seven animals and 10 mg/kg in five animals was evaluated, while five additional control animals received parenteral saline. The effect of reperfusion injury was evaluated in each bowel loop by interruption of blood supply for five minutes, followed by reperfusion. Blood was drawn at 0, 16, 20, 24 hours in the parenteral group for measurement of hSOD levels by radioimmunoassay. The loops were studied pathologically for extent of mucosal damage. In the intraluminal group, nine of 12 loops without SOD v three of 12 loops with SOD showed necrosis when rendered ischemic (P = .0196). In the parenteral group 22 of 24 loops were normal when pretreated with SOD and subjected to ischemia v five of ten when no SOD was given (P = .0139). In the parenteral group, mean baseline level of hSOD was 0.42 +/- 0.26 micrograms/mL. Levels peaked at 16 hours (3.64 +/- 1.75 micrograms/mL) and progressively decreased at 20 hours (2.85 +/- 1.34 micrograms/mL) and 24 hours (1.82 +/- 1.15 micrograms/mL). This preliminary animal study suggests that hSOD may be an effective method for the prevention of postischemic bowel injury, adding to the literature on the protective effects of SOD in various models of intestinal ischemia.

Racial/ethnic Differences in Clinical and Biochemical Type 2 Diabetes Mellitus Risk Factors in Children

To examine whether periadolescent children demonstrate the significant racial/ethnic differences in body fatness relative to BMI and in the prevalence and relationship of body composition to risk factors for type 2 diabetes (T2DM) as in adults.

Retinol binding protein 4 is associated with adiposity-related co-morbidity risk factors in children.

Abstract Objective: In adults, elevated levels of retinol binding protein 4 (RBP4) have been associated with biochemical markers of adiposity-related co-morbidities including insulin resistance, dyslipidemia, hypertension, and abdominal obesity. This study examined the relationship between RBP4 and risk factors for co-morbidities of adiposity in a population of ethnically diverse children in early- to mid-adolescence in the public school system of New York City. Materials/methods: We analyzed anthropometric (body mass index, % body fat, waist circumference), metabolic (lipids, glucose), and inflammatory (TNF-α, interleukin-6, C-reactive protein, adiponectin) markers for adiposity-related co-morbidities and serum alanine aminotransferase (ALT) in 106 school children (65 males, 41 females) 11–15 years of age (mean±SD=13.0±0.1 years) who were enrolled in the Reduce Obesity and Diabetes (ROAD) project. Insulin sensitivity was assessed by quantitative insulin sensitivity check index. Insulin secretory capacity was measured as acute insulin response and glucose disposal index. Results: Serum RBP4 was significantly correlated directly with ALT, triglycerides, and triglyceride z-score, and inversely correlated with adiponectin. Correlations with ALT and adiponectin remained significant when corrected for % body fat, age, and gender. There were significant ethnic differences in the relationship of RBP4 to ALT, glucose disposal index and adiponectin. Conclusions: In early- to mid-adolescents, circulating concentrations of RBP4 are correlated with multiple risk factors for adiposity-related co-morbidities. The observation that many associations persisted when corrected for % body fat, suggests that RBP4 can be viewed as an independent marker of adiposity-related co-morbidity risk in children.

Plasma Advanced Glycation End Products (AGEs), Receptors for AGEs and Their Correlation with Inflammatory Markers in Middle School-Age Children

Aim: Advanced glycation end products (AGEs) and/or their receptors (RAGE) are significantly positively correlated with adiposity, inflammation, dyslipidemia, and insulin resistance in adults. However, the relationships between AGEs, RAGE, and adiposity-related comorbidites in children have not been well studied. Methods: In a cross-sectional study of 88 children (age 11-15 years) from the New York area enrolled in the Reduce Obesity and Diabetes (ROAD) study, we examined the correlation of the AGE Nε-(carboxymethyl)lysine (CML), soluble RAGE (sRAGE), and endogenous secretory RAGE (esRAGE) with adiposity, inflammatory markers [interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-α], adiponectin, lipids, insulin sensitivity, and insulin secretory capacity. Results: Pediatric CML levels were ∼20% below average adult levels. CML was significantly (p < 0.05) positively correlated with age and insulin sensitivity and negatively with adiposity, dyslipidemia and IL-6. sRAGE correlated positively with esRAGE and negatively with adiposity and IL-6. Both sRAGE and esRAGE correlated negatively with insulin secretory capacity. Conclusion: Our findings suggest that unlike adults, CML is negatively associated with adiposity and adiposity-related comorbidity risk in children. As in adults, sRAGE and esRAGE were, to varying degrees, negatively correlated with body fatness and risk factors for adiposity-related comorbidities.

Growth Hormone Evaluation and Treatment in Prader-Willi Syndrome

Prader–Willi Syndrome (PWS) is characterized by infantile hypotonia, obesity, hypogonadism, mental deficiency, short stature, characteristic facial features, small hands and feet, and an interstitial deletion of chromosome 15(q11–13) in about one–half of the patients. Short stature and delayed skeletal maturation occur in 90% of children with PWS. The basis for the short stature, however, remains uncertain. Pituitary evaluation of growth hormone (GH) deficiency by pharmacological tests have varied from normal to impaired in PWS children (Bray et al, 1983; Lee et al, 1982).

The Effects of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase (rhSOD) in Premature Infants with Respiratory Distress Syndrome (RDS)

The Effects of Multiple Doses of Recombinant Human CuZn Superoxide Dismutase (rhSOD) in Premature Infants with Respiratory Distress Syndrome (RDS)