Rowena Cayabyab

Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns.

We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor α, IL-1β, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and 2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.

Bioactive Transforming Growth Factor-Beta in the Lungs of Extremely Low Birthweight Neonates Predicts the Need for Home Oxygen Supplementation

Transforming growth factor-β (TGF-β) is a peptide implicated in tissue injury and repair but its role in the premature human lung remains unclear. In the present study, we used a TGF-β responsive-promoter-luciferase construct in mink lung epithelial cells to quantify levels of biologically active TGF-β (BA-TGF-β) in the endotracheal aspirate (ETA) fluid from 16 extremely low birthweight neonates [6 M/10 F, mean GA 26 weeks (range 23–30), mean BW 774 g (range 555–1,075)]. ETA fluid was obtained on day 1 and then every 4 days up to 32 days. BA-TGF-β levels were low (92 ± 19 pg/ml) in the first 24 h of life and then increased 5- to 10-fold with peak BA-TGF-β levels (400 ± 50 pg/ml) on day 20–25. BA-TGF-β levels were higher in male than female infants (p = 0.0056). Prenatal steroids decreased significantly the amount of BA-TGF-β recovered. High initial levels of BA-TGF-β persisted over time and were predictive of the need for oxygen therapy at home. We conclude that abundant BA- TGF-β is present in the lungs of preterm infants and speculate that it may be involved in inflammatory and repair processes encountered in acute and chronic lung disease.

Interleukin-1β in the bronchoalveolar lavage fluid of premature neonates: a marker for maternal chorioamnionitis and predictor of adverse neonatal outcome

Objective: To determine whether the presence of the proinflammatory cytokine interleukin (IL)-1β in the lungs of preterm infants immediately after birth was associated with maternal inflammation and could predict adverse neonatal outcome. Study design: Prospective evaluation of serially obtained tracheal aspirates for the presence of IL-1β in 25 preterm infants (birth weight 595-1700 g; gestational age 24-32 weeks) with respiratory distress syndrome. The initial tracheal aspirate was obtained within 1 h after delivery. Results: An initial tracheal aspirate positive for IL-1β had a highly significant correlation with documented maternal chorioamnionitis for the given patient. In addition, the presence of IL-1β correlated significantly with elevated total cell count (2.62 vs. 0.96 × 106/ml, p = 0.0097), granulocyte count (2.12 vs. 0.22 × 106/ml, p = 0.001), macrophage count (0.28 vs. 0.01 × 106/ml, p = 0.02) and the presence of proinflammatory cytokines IL-6, IL-8 and tumor necrosis factor (TNF)-α. Preterm neonates positive for IL-1β in their initial sample were on prolonged assisted ventilation (38 vs. 16 days, p = 0.013) and oxygen supplementation (62 vs. 40.5 days, p = 0.0462) and required prolonged hospitalization (69 vs. 46 days, p = 0.0165). Conclusions: The concentration of IL-1β in the initial tracheal aspirate obtained from the lungs of preterm infants within the first hour of life may serve as a marker of antenatal/perinatal inflammation, probably due to maternal chorioamnionitis, and could predict an adverse clinical course and short-term outcome.

Differential regulation of IL-8 by IL-1beta and TNFalpha in hyaline membrane disease.

Mechanisms that regulate cytokine-mediated inflammation in the lungs of preterm infants, including factors which regulate production of the chemokine IL-8, remain poorly defined. Sequential bronchoalveolar lavage samples were obtained from preterm newborns with hyaline membrane disease over a 28-day period. Bronchoalveolar lavage cell cytokine relationships were evaluated and the differential regulation of IL-8 by IL-1β and TNFα was studied in a short-term culture system. In vivo, IL-8 and IL-lβ protein levels correlated closely with each other and with macrophage counts. In cell culture, exogenous anti-IL-1β antibody led to a 40% maximum inhibition (approximately) of IL-8 production by lipopolysaccharide stimulated lung inflammatory cells. Comparable amounts of exogenous anti-TNFα antibodies achieved a 15% maximum inhibition (approximately) of IL-8 production. Anti-IL-1β and anti-TNFα antibodies in combination did not inhibit IL-8 production beyond that achieved by anti-IL-lβ antibody alone. These results, in preterm newborns, support the concept of lung inflammation mediated in part by a macrophage, IL-1β, and IL-8 cell cytokine pathway. The results also suggest that factors other than IL-1β and TNFα regulate IL-8 expression in the lungs of preterm infants.

Constitutive IL-10 expression by lung inflammatory cells and risk for bronchopulmonary dysplasia.

Expression of IL-10 is decreased in lungs of preterm infants. We determined the constitutive and lipopolysaccharide (LPS)-induced IL-10 synthesis by lung inflammatory cells from preterm and term infants and examined their relationship to gestational age and/or incidence of bronchopulmonary dysplasia (BPD). A total of 37 infants; preterm neonates at gestational ages of 23–27 wk (group 1); 28–34 wk (group 2), and four full-term infants with meconium aspiration (group 3) were enrolled. One sample of lung inflammatory cells, obtained during postnatal d 1–3, and another during postnatal d 4–7 were cultured in vitro in presence or absence of 100 μg/mL of LPS. Secreted IL-10 was measured by ELISA. A positive relationship was found between gestational age and LPS-induced, but not constitutive IL-10 production within 1–3 d of life; group 1 on d 1–3 had a significant number of IL-10 nonresponders compared with group 2. All term neonates in group 3 had positive LPS-induced IL-10 response. Thus, in utero maturation of IL-10 gene expression is due to acquisition of inducibility. In contrast, constitutive IL-10 production within d 1–3 of life correlated with, and predicted the incidence of BPD in the highly vulnerable very premature infants.

Chorioamnionitis and Management of Asymptomatic Infants ≥35 Weeks Without Empiric Antibiotics

This study presents an alternative strategy eliminating immediate empirical antibiotic therapy in the management of asymptomatic chorioamnionitis-exposed infants ≥35 weeks’ gestation. BACKGROUND AND OBJECTIVE: Management of asymptomatic infants ≥35 weeks’ gestation born to mothers with chorioamnionitis remains controversial, with many clinicians considering the need for changes to the current guidelines. The study objective was to evaluate the outcomes of asymptomatic chorioamnionitis-exposed neonates without the use of immediate empirical antibiotics. METHODS: A retrospective data review was conducted from May 2008 to December 2014, including asymptomatic infants ≥35 weeks’ gestation with a maternal diagnosis of clinical chorioamnionitis. RESULTS: A total of 240 asymptomatic infants with chorioamnionitis exposure were identified. The majority of asymptomatic chorioamnionitis-exposed infants, 162 (67.5%), remained well in the mother-infant unit with a median stay of 2 days. There were 78 (32.5%) infants admitted to the NICU and exposed to antibiotics due to abnormal laboratory data or development of clinical symptoms. Of those infants admitted to the NICU, 19 (24%) received antibiotics for <72 hours, 47 (60%) were treated for culture-negative clinical sepsis, and 12 (15%) for culture-positive sepsis, with a median NICU stay of 7 days. CONCLUSIONS: Nonroutine use of empirical antibiotics in asymptomatic newborns ≥35 weeks’ gestation with maternal chorioamninonitis prevented NICU admission in two-thirds of these infants. This prevented unnecessary antibiotic exposure, increased hospitalization costs, and disruption of mother-infant bonding and breastfeeding. Laboratory evaluation and clinical observation without immediate antibiotic administration may be incorporated into a management approach in asymptomatic chorioamnionitis-exposed neonates. Additional studies are needed to establish the safety of this approach.

Graded oxygen saturation targets and retinopathy of prematurity in extremely preterm infants

Background:We compared the incidence of severe retinopathy of prematurity (ROP) and need for laser treatment before and after implementing graded pulse oximeter oxygen saturation (SpO2) targets in extremely preterm infants. Mortality and other secondary outcomes were compared.Methods:Before 2002, we used 90–94% as the SpO2 target in infants 240/7–276/7wk gestation and birth weight <1,000 g until 356/7 wk postmenstrual age (PMA). We implemented graded SpO2 targets based on vaso-obliterative and vaso-proliferative phases of ROP in 2002. Group 1 (1995–2001) before, and Group 2 (2003–2010) after implementation of graded SpO2 targets based on PMA (83–89% until 326/7 wk, 90–94% until 356/7 wk and >94% at ≥ 36 wk PMA).Results:There were 267 patients in Group 1 and 220 in Group 2. There was no significant difference in birth weight or gestational age. Severe ROP (adjusted OR: 0.18, 95% CI: 0.11, 0.30; P < 0.001) and laser surgery rates (adjusted OR: 0.31, 95% CI: 0.18, 0.52; P < 0.001) decreased significantly in Group 2. There was no difference in mortality (adjusted OR: 0.74, 95% CI: 0.37, 1.49; P = 0.40).Conclusion:In this retrospective cohort study, implementation of graded SpO2 targets decreased severe ROP and need for laser therapy, without increasing mortality.

TGFβ BIOACTIVITY AND ITS RELATIONSHIP WITH INFLAMMATION IN THE LUNGS OF PRETERM NEWBORNS WITH HYALINE MEMBRANE DISEASE. † 2009

TGFβ BIOACTIVITY AND ITS RELATIONSHIP WITH INFLAMMATION IN THE LUNGS OF PRETERM NEWBORNS WITH HYALINE MEMBRANE DISEASE. † 2009

Early postnatal weight gain as a predictor for the development of retinopathy of prematurity

Abstract Objective: The objective of this study is to validate the reliability of early postnatal weight gain as an accurate predictor of type 1 retinopathy of prematurity (ROP) requiring treatment in a large predominantly Hispanic US cohort with the use of an online tool called WINROP (weight, neonatal retinopathy of prematurity (IGF-1), neonatal retinopathy of prematurity). Study design: Retrospective cohort study consisted of preterm infants <32 weeks gestation and birth weight <1500 g. Weekly weights to 36 weeks post-menstrual age or discharge if earlier were entered into the WINROP tool. This tool generated alarm and risk indicator for developing ROP. The infants with type 1 ROP requiring treatment as well as all stages of ROP were compared with the alarms and risks generated by WINROP tool. Results: A total of 492 infants were entered into the WINROP tool. The infants who developed type 1 ROP requiring treatment, the WINROP tool detected 80/89 (90%) at less than 32 weeks gestation. Nine infants developed type 1 ROP were classified as low risk and did not alarm. Conclusions: Postnatal weight gain alone, in predominantly Hispanic US population, predicted type 1 ROP requiring treatment before 32 weeks of gestation in infants with a sensitivity of 90%. The tool appeared to identify majority of affected infants much earlier than the scheduled screening.

110 MANAGEMENT OF TRANSIENT HYPERGLYCEMIA IN VERY LOW BIRTH WEIGHT INFANTS WITH CONTINUOUS INSULIN INFUSION AND ITS EFFECT ON LACTIC ACID LEVELS.

Introduction Transient hyperglycemia (TH) develops in preterm infants on continuous glucose infusion despite receiving glucose infusion rates that matches their basal requirements. This has been attributed to a partially defective processing of proinsulin to insulin and relative insulin resistance requiring higher levels of insulin to achieve euglycemia. Treatment with insulin under euglycemic hyperinsulinemic clamp conditions in 4 clinically stable preterm infants has been shown to result in lactic acidosis. Objective To evaluate the effect of continuous insulin infusion during TH in sick, very low birth weight (VLBW) infants receiving total parenteral nutrition on lactic acidosis. Study Design Prospective, observational study of VLBW infants on continuous insulin infusion for TH with measurement of lactate levels. Results Values are expressed as mean and range. Seven VLBW infants with mean birth weight 738 g (538-1,263) and mean gestational age 26 wks (range 24-30) were on continuous insulin infusion for TH. All infants were on parenteral nutrition receiving protein and intralipids in addition to glucose initiated within 12 to 24 hours of life. Mean blood sugar level was 235 mg/dL (180-334) prior to start of insulin infusion at a mean dose of 0.04 U/kg/hr (0.01-0.05). Mean glucose infusion rate was 6.9 mg/kg/min (4.7-10.5). Mean lactate level prior to start of insulin infusion was 3.2 (0.7-8.1mmol/L) and mean lactate levels post insulin was 1.5 (0.5-3.8 mmol/L). Four of the 7 infants required 2 to 4 courses of insulin infusions for TH. One of the 4 neonates was septic with a congenital E. coli infection, and 3 were severely compromised at birth, requiring the use of pressors to stabilize their blood pressure. All infants received 1-3 insulin boluses of 0.1 unit/kg/dose prior to starting the insulin infusion. In all instances, the post-insulin infusion lactic acid levels were lower. None of the infants developed hypoglycemia during insulin infusion. Conclusions The use of continuous insulin infusion with or without an initial bolus dose for transient hyperglycemia in sick, VLBW infants is not associated with the development of lactic acidosis but may actually improve the preexisting acidosis. Our results are in favor of insulin infusion to correct the transient metabolic abnormalities and to maintain biological levels of insulin to achieve euglycemia during TH.