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Objective: To study neutrophil activation in circulation as a sign of systemic inflammation in preterm infants with respiratory distress syndrome., Methods: The study comprised very low birth weight preterm infants who had respiratory distress syndrome and required intubation and mechanical ventilation (n = 51), 1-day-old preterm infants who had no need for mechanical ventilation (n = 12), term infants (n = 47), and adult volunteers (n = 25). Neutrophil surface expression of CD11b was quantified with flow cytometry., Results: In preterm infants with respiratory distress syndrome, neutrophil CD11b expression during the first day of life was higher than in cord blood (mean: 165 relative fluorescence units [RFU] [standard deviation [SD]: 53], n = 29 vs 83 RFU [SD: 21], n = 11; 95% confidence interval [CI] for difference: 59-106) or in preterm infants without mechanical ventilation (106 RFU [SD: 33], n = 12; 95% CI for difference: 17-90). CD11b expression decreased by age of 10 days. CD11b expression was lower in preterm cord than in term cord blood (95% CI for difference: 5-53). However, in preterm infants with respiratory distress syndrome aged 2 to 5 days, it was higher than in term infants of that age., Conclusions: The observations demonstrate an early transient postnatal neutrophil activation indicative of systemic inflammation that may contribute to the tissue injury in preterm infants with respiratory distress syndrome.

Objective: To determine whether number and activation of circulating polymorphonuclear leukocytes (PMNs) and platelets are associated with disease severity in neonatal respiratory distress syndrome (RDS)., Design: Prospective study., Setting: Tertiary neonatal intensive care unit., Patients: Preterm infants with severe (n = 18) or mild to moderate (n = 18) RDS who were consecutively admitted., Interventions: PMN and platelet counts and plasma concentrations of elastase-alpha1-proteinase inhibitor (E-alpha1-PI) and thromboxane B2 (TxB2) were recorded each day during the first 5 days of life. E-alpha1-PI-to-PMN and TxB2-to-platelet ratios were calculated to correct for the influence of the PMN and platelet count on elastase and thromboxane release., Results: From day 2, the severe RDS group had lower median PMN counts (1.5 vs 4.5 x 10/L), lower mean platelet counts (136 vs 230 x 10/L), and more elastase and thromboxane release, indicated by higher median E-alpha1-PI-to-PMN (39.2 vs 13.0 ng/10 PMNs on day 2) and TxB2-to-platelet (2.61 vs 0.52 pg/10 platelets on day 3) ratios than the mild-to-moderate group. Lower PMN and platelet counts and higher elastase and thromboxane release were correlated with birth asphyxia (lower 5-minute Apgar scores and umbilical arterial PH values), higher respiratory requirements (fraction of inspired oxygen and peak inspiratory pressure), and decreased values for continuous measures of RDS severity (ventilatory efficiency index and PaO2-to-alveolar oxygen tension ratio)., Conclusion: Decreased PMN and platelet counts and increased elastase and thromboxane release are correlated with increased RDS severity. Birth asphyxia (hypoxia and acidosis) and tissue injury caused by high-pressure ventilation and hyperoxia may promote this activation process.

Objective: To explore the relationship between chorioamnionitis, postnatal cortisol concentrations, and acute respiratory distress in very low birth weight infants., Methods: Appropriate for gestational age infants weighing between 501 to 1500 g at birth were enrolled into this prospective, observational study, and data regarding respiratory distress on the first day of life were recorded. Serum cortisol concentrations were measured on (a) day 2, (b) day 3 or 4, and (c) day 5, 6, or 7 of life. On day (b) or (c), 3.5 microg/kg of cosyntropin (an adrenocorticotrophic hormone analog) was given, and a repeat specimen was drawn 30 minutes later. Chorioamnionitis was diagnosed by placental examination by one author (R.L.N.)., Results: Forty-two infants exposed to chorioamnionitis and 37 infants not exposed were enrolled. Chorioamnionitis correlated inversely with gestational age, and was associated with decreased measures of acute respiratory support (exogenous surfactant, fraction of inspired oxygen, and ventilator support at 12 and 24 hours). Infants with chorioamnionitis had higher cortisol concentrations, both basal and stimulated. Gestational age was not significantly related to basal cortisol, but did correlate positively with stimulated values. Cortisol values from the 16 infants exposed to prenatal glucocorticoid therapy were excluded from these analyses., Conclusions: These results provide evidence that prenatal inflammation leads to adrenal stimulation, resulting in increased cortisol secretion and accelerated lung maturation. The enhanced response to cosyntropin stimulation seen in these infants may reflect an increased adrenal capacity to respond to postnatal stressors. Because of the apparent magnitude of the effect of chorioamnionitis on cortisol measures, this factor should be included in future investigations of adrenal function in very low birth weight newborns.

Objective: As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied., Methods: Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period., Results: Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups., Conclusions: Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.

Objective: Bronchopulmonary dysplasia (BPD) of preterm neonates is associated with an increased recruitment of inflammatory cells into the airways. To evaluate further the role of inflammation in the pathogenesis of BPD, tracheobronchial aspirate fluid of neonates with birth weight < 1200 g (n = 59) was sequentially analyzed in a prospective study., Methods: Tracheobronchial aspirate fluid was assessed for chemotactic activity, neutrophil cell count, concentrations of elastase-alpha 1-proteinase inhibitor and activity of free elastase, concentrations of chemoattractants (complement component C5-derived anaphylatoxin, leukotriene B4, interleukin-8), and albumin concentrations as well as alpha 1-proteinase inhibitor activity. The secretory component for immunoglobulin A was used as reference protein. Only specimens without evidence of microbiological colonization were studied., Results: In neonates with prolonged respiratory disease (BPD-risk neonates, n = 24, fraction of inspired oxygen > or = 0.3 and/or peak inspiratory pressure > or = 16 cm H2O at day 10 postnatal age, birth weight 892 +/- 36 g, gestational age 27.2 +/- 0.3 weeks) chemotactic activity, cell count, concentrations of the chemoattractants complement component C5-derived anaphylatoxin, leukotriene B4, interleukin-8, as well as levels of elastase-alpha 1-proteinase inhibitor were significantly higher at day 10 and/or day 15 of postnatal age compared with neonates without chronic pulmonary disease (total n = 35; day 10, n = 11; day 15, n = 8). There was no difference in free elastolytic activity. Concentrations of albumin as well as alpha 1-proteinase inhibitor activity were higher in BPD-risk patients on day 15, indicating an increased pulmonary leak., Conclusion: We conclude that preterm neonates at risk for the development of BPD show an enhanced inflammatory reaction in the lungs and an associated increase in pulmonary microvascular permeability. We speculate that inflammation may play an important role in the pathogenesis of BPD.

The presence of surfactant protein antigenemia and of surfactant protein antibodies was determined in serum from surfactant-treated and control infants with respiratory distress syndrome who were enrolled in a prospective randomized clinical trial. The surfactant used for treatment (surfactant TA) contained surfactant proteins (SPs) B and C and no SP-A. Enzyme-linked immunosorbent assays (ELISAs) that identify surfactant-associated proteins and ELISAs that identify IgG or IgM directed against surfactant proteins were used to investigate sera from these infants obtained prior to treatment, at 1 week of age, and at 2 months of age. There were no significant differences between average values in the surfactant-treated and control groups at each time period. However, in the control group, averaged results from ELISAs that identify SP-A and that identify IgM antibodies to SP-A or to SP-B, C showed significant differences between pretreatment sera and sera obtained at 1 week of age. No significant differences were noted in averaged results for IgG. Positive ELISA values were more frequently found in the control group than in the surfactant-treated group with regard to SP-A, and IgM against SP-A and SP-B, C in sera from neonates at 1 week of age. No positive ELISA values were found in sera from infants at 2 months of age. It is concluded that some patients with severe respiratory distress syndrome presumably leak surfactant proteins into the circulation and that this induces transient low titers of IgM antibody. This occurrence is decreased with surfactant treatment. Surfactant treatment may reduce leak of surfactant proteins into the vascular space by reducing lung damage.

Serum from premature infants enrolled in either single-dose or multidose surfactant replacement studies with bovine lung-based exogenous surfactant (Survanta) were analyzed for antibodies reactive with mixtures of bovine surfactant proteins SP-B and SP-C. Sera from 404 premature infants enrolled in single-dose studies and 1024 premature infants enrolled in multidose studies were analyzed, representing a total of 987 samples and 2743 serum samples, respectively. The sera were obtained from treated and control infants at the time of treatment and 1 week, 4 weeks, and 6 months thereafter. Polyclonal antisera generated in rabbits against the small molecular weight proteins were uniformly reactive with the bovine surfactant test antigens; however, antibodies reacting with the surfactant proteins were never detected by immunoblot analysis with the infant sera. Antibodies against common human viral antigens were readily detected in infant serum samples. The horseradish-peroxidase conjugated second antibodies (antihuman immunoglobin G or antihuman immunoglobins A, G, and M) used in the studies were highly reactive with both immunoglobin G and immunoglobin M classes of human antibodies. Therefore there was failure to detect specific immunological responses to the bovine surfactant proteins present in Survanta after single or multiple doses of exogenous surfactant administered in the perinatal period.

Immunofluorescence was performed on lung tissue obtained at necropsy from 18 newborn infants, including five with group B streptococcal (GBS) sepsis, seven with idiopathic respiratory distress syndrome (IRDS), and six control infants who died from other causes. Deposits of C3, IgG, and fibrin were found within hyaline membranes of infants who died with GBS sepsis or IRDS within 48 hours after birth. In some cases C4, factor B, and IgM were also observed. In five infants with IRDS who died more than five days after birth, immunofluorescent lung findings were less common and less intense. Hyaline membranes, attributed to mechanical ventilators and oxygen therapy in two infants who did not have GBS infection or IRDS, were negative for complement and immunoglobulins although fibrin was detected in one specimen. These data suggest that immunologic processes may contribute to the pathogenesis of certain types of acute lung injury, particularly in infants who die from GBS infection or IRDS during the early neonatal period.