Cytokine elevations in infants with bacterial and aseptic meningitis.

We sought to determine whether the detection of cytokines, produced during the inflammatory response, would aid in the diagnosis of meningitis in young infants. We measured cerebrospinal fluid (CSF) and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) in 62 infants less than 6 months of age whose condition was evaluated for meningitis. Twenty infants had culture-proved meningitis, 22 had aseptic meningitis, and 20 control infants had no evidence of meningitis. The CSF IL-6 levels were elevated in all 20 infants with bacterial meningitis and in 9 of 22 infants with aseptic meningitis but were undetectable in all control subjects. Furthermore, CSF IL-6 levels were 10 times greater in infants with bacterial versus aseptic meningitis (p < 0.001). Levels of TNF in CSF were detected in 12 of 20 infants with bacterial meningitis and were undetectable in infants with aseptic meningitis and in control infants (p < 0.02). Plasma IL-6 and TNF levels were unreliable for the detection of meningitis in this patient population. We conclude that the presence of IL-6 in the CSF reliably identifies infants with meningitis and that the presence of CSF TNF is a highly specific indicator of bacterial meningeal inflammation.

Prospective analysis of coagulase-negative staphylococcal infection in hospitalized infants.

Coagulase-negative staphylococci are the major cause of late-onset nosocomial neonatal sepsis. We prospectively examined all infants less than 6 months of age hospitalized at Children's Hospital of Philadelphia from whom at least one of two or more blood cultures grew coagulase-negative staphylococci. We considered as infections only those episodes in which multiple blood cultures grew identical isolates. Among 59 episodes that yielded specimens meeting study criteria, 25 were considered infection and 34 contamination. Cultures from infected infants yielded significantly higher numbers of coagulase-negative staphylococci than cultures representing contamination (p = 0.001). Infected infants were more likely to have central venous lines (p = 0.009), and to have received any parenteral nutrition (p = 0.002) or lipids (0.017). Hematologic values were not helpful in distinguishing between infected and uninfected infants. Isolates representing true infection were not different from contaminants in the frequency of positivity for putative virulence phenotypes. Our data corroborate previous studies indicating risk factors and predictors of coagulase-negative staphylococcal infection.

Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis.

We hypothesized that plasma levels of cytokines such as interleukin-6 and tumor necrosis factor (TNF) are elevated in critically ill infants with sepsis and necrotizing enterocolitis (NEC) and that the magnitude of their elevation is correlated with mortality rate. We measured plasma levels of interleukin-6 and TNF in 62 newborn infants with suspected sepsis or NEC. Eighteen infants had bacterial sepsis, 9 had bacterial sepsis plus NEC, and 15 had NEC but negative culture results. Twenty comparably ill infants with negative results on culture of systemic specimens served as study control subjects. Interleukin-6 levels were five- to tenfold higher in infants with bacterial sepsis plus NEC at the onset of disease than in infants with bacterial sepsis alone, in infants with NEC but negative culture results, and in control infants (p < 0.01). These differences persisted throughout the 48-hour study period. Interleukin-6 levels were also significantly higher in nonsurvivors than in survivors (p < 0.001). In contrast, plasma TNF values were not consistently increased in any of the groups. We conclude that plasma interleukin-6 is a more reliable indicator of bacterial sepsis and NEC than plasma TNF and may identify infants who might benefit from immunotherapeutic strategies.

Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression.

Misalignment of pulmonary veins with alveolar capillary dysplasia is recognized as a rare cause of persistent pulmonary hypertension of the neonate. Until now, misalignment of pulmonary veins was thought to be a random occurrence, but its appearance in siblings at our institution suggests that there may be a familial predisposition. There have been reports of variable expression and variable severity in this disease; our report describes this variability in family members.

Idiopathic arterial calcification of infancy: prenatal and postnatal effects of therapy in an infant.

In an infant with idiopathic arterial calcification of infancy, prenatal diagnosis of arterial calcification was made by ultrasonography and allowed initiation of therapy in utero. Etidronate therapy produced apparent radiographic and ultrasonographic improvement in the degree of vascular calcification but did not prevent the lethal progression of intimal vascular occlusive disease.

Correlation of plasma cytokine elevations with mortality rate in children with sepsis.

Cytokines are thought to be important endogenous mediators of the host immune response to bacterial infection. We hypothesized that plasma levels of cytokines are elevated in children with sepsis and that the magnitude of elevation of these cytokines is correlated with severity of illness and mortality rate. We determined plasma levels of tumor necrosis factor, interleukin-6, and interleukin-1 in 21 children with sepsis. Plasma samples were collected at presentation and at 12, 24, and 48 hours thereafter. Cytokine levels were elevated in pediatric patients with bacterial sepsis during the first 48 hours after presentation; levels were undetectable in study control subjects. The tumor necrosis factor and interleukin-6 levels (p less than 0.001), as well as levels of interleukin-1 (p = 0.05), were significantly higher in nonsurvivors than in survivors and were independent of severity of illness (pediatric risk of mortality (PRISM) score) at presentation. Elevations of tumor necrosis factor and interleukin-6 were sustained for longer than 24 to 48 hours in nonsurvivors: II-1 concentrations were significantly increased only at time zero. Of 11 children with an interleukin-6 value greater than 2 ng/ml during the first 48 hours, 10 died; only one of 10 not reaching that level died (p less than 0.001). Cytokines were elevated as frequently with gram-positive as with gram-negative infections. We speculate that cytokine determinations may identify children who might benefit from immunotherapeutic interventions.

Surface colonization with coagulase-negative staphylococci in premature neonates.

To follow the emergence of surface colonization with coagulase-negative staphylococci in neonates, we sampled four surface sites (axilla, ear, nasopharynx, and rectum) in 18 premature infants during the first 4 weeks of life. Swabs were obtained on the first day of life, twice weekly for 2 weeks, and weekly thereafter. Isolates were characterized by species, biotype, antibiotic susceptibility patterns, and slime production. Over 4 weeks the percentage of infants with Staphylococcus epidermidis as the only surface coagulase-negative staphylococci rose from 11% to 100%. Predominance of a single S. epidermidis biotype increased from none to 89%. Multiple antibiotic resistance rose from 32% to 82% of isolates, and the prevalence of slime production increased from 68% to 95%. This microbiologic pattern was established by the end of the first week of life and persisted throughout the month of study. In three infants, S. epidermidis sepsis developed with organisms identical to their predominant surface isolate. We conclude that species, multiple antibiotic resistance, and slime production appear to confer a selective advantage for the surface colonization of premature newborn infants in the intensive care nursery environment. Infants so colonized may be at greater risk for subsequent infection with these strains of coagulase-negative staphylococci.

Effects of dexamethasone and indomethacin on elastase, alpha 1-proteinase inhibitor, and fibronectin in bronchoalveolar lavage fluid from neonates.

Elastase activity and concentrations of alpha 1-proteinase inhibitor, albumin, and fibronectin were measured in bronchoaleolar lavage (BAL) fluid from ventilated lungs in preterm neonates with lung disease before and after treatment with dexamethasone or indomethacin. Treatment with dexamethasone was associated with a significant decrease in BAL elastase activity but no change in fibronectin, albumin, or alpha 1-proteinase inhibitor concentrations. In contrast, treatment with indomethacin was associated with an increase in BAL elastase activity and fibronectin concentration, with no change in albumin or alpha 1-proteinase inhibitor concentrations. Control groups showed no changes in these BAL fluid biochemical markers during a similar time period. These data indicate that treatment with corticosteroids decreases lung inflammation as measured by BAL elastase activity. Corticosteroid treatment may not inhibit the development of pulmonary fibrosis, because fibronectin concentrations in BAL fluid were unaffected. Indomethacin treatment may augment lung inflammation and fibrosis by increasing BAL elastase activity and fibronectin concentration.

Tracheal lavage and plasma fibronectin: relationship to respiratory distress syndrome and development of bronchopulmonary dysplasia.

Plasma for fibronectin determinations was obtained from 39 neonates with uncomplicated respiratory distress syndrome (RDS) and from 15 infants with RDS who developed bronchopulmonary dysplasia (BPD). Tracheal lavage fibronectin and albumin concentrations were measured in 15 infants with RDS and 15 with BPD. Control plasma fibronectin values were obtained from 20 healthy preterm infants on days 1, 2, 3, 14, and 30 of life. Control tracheal lavage fibronectin and albumin concentrations were measured in 17 neonates of various gestational ages who required tracheal intubation for nonpulmonary indications. Mean plasma fibronectin concentrations from patients with RDS was 121 +/- 11 micrograms/ml on days 1, 2, and 3, versus control level of 163 +/- 12 micrograms/ml (P less than 0.01). Mean tracheal lavage fibronectin/albumin ratio was 3.8 +/- 0.6 ng per microgram of albumin on days 1 to 5 for infants with RDS, versus control level of 5.6 +/- 3.6 (P = NS). Tracheal lavage fibronectin/albumin ratio from patients with BPD was elevated at 16.3 +/- 5.0 ng fibronectin per microgram of albumin on days 14 to 21, and 23.6 +/- 7.4 on day 30 (P less than 0.05 versus control and and versus RDS days 1 to 10). Low plasma fibronectin concentrations early in RDS may contribute to the development of pulmonary capillary leak. High tracheal lavage fibronectin levels may foster the development of pulmonary fibrosis in patients with BPD.