Prolonged intravenous immunoglobulin treatment in very low birth weight infants with late onset sepsis.

BACKGROUND: Neonatal infections are a leading cause of morbi-mortality despite advances in antimicrobials and neonatal care. Preterm infants have greater susceptibility to sepsis due to an immature immune system and lower immunoglobulin levels. Intravenous immunoglobulins (IVIG) have been used in several studies as an adjuvant treatment to improve this physiological immune deficiency, with different outcomes. METHODS: Very low birth weight (VLBW) infants who developed sepsis in the neonatal ICU were studied. They were randomly divided in 2 groups: one group was treated with antibiotics (Group I), and the other received antibiotics plus a 500 mg/kg/day of IVIG during 7 days (Group II). Serum IgG concentration was determined at initiation, during and after treatment Group I, and daily during the 7 days of therapy in Group II. RESULTS: The baseline IgG concentration in group II was 486 g/dL, and increased to 852 mg/dL after the first dose of IVIG (p < 0.01). After the seventh day of infusion a mean IgG level of 1898 mg/dL was achieved. A direct correlation (r = 0.94) between IgG concentration and days of treatment was observed. Blood cultures were positive in 70% of the infants in group I and 75.5% in group II. Staphylococcus epidermidis was the most frequent isolated bacteria in blood cultures. The lethality rate was 25.0% in group I and 5.0% in Group II (p < 0.03). We did not observe collateral effects with the administration of IVIG. CONCLUSIONS: Prolonged therapy with IVIG seems to be safe and effective as an adjuvant treatment in VLBW infants with sepsis.

Intrauterine infection, immune system and premature birth.

Preterm birth accounts for nearly one million deaths among children under five years of age, and although its etiopathogenesis is not fully elucidated, ascending intrauterine infection and fetal inflammatory response seem to be the main triggers. The intense inflammatory response mediated by IL-1ß, TNF-α, PAF, IFN-γ and IL-6, PGE2 and MMP-1 and MMP-9 causes fetal membrane damage and rupture, increased uterine contractions and biochemical and structural changes in the cervix. Furthermore, preterm neonates have deficient innate and adaptive immune responses characterized by reduced levels of IgG, opsonization and phagocytosis, as well as increased activation of Th1 cells in relation to Th2 cells. Therefore, this triad is favors the occurrence of neonatal complications, such as respiratory distress syndrome, necrotizing enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia. Due to serious maternal and child health complications of intrauterine infection, several studies have tried to identify biomarkers for the early diagnosis of this entity. This literature review aims to discuss the main scientific findings regarding the association between ascending intrauterine infection, immune system and preterm birth.

Intestinal mucosal defense system, Part 1. Consensus recommendations for immunonutrients.

When microbial communities colonize in the developing intestinal tract after birth, microorganisms interact with specific apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inflammatory cytokines, thus providing protection from pathogen-induced mucosal damage. Multiple immune modulatory factors in human milk and innate humoral factors also control inflammatory responses, providing additional protective effects. Our understanding of the role of the luminal microbial communities or microbiota is growing rapidly as novel technologies provide new insights into their taxonomy, function during early development, and impact on life-long health. Multiple studies have evaluated the effects of the specific nutrients, glutamine, arginine, nucleotides, polyunsaturated fatty acids, and lactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to modulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is yet known to design specific clinical care practices that support a healthy microbiota.

Intestinal mucosal defense system, Part 2. Probiotics and prebiotics.

The interplay between microorganisms and the intestine of newborn infants is associated with diverse functional and clinical outcomes that result from the specific interactions among microbial communities, their products, and the unique characteristics of the gastrointestinal tract. Multiple mechanisms of action for infant formula ingredients with probiotic activity appear to exist. These mechanisms are thought to protect the host not only from intestinal diseases but also from systemic infection. However, questions about the safety of probiotics for preterm infants remain unanswered, particularly with regard to sepsis, immunomodulatory effects, and microbial resistance. Few well-designed studies have been conducted to evaluate the effects of probiotic, prebiotic, and synbiotic ingredients on relevant clinical outcomes in preterm infants. Although existing data are encouraging, there is insufficient evidence to recommend the routine use of these ingredients in all preterm infants.

In vitro secretion profile of pro-inflammatory cytokines IL-1ß, TNF-α, IL-6, and of human beta-defensins (HBD)-1, HBD-2, and HBD-3 from human chorioamniotic membranes after selective stimulation with Gardnerella vaginalis.

PROBLEM: Preterm labor associated with infection is a major clinical condition; in this work, we analyze the response of human chorioamniotic membranes stimulated with Gardnerella vaginalis. METHOD OF STUDY: Using a two-compartment experimental model, 1 × 10(6) CFU/mL of G. vaginalis were added to either the amnion or choriodecidua face or to both. Concentrations of IL-1ß, TNF-α, and IL-6, as well as human beta defensins (HBD) 1-3 were quantified by ELISA. RESULTS: In comparison with control conditions and regardless of the stimulation modality, IL-1ß and IL-6 increased 4-fold and 28-fold, respectively, in the choriodecidual compartment. HBD-1 increased 2-fold mainly in the amniotic compartment when the stimulus was applied directly to this region. HBD-2 and HBD-3 increased an average of 2- and 8-fold, respectively, in the choriodecidual region. CONCLUSIONS: Stimulation with G. vaginalis induced a tissue-specific secretion profile of 1L-1ß, IL-6, and HBD 1-3 in the chorioamniotic membranes.

Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G.

OBJECTIVE: In a prospective, randomized, placebo-controlled, multicenter study, we evaluated the prevention of neonatal infections with intravenous immunoglobulin G (IVIgG) prophylaxis for preterm infants (gestational age <33 weeks) with umbilical cord blood IgG levels < or =4 g/L. STUDY DESIGN: Intravenous IgG or placebo (albumin), 1 g/kg body weight, was given on days 0, 3, 7, 14, and 21 to 81 infants with umbilical cord blood IgG levels < or =4 g/L: (1) IVIgG group, n = 40, mean (SD) gestational age 27.5 (2.2) weeks and birth weight 1.06 (0.39) kg; (2) placebo group, n = 41, mean (SD) gestational age 27.7 (2.5) weeks and birth weight 1.13 (0.38) kg. Infants with umbilical cord blood IgG levels >4 g/L (n = 238) served as a separate comparison group. Neonatal infections according to European Society of Pediatric Infectious Disease criteria were monitored until 28 days of life. RESULTS: Infants with IgG levels < or =4 g/L at birth who received IVIgG had no significant reduction in infectious episodes or mortality rate when compared with those given placebo. However, infants with a serum concentration of IgG >4 g/L at birth had significantly fewer infectious episodes (culture-proven sepsis) than infants with low serum concentrations of IgG (< or =4 g/L) when compared at the same gestational ages (26 to 29 weeks, P <.003). CONCLUSIONS: Prophylactic immunotherapy with IVIgG did not improve the immune competence in preterm infants with low serum IgG concentrations at birth. We speculate that a spontaneously high serum IgG concentration at birth reflects placenta function and is an indicator of a more mature immune system capable of protecting the preterm infant against severe neonatal infections.

Premature infants respond to early-onset and late-onset sepsis with leukocyte activation.

OBJECTIVE: Leukocyte differentiation antigens are expressed on the cell membrane during activation. The purpose of this study was to evaluate leukocyte activation in premature neonates with sepsis. Paired blood samples from the same individual while sick and while convalescent were examined to quantify the expression of leukocyte antigens in these clinical states. METHODS: Mononuclear blood cells from 21 premature infants (24 to 30 weeks' gestation) were analyzed. The "sick" samples were drawn at the time of workup for sepsis; "convalescent" samples were drawn 20 days later. Samples were incubated with monoclonal antibodies to the lymphocyte antigens CD3, CD19, CD25, CD26, CD71, and CD69 and neutrophil antigens CD11b, CD11c, CD13, CD15, CD33, and CD66b. The cells were lysed, fixed, and analyzed by flow cytometry. RESULTS: Twenty-one infants enrolled in the study had multiple sepsis evaluations and had more than one sample available for a paired observation. CD33, CD66b, and CD19 levels were significantly elevated in both the presumed sepsis and culture-proven sepsis groups when compared with the samples drawn from those same patients when healthy. Expression of CD33 and expression of CD66b were correlated, and in a multivariate analysis the elevation of antigen expression was predictive of sepsis. CONCLUSIONS: Leukocytes from preterm newborn infants respond to infection with an increased expression of CD19, CD33, and CD66b on their cell surfaces.

Granulocyte colony-stimulating factor as a marker for bacterial infection in neonates.

OBJECTIVE: To evaluate granulocyte colony-stimulating factor (G-CSF) as an early marker of bacterial or fungal infection in neonates. STUDY DESIGN: We measured G-CSF levels in infants of varying gestational and postnatal ages. We separated the infants into three groups: group 1, positive bacterial or fungal blood culture result; group 2, negative blood culture result but evidence of clinical sepsis; and group 3, negative blood culture result and no or weak evidence of sepsis. Comparison of mean G-CSF levels by group was accomplished by an analysis of variance. RESULTS: One hundred seventy-six evaluations for sepsis were done for 156 infants with gestational ages ranging from 24 to 43 weeks; 50% of these infants were less than 35 weeks of gestational age. The mean G-CSF levels of groups 1 and 2 were significantly higher than those of group 3. The mean G-CSF level of each group was 2278 pg/ml (group 1), 1873 pg/ml (group 2), and 280 pg/ml (group 3) (p < 0.001). On the basis of a cutoff level of 200 pg/ml, the sensitivity of the test was 95%, specificity 73%, positive predictive value 40%, and negative predictive value 99%. CONCLUSION: G-CSF levels represent a sensitive marker of infection in neonates of all gestational ages.

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.

Response to Haemophilus influenzae type b conjugate vaccine in chronically ill premature infants.

Twenty-two premature infants with chronic lung disease (median gestational age 28 weeks) received polyribosylribitol phosphate-outer membrane protein conjugate Haemophilus vaccine at 2 and 4 months of chronologic age. The proportions with antibodies to polyribosylribitol phosphate at levels > 1 microgram/ml after doses 1 and 2 were 27% and 55%; geometric mean titers were 0.43 and 0.73 microgram/ml, significantly lower than values for term infants.

Intravenous immune globulin therapy for early-onset sepsis in premature neonates.

Newborn infants may have IgG deficiencies that increase their susceptibility to bacterial infection. To determine whether intravenous immune globulin (IVIG) therapy improves survival rates in early-onset sepsis, we prospectively entered 753 neonates (birth weight 500 to 2000 gm, gestation less than or equal to 34 weeks, age less than or equal to 12 hours) into a multicenter, double-blind, controlled trial. Blood culture specimens were obtained and infants randomly assigned to receive 10 ml (per kilogram) intravenously of a selected IVIG (500 mg/kg) or albumin (5 mg/kg) preparation. Maternal and neonatal risk factors were not different between groups. Thirty-one babies (4.2%) had early-onset sepsis; the causative organisms were group B streptococcus (12 babies), Escherichia coli (6), and others (13). Of these 31 neonates, 7 (23%) died. Total serum IgG was higher for 7 days after IVIG therapy than after albumin treatment (p less than 0.05). During these 7 days, 5 (30%) of 17 albumin-treated and none of 14 IVIG-treated patients died (p less than 0.05). The survival rate at 56 days of age, however, was not significantly improved. Group B streptococcus type-specific IgG antibody was significantly increased after IVIG treatment and appeared to be related to the amount of IVIG specific antibody. Infusion-related adverse reactions were less frequent in patients receiving IVIG therapy (0.5%) than in those receiving albumin. The IVIG therapy in neonates with early-onset sepsis, while reducing the early mortality rate, did not significantly affect the overall survival rate. Further studies are necessary to confirm these findings and to determine more effective therapeutic regimens.

Infectoepidemiologic and immunologic implications of Campylobacter coli enteritis in one newborn monozygotic twin pair

Como as características clínicas da infecçäo humana por campylobacter em pacientes recém-nascidos näo estäo ainda bem documentadas, considerou-se interessante comunicar a ocorrência de dois casos simultâneos de enterite por C. coli em gêmeos monozigotos. Discute-se a história clínica, os aspectos epidemiológicos e microbiológicos, o desenvolvimento de imunidade bem cocmo a síntese de Ig totais, tendo em consideraçäo as estreitas relaçöes genético-ecológicas destes dois casos

Infectoepidemilogic and immunologic implications of Campylobacter coli enteritis in one newborn monozygotic twin pair.

Since campylobacter infections in humans at early age have not been thoroughly documented yet, it seemed interesting to report the occurrence of two simultaneous cases of C. coli enteritis in one newborn monozygotic twin pair. Their clinical history, epidemiology and microbiological analysis, development of specific serum and mucosal immunity as well as total Ig synthesis are discussed on the basis of their close genetic and environmental relationships.

Sequelae of maternally derived cytomegalovirus infections in premature infants.

Eighteen of 106 (17%) infants of seropositive mothers, with birth weights less than 1500 gm, acquired cytomegalovirus from a maternal source. Neutropenia, lymphocytosis, thrombocytopenia, and hepatosplenomegaly developed in some infants concomitant with the onset of CMV excretion. Infected infants who excreted CMV at less than 7 weeks of age had longer oxygen requirements than infants who did not excrete CMV until they were older. Passively derived maternal antibody to CMV fell more rapidly over the first few months of life in sick premature infants than would be expected in term infants. Among six infected premature infants, five had undetectable antibody titers when CMV excretion began. Loss of passively acquired antibody and early excretion of virus appear to be associated with symptomatic CMV infections in premature infants of seropositive mothers.