Maria Paola Ronchetti

Low Serum Levels of Mannose Binding Lectin Are a Risk Factor for Neonatal Sepsis

Mannose binding lectin (MBL) is a soluble pattern recognition receptor of innate immunity that binds a wide range of pathogens and exerts opsonic effects. We investigated the association between serum MBL levels and development of sepsis in infants admitted to neonatal intensive care units (NICUs). Serum MBL levels on admission were measured by enzyme-linked immunosorbent assay (ELISA) in 206 neonates consecutively admitted to an NICU of whom 138 did not develop hospital-acquired sepsis and 68 did. Of these 68, 40 had confirmed sepsis with positive blood cultures, 19 clinically suspected sepsis, with negative blood cultures, and nine had clinically suspected sepsis with blood culture yielding coagulase-negative staphylococci (CoNS). Serum MBL levels on admission were significantly lower in infants with sepsis [0.45 μg/mL; interquartile range (IQR) 0.09–1.68], particularly in those with confirmed sepsis (0.17 μg/mL; IQR 0.05–0.96), compared with infants without sepsis (1.45 μg/mL; IQR 0.43–3.52), and infants with CoNS-positive blood culture (1.70 μg/mL: IQR 0.85–3.60). After adjusting for duration of exposure gestational age (GA) and birth weight (BW), the association of low MBL levels with development of sepsis was maintained [odds ratio (OR) = 0.52; 95% confidence interval (CI): 0.36–0.75]. The measurement of serum MBL levels on admission in NICU may help to identify neonates at higher risk of developing sepsis.

Procalcitonin in detecting neonatal nosocomial sepsis

Objective To investigate the accuracy of procalcitonin (PCT) as a diagnostic marker of nosocomial sepsis (NS) and define the most accurate cut-off to distinguish infected from uninfected neonates. Setting Six neonatal intensive care units (NICUs). Patients 762 neonates admitted to six NICUs during a 28-month observational study for whom at least one serum sample was taken on admission. Main outcome measures Positive and negative predictive values at different PCT cut-off levels. Results The overall probability of an NS was doubled or more if PCT was >0.5 ng/ml. In very-low-birth-weight (VLBW) infants, a cut-off of >2.4 ng/ml gave a positive predictive value of NS near to 50% with a probability of a false-positive diagnosis of NS in about 10% of the patients. Conclusions In VLBW neonates, a serum PCT value >2.4 ng/ml prompts early empirical antibiotic therapy, while in normal-birth-weight infants, a PCT value ≤2.4 ng/ml carries a low risk of missing an NS.

Hearing impairment in congenital diaphragmatic hernia: the inaudible and noiseless foot of time

AIM OF THE STUDY Infants with congenital diaphragmatic hernia (CDH) are at high risk of sensorineural hearing loss (SNHL). Extracorporeal membrane oxygenation is known to increase this risk, but little is known about other potential causes. We evaluated the impact of several risk factors on SNHL development in CDH survivors not treated with extracorporeal membrane oxygenation. METHODS All high-risk CDH survivors consecutively treated between 1999 and 2005 were included. SNHL was diagnosed based on formal assessment with standard audiologic tests. Patients with and without SNHL were compared for patient-related and treatment-related risk factors. Subsequently, a logistic regression analysis was performed to identify independent risk factors associated with SNHL development. MAIN RESULTS Out of 87 CDH survivors, 82 had a formal audiologic evaluation and 40 (49%) had SNHL. Patients with SNHL had significantly lower gestational age (P = .045); higher prevalence of sepsis (P < .001); older age at audiologic examination (P < .001); more episodes of hypocapnia (P = .045); higher prevalence of inhaled nitric oxide use (P = .005); longer mechanical ventilation (P = .009); and longer aminoglycosides (P = .006), furosemide (P = .004), and pancuronium bromide (P = .001) treatments. On logistic regression analysis, the only variable independently associated with the development of SNHL was patients age at audiologic follow-up (P = .012). CONCLUSIONS Several risk factors were associated with SNHL development at univariate analysis. After logistic regression, only age at evaluation remained independently associated with SNHL. Routine audiologic follow-up is advocated in all CDH patients. Further studies are needed to define if other (genetic) factors may be involved in the pathogenesis of SNHL in patients with CDH.

Determinants of Nosocomial Infection in 6 Neonatal Intensive Care Units: An Italian Multicenter Prospective Cohort Study

BACKGROUND Nosocomial infections are still a major cause of morbidity and mortality among neonates admitted to neonatal intensive care units (NICUs). OBJECTIVE To describe the epidemiology of nosocomial infections in NICUs and to assess the risk of nosocomial infection related to the therapeutic procedures performed and to the clinical characteristics of the neonates at birth and at admission to the NICU, taking into account the time between the exposure and the onset of infection. DESIGN A multicenter, prospective cohort study. PATIENTS AND SETTING A total of 1,692 neonates admitted to 6 NICUs in Italy were observed and monitored for the development of nosocomial infection during their hospital stay. METHODS Data were collected on the clinical characteristics of the neonates admitted to the NICUs, their therapeutic interventions and treatments, their infections, and their mortality rate. The cumulative probability of having at least 1 infection and the cumulative probability of having at least 1 infection or dying were estimated. The hazard ratio (HR) for the first infection and the HR for the first infection or death were also estimated. RESULTS A total of 255 episodes of nosocomial infection were diagnosed in 217 neonates, yielding an incidence density of 6.9 episodes per 1,000 patient-days. The risk factors related to nosocomial infection in very-low-birth-weight neonates were receipt of continuous positive airway pressure (HR, 3.8 [95% confidence interval {CI}, 1.7-8.1]), a Clinical Risk Index for Babies score of 4 or greater (HR, 2.2 [95% CI, 1.4-3.4]), and a gestational age of less than 28 weeks (HR, 2.1 [95% CI, 1.2-3.8]). Among heavier neonates, the risk factors for nosocomial infection were receipt of parenteral nutrition (HR, 8.1 [95% CI, 3.2-20.5]) and presence of malformations (HR, 2.3 [95% CI, 1.5-3.5]). CONCLUSIONS Patterns of risk factors for nosocomial infection differ between very-low-birth-weight neonates and heavier neonates. Therapeutic procedures appear to be strong determinants of nosocomial infection in both groups of neonates, after controlling for clinical characteristics.

Role of mannose-binding lectin in nosocomial sepsis in critically ill neonates.

We investigated the association of mannose-binding lectin (MBL) serum levels with nosocomial sepsis (NS), their changes overtime during infection, their relation with pathogens, with the MBL2 genotype and their relationship with mortality. In a prospective observational study, we included 365 critically ill neonates: 261 had no infection and 104 had at least 1 septic event. The median MBL serum concentration was significantly lower in infected than in noninfected neonates (p < 0.001). Low MBL levels on admission increased the risk of infection, independently from gestational age and invasive procedures. The median peak MBL level during infection was higher than the median level on admission (p < 0.001) and was correlated with it (r(2) = 0.83, p < 0.001). Moreover, MBL levels on admission were not associated with death (OR = 0.80, 95% CI = 0.56-1.14, p = 0.21). Similarly, no association was found between MBL peak levels during infection and death among infected neonates (OR = 1.10, 95% CI = 0.78-1.57, p = 0.57). In 127 neonates (42 infected) genotyped for exon-1 and -221 promoter MBL2 variants, we did not find significant difference in the frequencies of MBL2 genotypes between infected and noninfected neonates. Moreover, no association was found between MBL2 genotypes and death.

A polymorphism in the macrophage migration inhibitory factor promoter is associated with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a common adverse outcome of prematurity, causing severe morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) has been recently shown to favor murine fetal lung development. In this prospective study, we evaluate the expression of MIF in the lung and in the serum of preterm infants (n = 50) and investigate whether the −173 G/C MIF promoter polymorphism is associated with the risk of BPD (n = 103). MIF was highly expressed in lung tissue from preterm infants. Serum MIF levels were measured by ELISA at d 1 after birth. MIF levels were increased [median (interquartile range), 71.01 (44.9–162.3) ng/mL], particularly in those infants with RDS [110.4 (59.4–239.2) ng/mL] compared with healthy adults [2.4 (1.2–5.0) ng/mL], (p < 0.001). The MIF −173*C allele, which predisposes to higher MIF production, was associated with a lower incidence of BPD (OR, 0.2; 95% CI, 0.04–0.93), independently from mechanical ventilation and oxygen exposure (p = 0.03). In conclusion, these data show that MIF expression is increased in lung and serum of preterm infants and suggest that the high producing MIF −173*C allele may be a protective factor for BPD.

Use of Early Biomarkers in Neonatal Brain Damage and Sepsis: State of the Art and Future Perspectives

The identification of early noninvasive biochemical markers of disease is a crucial issue of the current scientific research, particularly during the first period of life, since it could provide useful and precocious diagnostic information when clinical and radiological signs are still silent. The ideal biomarker should be practical and sensitive in the precocious identification of at risk patients. An earlier diagnosis may lead to a larger therapeutic window and improve neonatal outcome. Brain damage and sepsis are common causes of severe morbidity with poor outcome and mortality during the perinatal period. A large number of potential biomarkers, including neuroproteins, calcium binding proteins, enzymes, oxidative stress markers, vasoactive agents, and inflammatory mediators, have been so far investigated. The aim of the present review was to provide a brief overview of some of the more commonly investigated biomarkers used in case of neonatal brain damage and sepsis.

MBL2 gene polymorphisms increase the risk of adverse neurological outcome in preterm infants: a preliminary prospective study

Background:As described in animal models, the lectin-complement pathway is central to the propagation of ischemia–reperfusion injuries in many tissues, including the brain. Similarly, it might affect the genesis of brain damage in preterm infants. MBL2 gene single-nucleotide polymorphisms (SNPs), regulating mannose-binding lectin (MBL) serum levels, could predict the risk of adverse neurological outcome in these infants.Methods:To evaluate the association between SNPs of the MBL2 gene and long-term neurological outcomes in preterm infants, 75 infants (gestational age (GA) ≤ 32 wk) were observed in a prospective longitudinal study and assessed by clinical and instrumental exams at 12 and 24 mo of corrected age (CA). They were genotyped for the promoter polymorphism -221 and for the exon-1 variant alleles (at codons 52, 54, and 57) of the MBL2 gene.Results:The MBL2 exon-1 OO genotype was more frequent in children with an adverse neurological outcome (5/35; 7%) than in controls (0/40; 0%), P = 0.045. The risk of intraventricular hemorrhage in carriers of the genotype OO was marked, without reaching statistical significance (odds ratio: 8.67; 95% confidence interval: 0.87–86.06; P = 0.07).Conclusion:Preterm infants who are carriers of MBL2 exon-1 OO genotype are exposed to an increased risk of adverse neurological outcomes.

Shunt lock therapy with micafungin to treat shunt-associated Candida albicans meningitis in an infant

Neonatal Intensive Care Unit, Department of Neonatology, Bambino Gesu’ Children’s Hospital, Rome, Italy; Neurosurgery Unit, Department of Neurosurgery, Bambino Gesu’ Children’s Hospital, Rome, Italy; Infectious Diseases Section, Department of Public Health and Infectious Diseases, ‘La Sapienza’ University, Rome, Italy; Laboratory of Biochemistry, Department of Specialist Pediatrics, Bambino Gesù Children’s Hospital, Rome, Italy

High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis

ABSTRACT High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect.