Unmyelinated white matter loss in the preterm brain is associated with early increased levels of end-tidal carbon monoxide.

OBJECTIVE: Increased levels of end-tidal carbon monoxide (ETCOc) in preterm infants during the first day of life are associated with oxidative stress, inflammatory processes and adverse neurodevelopmental outcome at 2 years of age. Therefore, we hypothesized that early ETCOc levels may also be associated with impaired growth of unmyelinated cerebral white matter. METHODS: From a cohort of 156 extremely and very preterm infants in which ETCOc was determined within 24 h after birth, in 36 infants 3D-MRI was performed at term-equivalent age to assess cerebral tissue volumes of important brain regions. RESULTS: Linear regression analysis between cerebral ventricular volume, unmyelinated white matter/total brain volume-, and cortical grey matter/total brain volume-ratio and ETCOc showed a positive, negative and positive correlation, respectively. Multivariable analyses showed that solely ETCOc was positively related to cerebral ventricular volume and cortical grey matter/total brain volume ratio, and that solely ETCOc was inversely related to the unmyelinated white matter/total brain volume ratio, suggesting that increased levels of ETCOc, associated with oxidative stress and inflammation, were related with impaired growth of unmyelinated white matter. CONCLUSION: Increased values of ETCOc, measured within the first 24 hours of life may be indicative of oxidative stress and inflammation in the immediate perinatal period, resulting in impaired growth of the vulnerable unmyelinated white matter of the preterm brain.

Maternal and neonatal anti-cytomegalovirus IgG level and risk of postnatal cytomegalovirus transmission in preterm infants.

Immunological mechanisms influencing the risk of mother-to-child cytomegalovirus (CMV) transmission in preterm infants have not been studied sufficiently. In this study, the correlation between maternal and neonatal serum anti-CMV IgG levels and risk of postnatal CMV transmission in preterm infants was assessed. Anti-CMV IgG levels of 79 CMV seropositive mothers and their 94 infants were determined in peripheral blood samples collected within 3 days after delivery. Postnatal CMV infection was detected in 39/94 (41%) infants by PCR on urine at term-equivalent age (gestational age 40 weeks) after congenital infection was excluded. Maternal or infant anti-CMV IgG levels were not significantly different between infants with and without postnatal CMV infection. The anti-CMV IgG infant-mother ratio showed a significant positive correlation with gestational age (range 25-32 weeks, R(2) = 0.218, P < 0.001), reaching 1.0 at 32 weeks of gestation. Anti-CMV IgG infant-mother ratio was significantly lower in infants with postnatal CMV infection (P = 0.015). In conclusion, the risk of postnatal CMV transmission is related to low gestational age and low anti-CMV IgG infant-mother ratio.

The effect of a computerized prescribing and calculating system on hypo- and hyperglycemias and on prescribing time efficiency in neonatal intensive care patients.

BACKGROUND: Prescribing glucose requires complex calculations because glucose is present in parenteral and enteral nutrition and drug vehicles, making it error prone and contributing to the burden of prescribing errors. OBJECTIVE: Evaluation of the impact of a computerized physician order entry (CPOE) system with clinical decision support (CDS) for glucose control in neonatal intensive care patients (NICU) focusing on hypo- and hyperglycemic episodes and prescribing time efficiency. METHODS: An interrupted time-series design to examine the effect of CPOE on hypo- and hyperglycemias and a crossover simulation study to examine the influence of CPOE on prescribing time efficiency. NICU patients at risk for glucose imbalance hospitalized at the University Medical Center Utrecht during 2001-2007 were selected. The risks of hypo- and hyperglycemias were expressed as incidences per 100 patient days in consecutive 3-month intervals during 3 years before and after CPOE implementation. To assess prescribing time efficiency, time needed to calculate glucose intake with and without CPOE was measured. RESULTS: No significant difference was found between pre- and post-CPOE mean incidences of hypo- and hyperglycemias per 100 hospital days of neonates at risk in every 3-month period (hypoglycemias, 4.0 [95% confidence interval, 3.2-4.8] pre-CPOE and 3.1 [2.7-3.5] post-CPOE, P = .88; hyperglycemias, 6.0 [4.3-7.7] pre-CPOE and 5.0 [3.7-6.3] post-CPOE, P = .75). CPOE led to a significant time reduction of 16% (1.3 [0.3-2.3] minutes) for simple and 60% (8.6 [5.1-12.1] minutes) for complex calculations. CONCLUSIONS: CPOE including a special CDS tool preserved accuracy for calculation and control of glucose intake and increased prescribing time efficiency.

Cerebral white matter and neurodevelopment of preterm infants after coagulase-negative staphylococcal sepsis.

OBJECTIVE: Coagulase-negative staphylococci are the most common pathogens causing late-onset sepsis in the neonatal intensive care unit. Neonatal sepsis can be associated with cerebral white matter damage in preterm infants. Neurodevelopment has been shown to be correlated with apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivities of the white matter. DESIGN: Prospective cohort study. SETTING: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital. PATIENTS: Seventy preterm infants (gestational age <32 wks), 28 with coagulase-negative staphylococcal sepsis (group 1) and 42 without sepsis (group 2). INTERVENTION: The values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of three white matter regions (parietal, frontal, and occipital), estimated with diffusion-tensor magnetic resonance imaging with a 3.0-T magnetic resonance imaging system, were obtained at term-equivalent age. Neurodevelopmental outcome assessments were performed at 15 months (Griffiths Mental Developmental Scales) and 24 months (Bayley Scales of Infant and Toddler Development, Third Edition) corrected age. MEASUREMENTS AND MAIN RESULTS: Values of apparent diffusion coefficients, fractional anisotropy, and axial and radial diffusivity of the left and right white matter regions were equal in all patients. There was no significant difference in apparent diffusion coefficient values (mean of total: 1.593 ± 0.090 × 10mm(-3)/sec(2) and 1.601 ± 0.117 × 10mm(-3)/sec(2), respectively, p = .684), fractional anisotropy values (mean of total: 0.19 ± 0.04 and 0.19 ± 0.03, respectively, p = .350), radial diffusivity (mean of total: 1.420 ± 0.09 × 10mm(-3)/sec(2)and 1.425 ± 0.12 × 10mm(-3)/sec(2), respectively, p = .719), and axial diffusivity (mean of total: 1.940 ± 0.12 × 10mm(-3)/sec(2) and 1.954 ± 0.13 × 10mm(-3)/sec(2), respectively, p = .590) in the three combined regions between the two groups. No significant differences were found in neurodevelopmental outcome at 24 months. CONCLUSIONS: No association was found between coagulase-negative staphylococcal sepsis in preterm infants and cerebral white matter damage as determined by values of apparent diffusion coefficients, fractional anisotropy, and radial and axial diffusivity at term-equivalent age, and no adverse effect was seen on early neurodevelopmental outcome.

Reduced expression of PBP-2A by neonatal mecA-positive coagulase-negative staphylococci (CoNS) blood isolates: ß-lactams are useful first-line agents for the treatment of neonatal CoNS sepsis, restricting the use of vancomycin.

OBJECTIVES: Vancomycin use for neonatal coagulase-negative staphylococci (CoNS) sepsis is based on a high CoNS carriage rate of mecA, encoding penicillin-binding protein (PBP)-2a, with low affinity for, and associated with resistance to, ß-lactam antibiotics. The relationship between mecA gene carriage, phenotypic expression of the gene by PBP-2a production and in vitro resistance to the ß-lactam antibiotics oxacillin, cefazolin and amoxicillin/clavulanate was determined for 85 CoNS blood isolates randomly obtained from our collection of isolates from neonates with CoNS sepsis. METHODS: The relationship between mecA gene carriage, phenotypic expression of the gene by PBP-2a production and in vitro resistance to the ß-lactam antibiotics oxacillin, cefazolin and amoxicillin/clavulanate was determined for randomly obtained CoNS blood isolates from our collection of isolates from neonates with CoNS sepsis. The mecA gene was detected using multiplex PCR, and PBP-2a expression was determined using a latex agglutination (LA) test (Oxoid). ß-Lactam susceptibility was determined using the Phoenix automated system and, in addition, by Etest with interpretation of MIC values according to the reference MIC breakpoints adopted from the CLSI guidelines M100-S20, Infobase™. RESULTS: Among 85 CoNS blood isolates, 73 (86%) were mecA positive and 12 (14%) were mecA negative. None of the mecA-negative isolates expressed PBP-2a and all were ß-lactam susceptible. All mecA-positive CoNS isolates were oxacillin resistant, although most oxacillin MICs were not very high, ranging from 2 to 8 mg/L for the majority of isolates. Only 8/73 (11%) mecA-positive CoNS isolates had oxacillin MICs ≥32 mg/L (range 32 to >256 mg/L). mecA-positive CoNS blood isolates, although fully resistant to oxacillin, were almost universally susceptible to cefazolin and amoxicillin/clavulanate, which was associated with a low expression rate of PBP-2a. CONCLUSIONS: ß-Lactam antibiotics are useful for the treatment of neonatal CoNS sepsis, reserving vancomycin for selected cases.

Shortening the antibiotic course for the treatment of neonatal coagulase-negative staphylococcal sepsis: fine with three days?

BACKGROUND: The incidence of coagulase-negative staphylococcal (CoNS) sepsis is high in neonatal intensive care units (NICUs) and treatment significantly adds to the antibiotic pressure, increasing the threat of resistance. Because infants recover within 24-48 h, blood cultures are negative within 48 h and CRP normalizes within 72 h, we reduced anti-CoNS treatment from 7 to 3 days in infants with uncomplicated CoNS sepsis. OBJECTIVES: The aim of the study was to evaluate the effect of short (3 days) treatment duration for CoNS sepsis. METHODS: All infants with CoNS sepsis from January 2006 to September 2010 were evaluated. Before 2008 the duration of anti-CoNS treatment was 7 days, but in 2008 it was reduced to 3 days, provided that infants recovered within 48 h, CRP value decreased, thrombocytes were normal and central venous catheters were either not present or removed. Clinical results of treatment for 3 days were compared with 7 days of treatment. RESULTS: There were 142 infants with CoNS sepsis who were eligible for 3 days of antimicrobial treatment duration, 62 (44%) from the period 2006-2008 were treated over 7 days (Group 1) and 80 (56%) from the period 2008-2010 were treated over 3 days (Group 2). Clinical characteristics were not different between the groups. All infants recovered within 48 h and CoNS sepsis did not relapse. CONCLUSIONS: Antibiotic treatment for CoNS sepsis may be shortened to 3 days when clinical improvement is rapid and central lines are not present. Prospective randomized studies are needed to confirm the results of this single-center study. Future studies may reveal the effects on the development of antimicrobial resistance.

Early end-tidal carbon monoxide levels and neurodevelopmental outcome at 3 years 6 months of age in preterm infants.

AIM: Increased end-tidal carbon monoxide (ETCOc) and cytokines in preterm infants are related to bronchopulmonary dysplasia and intraventricular haemorrhages. The aim was to study the predictive value of ETCOc and cytokine levels for long-term outcome. METHODS: This study comprised 105 very preterm infants (57 males, 48 females; gestational age range 25 wks 5d-31 wks 4d; birthweight 610-2100 g) who were admitted to a neonatal intensive care unit between 1 February and 31 December 2002. ETCOc, plasma tumour necrosis factor alpha (TNF-α) and interleukins (IL) 6 and 8, and malondialdehyde (MDA, a marker of lipid peroxidation), were measured at days 1, 3, and 5 of life and related to outcome at 3 years 6 months of age (Griffiths Mental Developmental Scales). RESULTS: Of the 105 infants, 69 were eligible for follow-up (37 males; 32 females; bronchopulmonary dysplasia, n = 12). ETCOc at 0 to 24 hours was higher in infants with adverse outcome (Griffiths developmental quotient <85, n = 15) compared with favourable outcome (2.7SD 0.7 vs 2.0SD 0.5; p < 0.05). MDA and cytokines did not differ between groups. Regression analysis with bootstrapping of independent variables (gestational age, birthweight, ETCOc, TNF-α, IL-6, IL-8, and bronchopulmonary dysplasia) showed that ETCOc was the only parameter that correlated with outcome. The sensitivity and negative predictive value of ETCOc for adverse outcome were 93% and 85% respectively. INTERPRETATION: Adverse neurodevelopmental outcome is associated with increased endogenous carbon monoxide. ETCOc less than 2.0 ppm during the first day indicates a favourable outcome.

A seven-year survey of management of coagulase-negative staphylococcal sepsis in the neonatal intensive care unit: vancomycin may not be necessary as empiric therapy.

BACKGROUND: The typical empiric therapy for coagulase-negative staphylococcal (CONS) sepsis includes vancomycin. In our neonatal intensive care unit, we have consistently avoided the use of vancomycin to treat CONS sepsis, except for specific cases, and have used instead cefazolin as empiric agent. OBJECTIVES: The clinical outcome of infants with CONS sepsis was evaluated in relation to the susceptibility of CONS blood isolates to cefazolin over a period of 7 years. METHODS: Clinical characteristics, symptoms of sepsis and antibiotic use were studied retrospectively. Susceptibility of CONS blood isolates to cefazolin was determined by E-test. RESULTS: Of 163 infants with proven CONS sepsis, 121/140 (86%) infants with a cefazolin-susceptible (minimum inhibition concentration (MIC) ≤8 mg/l) and 21/23 (91%) with a cefazolin-resistant (MIC ≥32 mg/l) blood isolate were treated with cefazolin. 21 (13%) infants were switched to vancomycin, in only 3 of them CONS had become resistant to cefazolin. The majority (81%) of the infants with a good response to cefazolin had the indwelling central venous catheter removed, in contrast to only 22% of the infants with cefazolin treatment failure. Median cefazolin MIC values were 0.75-2 mg/l during the study period. CONCLUSIONS: The great majority of infants with CONS sepsis was successfully treated with cefazolin. The use of vancomycin could be restricted to specific cases. Despite the consistent use of cefazolin in neonatal CONS sepsis over an extended period of time, cefazolin MIC values remained low and in the susceptible range. Removal of the central venous catheter in infants with clinical symptoms of sepsis is an important therapeutic measure.

Prevention of neonatal late-onset sepsis associated with the removal of percutaneously inserted central venous catheters in preterm infants.

OBJECTIVES: Indwelling central venous catheters are the most important risk factors for the development of sepsis attributable to coagulase-negative staphylococci among preterm infants admitted to neonatal intensive care units. In addition, removal of a central venous catheter also may cause coagulase-negative staphylococci sepsis, which may be prevented by the short-term administration of an anti-staphylococcal agent during the procedure of removal. The administration of a specific anti-staphylococcal agent (cefazolin) was evaluated for the prevention of central venous catheter removal-associated coagulase-negative staphylococci sepsis. DESIGN: A prospective, open, randomized, controlled intervention study. SETTING: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital. PATIENTS: Eighty-eight preterm infants (gestational age <37 wks) admitted to the neonatal intensive care unit with indwelling percutaneously inserted central venous catheters. INTERVENTION: From April 2007 to January 2010, infants were randomized to receive two doses of cefazolin during removal of the percutaneously inserted central venous catheter (intervention group, n = 44) or no antimicrobial agent (control group, n = 44). Percutaneously inserted central venous catheter removal-associated sepsis was defined as sepsis occurring <48 hrs after removal of the percutaneously inserted central venous catheter. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics and central venous catheter duration did not show differences between both groups. Five infants (11%) of the control group developed coagulase-negative staphylococci sepsis <48 hrs after removal of the percutaneously inserted central venous catheter compared to none (0%) in the intervention group (p = .021). CONCLUSIONS: Two doses of the anti-staphylococcal agent cefazolin during the procedure of removal of a percutaneously inserted central venous catheter were effective in the prevention of coagulase-negative staphylococci sepsis. It is recommended to include this regimen in the guidelines on management of central venous catheters in very-low-birth-weight infants.

Improvement of adherence to hand hygiene practice using a multimodal intervention program in a neonatal intensive care.

Nosocomial infections are serious complications among preterm infants admitted to neonatal intensive care units (NICU). Hand hygiene is one of the most effective measures to prevent these infections. This study, performed in a tertiary level NICU, highlights the importance of a multimodal intervention program for adherence to hand hygiene. The compliance with hand hygiene among health care workers of the NICU increased significantly from 23% in the baseline assessment to 50% in the second assessment and the incidence of sepsis decreased from 13.4% to 11.3% after implementation of an intervention program.

Prognosis for neonates with enterovirus myocarditis.

OBJECTIVE: To assess the severity of the disease and the long-term cardiac prognosis for neonates who developed enterovirus (EV) myocarditis within the first weeks of life. DESIGN: Clinical presentation, echocardiographic and ECG findings and the outcome of seven infants with EV myocarditis admitted to the intensive care unit are reported. Additionally, 28 previously reported cases are described. RESULTS: Seven neonates presented with cardiac failure within 17 days after birth requiring respiratory and circulatory support. Echocardiography showed dilatation and severe dysfunction of the left ventricle in all and mitral regurgitation in six. In six patients the echocardiographic pattern resembled myocardial infarction. ECG showed complete loss of the R-wave and a new Q-wave in the left precordial leads in all. Two infants died and five developed long-term cardiac sequelae requiring medication. In all survivors aneurysm formation in the left ventricular wall was found weeks to months later. One patient is awaiting heart transplantation. Coxsackie virus B was detected in blood, cerebrospinal fluid, nasopharyngeal swab or stool by PCR or culture. The mortality of previously described neonates combined with our seven cases was 31% (11/35). Among the survivors 66% (16/24) developed severe cardiac damage. Only 23% (8/35) of the infants fully recovered. CONCLUSIONS: EV myocarditis is a rare but severe disease in the neonatal period, which often leads to death or results in serious chronic cardiac sequelae like chronic heart failure, aneurysm formation within the left ventricle and mitral regurgitation. Chronic cardiac drug therapy is necessary in the majority of these patients.

Variation in antibiotic use in neonatal intensive care units in the Netherlands.

OBJECTIVES: To examine the variation in quantity and classes of antibiotics used in all 10 tertiary care neonatal intensive care units (NICUs) in the Netherlands during 2005. METHODS: We collected data from all tertiary care NICUs in the Netherlands on clinical and demographic characteristics and the type and quantity of systemic antibiotic use [expressed as defined daily doses (DDD)/100 admissions] in 2005. Antibiotics were ranked by volume of DDDs, and those antibiotics which accounted for 90% of the total volume of use [drug utilization (DU) 90%] were noted. RESULTS: Antibiotic consumption ranged from 130 to 360 DDD/100 admissions. In total, 9-24 different antibiotics were used, of which 3-10 were in the DU90% segment. CONCLUSIONS: By comparing antibiotic use in Dutch NICUs we found a considerable variation in the number of different antibiotics used and in the total amount of antibiotic use. Further exploration of the opportunities to reach consensus in antibiotic policy, and to increase attention to antibiotic stewardship, is recommended.

Long-term trends in the epidemiology of neonatal sepsis and antibiotic susceptibility of causative agents.

BACKGROUND: In an era with increased maternal antibiotic use, patterns in early- and late-onset sepsis and antibiotic susceptibility may have changed. OBJECTIVES: To identify longitudinal trends in causative microorganisms for neonatal sepsis and analyze antibiotic susceptibility of all blood isolates of infants with sepsis. METHODS: Early- and late-onset sepsis cases from 29 years (1978-2006) were studied retrospectively, in five clusters of 5 years (period I-V) and one cluster of 4 years (period VI), including antibiotic susceptibility profiles of blood isolates during the years 1999-2006. RESULTS: The incidence of early-onset sepsis decreased (p < 0.01) from 4% during period I (1978-1982) to 1.2% during period VI (2003-2006). 78% of the infants with group B streptococcal (GBS) sepsis were premature during period I, compared to 47% during period VI (p < 0.05). The incidence of early-onset Gram-negative infections remained low during all periods. The incidence of late-onset sepsis, predominantly caused by coagulase-negative staphylococci (CONS) and Staphylococcus aureus, increased since period III from 7.1 to 13.9% in period VI (p < 0.01). Infections due to fungi or yeasts were rare (incidence <0.3%). The majority of CONS blood isolates were oxacillin-resistant, but vancomycin-susceptible. 95% of CONS blood isolates were susceptible for first-generation cephalosporins. Amoxicillin/clavulanic acid-resistant Escherichia coli were infrequent causes of infection. CONCLUSIONS: The incidence of early-onset sepsis mainly caused by GBS decreased. In contrast, the incidence of late-onset sepsis, predominantly caused by CONS, increased significantly. The incidence of fungal and yeast infections remained low. The majority of CONS blood isolates were susceptible for first-generation cephalosporins.

Removal of percutaneously inserted central venous catheters in neonates is associated with the occurrence of sepsis.

BACKGROUND: Clinical signs of sepsis are frequently observed after removal of a percutaneously inserted central venous catheter (PCVC) in neonates admitted at our Neonatal Intensive Care Unit (NICU). To substantiate this finding and to evaluate the effect of antibiotics administered at the time of removal of a PCVC, we conducted a retrospective study among all infants with a PCVC, admitted at our NICU during 2002 and 2005. METHODS: Clinical data, infectious complications and use of antibiotics were studied retrospectively. RESULTS: A PCVC was inserted in 345 infants. Sepsis occurred in 90/345 (26%) infants, in 50/90 (56%) during indwelling PCVC and in 40/90 (44%) after removal of the PCVC. Of the latter 40 sepsis episodes, 24 (60%) occurred within 5 days after removal of a PCVC with a clustering of 21 cases of sepsis within 72 h after the removal. The remaining 16 episodes occurred after 7 days. Administration of antibiotics during removal of the PCVC significantly reduced the incidence of sepsis: 22/213 (10.3%) cases of sepsis occurred when no antibiotics were administered versus 2/132 (1.5%) cases of sepsis when antibiotics were administered (p = 0.002). CONCLUSION: Our study suggests that peripherally inserted central venous catheters are associated with sepsis not only during the indwelling period of the catheter, but also after removal. Administration of antibiotics targeted at the time of removal of the catheter significantly reduced the incidence of sepsis. Future prospective studies are warranted to confirm this observation.

Oxidative stress and proinflammatory cytokine levels are increased in premature neonates of preeclamptic mothers with HELLP syndrome.

BACKGROUND: Respiratory distress syndrome (RDS) incidence is increased in infants of preeclamptic mothers with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. RDS and HELLP syndrome have been associated with oxidative stress and inflammatory processes. OBJECTIVES: We hypothesize that end-tidal carbon monoxide corrected for inhaled CO (ETCOc), malondialdehyde (MDA) (markers of oxidative stress) and proinflammatory cytokine (IL-6, IL-8) production are higher in infants of preeclamptic mothers with HELLP syndrome than in those of preeclamptic mothers without HELLP syndrome. METHODS: Prospective study of 36 infants of preeclamptic mothers (GA <32 weeks) admitted to the Neonatal Intensive Care Unit. ETCOc was measured at 0-12, 48-72 and 168 h postnatally using the CO-Stattrade mark End-Tidal Breath Analyzer. Simultaneously, blood was sampled for MDA, IL-8 and IL-6. RESULTS: At 0-12 h, ETCOc, MDA and IL-8 values (median[range]) were significantly higher in HELLP infants than in infants from preeclamptic mothers without HELLP (ETCOc 2.2 [1.5-3.9] vs. 1.8 [0.5-2.9] ppm; MDA 2.3 [1.3-4.1] vs. 1.5 [0.4-3.1] mumol/l; IL-8 145 [24-606] vs. 62 [26-397] pg/ml; all p <0.05). MDA remained significantly higher during the first 168 h of life (2.3 [0.8-5.8] vs. 1.1 [0.8-3.7] mumol/l, p = 0.02). CONCLUSION: Oxidative stress and proinflammatory cytokine levels are increased in infants of preeclamptic mothers with HELLP syndrome. These processes may cause inactivation of surfactant explaining the increased RDS incidence in these infants.

Severe neonatal parechovirus infection and similarity with enterovirus infection.

BACKGROUND: Enteroviruses (EV) are an important cause of neonatal disease including hepatitis, meningoencephalitis, and myocarditis that can lead to death or severe long-term sequelae. Less is known about severe neonatal infection caused by the parechoviruses (PeV) of which type 1 (PeV1) and type 2 (PeV2) were previously known as echovirus 22 and echovirus 23. They belong to the same family of Picornaviridae as the EV. Of the PeV, so far only PeV3 has been associated in 2 recent reports with severe neonatal infection including involvement of central nervous system. METHODS: We compared the clinical signs, diagnosis, laboratory data, cerebral imaging, and neurodevelopmental outcome of 11 neonates with PeV infection with 21 infants with EV infection treated in our hospital between 1994 and 2006. The diagnosis of EV infection or PeV infection was confirmed by a positive EV and/or PeV real time-polymerase chain reaction on blood, cerebrospinal fluid, (CSF) or stool or a viral culture of stool, nasopharyngeal swab, and/or CSF. RESULTS: The 32 infants presented with sepsis-like illness and the most frequent signs were: fever, seizures, irritability, rash, and feeding problems. All patients received antibiotic treatment. Eleven of 21 infants infected with EV and 7 of 11 infants infected with PeV were full-term. Differentiation between the infants infected with EV and PeV on the basis of fever, irritability, rash, and seizures was not possible. Myocarditis was exclusively seen in 4 patients infected by EV. Eight of 11 patients with a PeV infection had meningoencephalitis of whom only 1 infant developed pleocytosis in the CSF. Serum C-reactive protein and CSF protein values were significantly higher in infants with EV infection than in those with PeV infection. Cerebral imaging of all infants with EV or PeV cerebral infection showed mild to severe white matter abnormalities. In 1 infant with EV infection and 3 infants with PeV infection, neurodevelopmental delay occurred. Mortality and long-term sequelae were mainly associated with myocarditis in the infants who were infected with EV (4 of 21). CONCLUSIONS: It is not possible to distinguish neonatal PeV from EV infection on the basis of clinical signs. Neonates with PeV or EV infection present with sepsis-like illness and the most frequent signs are fever, seizures, irritability, rash, and feeding problems.

Toll-like receptor 2 polymorphism is associated with preterm birth.

Evidence is increasing for a role of polymorphisms in maternal or fetal innate immune response genes in preterm birth. Toll-like receptors (TLRs) are important receptors in the innate immunity. The genotype distribution of two TLR2 single nucleotide polymorphisms (SNPs) and one TLR4 SNP were determined among 524 neonates and associated with gestational age (GA). Genomic DNA was isolated from prospectively collected blood samples and polymorphisms in TLR2 (T-16934A, RS4696480 and Arg753Gln, RS5743708) and TLR4 (Thr399Ile, RS4986791) were determined using sequence specific primers by PCR. Allele frequencies of two TLR2 SNPs and one TLR4 SNP were analyzed according to prematurity. Analysis among 305 infants, after exclusion of infants born after multiple pregnancy or because of preeclampsia, revealed significantly shorter GAs for infants carrying two polymorphic TLR2 alleles (-16934TA/AA and 753ArgGln/GlnGln) compared with infants carrying one polymorphic and one wild-type allele or two wild-type alleles (median GA 30.6 wk versus 34.1-36.8 wk, respectively, p < 0.02). Carriage of two variant TLR2 alleles potentially leads to aberrant innate immune responses, which may have contributed to very preterm birth.

Innate immunity: toll-like receptors and some more. A brief history, basic organization and relevance for the human newborn.

The discovery of Toll-like receptors (TLRs) as essential components of the innate immune system has greatly advanced our knowledge and understanding of immune responses to infection and how these are regulated. Innate immunity in general and TLRs in particular play a crucial role in the front line of host defenses against microbes, but also are a key element in the proper functioning of the immune system at large in vertebrate animals. The innate immune system has been identified as a collection of factors, both cell-associated and cell-free, that comprises an impressively effective and well-organized system that is capable of immediate recognition of a whole array of microbes and microbial components. The cell-bound TLRs fulfill a central role in the process from pathogen recognition to activation of adaptive immunity. From the cell-free factors the plasma protein mannose-binding lectin (MBL) has been studied most extensively. Associations have already been documented between TLR polymorphisms in man and TLR deficiency in animals and an increased susceptibility to infection. The effect of MBL on infectious disease susceptibility only seems to emerge when host defenses are compromised by a severe underlying condition. The functional state of the various components of innate immunity at birth is largely unknown and only recently a number of studies have assessed this feature of the innate immune system. In addition, for the human newborn the innate immune system may have a broader significance; it may well be the key system determining the course of inflammatory events associated with premature birth, a notion that is emphasized by the recently described association between TLR polymorphisms and prematurity. However, there are still many open questions, particularly about the exact relation between individual TLRs and infectious disease susceptibility and how TLRs cooperate in resistance to infection and in initiating adaptive immune responses. With regard to the human newborn, the most relevant question that needs to be resolved is the precise role of innate immunity in the pathogenesis of prematurity.