Bernhard Resch

An Update on the Use of C-Reactive Protein in Early-Onset Neonatal Sepsis: Current Insights and New Tasks

C-reactive protein (CRP) is one of the most studied and most used laboratory tests for neonatal sepsis. As part of the acute-phase reaction to infection, it plays a central role in the humoral response to bacterial invasion. The delayed synthesis during the inflammatory response accounts for its low sensitivity during the early phases of the disease. Diagnostic accuracy clearly improves by the performance of serial determinations and by the combination with earlier markers such as interleukins or procalcitonin. CRP is as well particularly useful for monitoring the response to treatment and guiding antibiotic therapy, though nothing replaces the clinical impression and the gold standard (i.e. culture results). In spite of the large amount of research done on CRP in neonates, some topics are still not fully understood, such as the influence of noninfectious factors on CRP levels in healthy as well as in symptomatic neonates and the role of gestational age and birthweight on CRP kinetics. In this review, we aim to give an update on the current evidence on the use of CRP in neonates.

Procalcitonin and interleukin-6 in the diagnosis of early-onset sepsis of the neonate

The reliability of procalcitonin (PCT) and interleukin‐6 (IL‐6) was determined and compared with that of C‐reactive protein (CRP) in the diagnosis of early‐onset sepsis of the neonate within the first 12 h of life. ROC analysis of values of 41 neonates with blood‐cultures‐positive and clinical sepsis compared with those of 27 uninfected neonates revealed sensitivities for PCT (≥6ng/mL), IL‐6 (≥60pg/mL), and CRP (≥2.5 mg/L) of 77%, 54%, and 69% and specificities of 91%, 100% and 96%, respectively. Sensitivity of CRP at ≥8 mg/L was 49% (p= 0.012 compared to PCT).

Risk factors and determinants of neurodevelopmental outcome in cystic periventricular leucomalacia

Abstract The aim of the study was to determine risk factors for the development of cystic periventricular leucomalacia (PVL) and to correlate ultrasound findings with neurodevelopmental outcome. By means of a retrospective case-control study (matched for gestational age, birth weight, sex, and year of birth) and a cohort analysis of all preterm infants with cystic PVL documented by ultrasound scans hospitalised at a local tertiary care centre between 1988 and 1998, 98 preterm infants with a gestational age ranging from 26 to 35 weeks were diagnosed as having cystic PVL. The mean day of diagnosis of periventricular echodensities was 3 ± 2 days (range 1–11 days), and of cystic PVL 21 ± 8 days (range 2–47 days). Of 79 infants (1988–1997) eligible for neurodevelopmental follow-up (91%), hemi-, di-, or tetraplegia was diagnosed in 61 (77%), normal mental outcome in 22 (28%), associated visual disorders in 41 (52%) and seizure disorders in 12 (15%) infants. Significant risk factors associated with the development of cystic PVL were premature rupture of membranes, chorioamnionitis, and hyperbilirubinaemia (odds ratios 4.665, 6.026, and 2.460 respectively). Subgroup analysis according to gestational age (26–28, 29–32, 33–35 weeks) revealed similar results despite spontaneous labour (26–28 weeks; odds ratio 4.808) and pre-eclampsia (33–35 weeks; odds ratio 3.517). Multiple pregnancy was associated with a twofold increased risk (odds ratio 2.075). The white matter damage probably accounted for the significantly higher prevalence of apnoeas (P < 0.001) and neonatal seizures (P < 0.001). Cysts located bilateral or parieto-occipital were associated with a higher risk of cerebral palsy (odds ratios 6.933 and 4.327 respectively). Solely anterior located cysts were associated with normal neurological outcome. Increasing size of the cysts was associated with increasing risk of cerebral palsy with a cut-off value of 10 mm (odds ratio 3.300 and above) and all infants with cysts of more than 20 mm diameter had cerebral palsy. Conclusion The high prevalence of premature rupture of the membranes and chorioamnionitis further supports the role of intra-uterine infection in the pathogenesis of periventricular leucomalacia. The overall prognosis of cystic periventricular leucomalacia is poor.

Risk Factors for Severe Respiratory Syncytial Virus Lower Respiratory Tract Infection

RSV infection is a leading cause of lower respiratory tract infection, especially in High-risk infants with a history of prematurity, bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), neuromusculair impairment, immunodeficiency, and Down syndrome. Host related risk factors that have been identified to be associated with severe RSV related lower respiratory tract infection include young age below 6 months at the beginning of RSV season, multiple birth, male sex, low socioeconomic status and parental education, crowded living conditions, young siblings, maternal smoking and indoor smoke pollution, malnutrition/small for gestational age, family history of atopy or asthma, low cord serum RSV antibody titers, and living at altitude. Risk factors increasing the risk of acquisition of RSV have been identified to be birth before and/or during RSV season, day care attendance, presence of older siblings in school or day-care, and lack of breast feeding. Some of these risk factors are discussed controversially and some of them are found continuously throughout the literature. Given the high cost of RSV prophylaxis, especially for the large population of late preterm infants, algorithms and risk score systems have been published that could identify high-risk infants for treatment with palivizumab out of this gestational age group. Several models reported on an average sensitivity and specificity of 70 percent and, thus, are helpful to identify infants at high risk for severe RSV infection and need for prophylaxis with palivizumab.

Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review

To analyse current data on transmission of human cytomegalovirus (HCMV) via breast milk with subsequent symptomatic HCMV infection of the preterm infant and to report on long-term follow-up, a systematic literature review was performed using EMBASE, MEDLINE and CINAHL (January 1966 to December 2008) Studies were included for analysis if congenital HCMV infection was excluded and transmission via breast milk was either confirmed or strongly suspected. Twenty-six studies were included for analysis. Maternal HCMV-IgG-positivity was reported to be in the range 51.6-100% (median 81.6%), HCMV-IgG detection in breast milk in the range 67-97.2% (median 80%) and HCMV-positivity of the infants in the range 5.7-58.6%. Symptomatic HCMV disease occurred in 0-34.5% (median 3.7%) and severe sepsis-like syndrome in 0-13.8% (median 0.7%). Data on long-term outcome of preterm infants with symptomatic HCMV infection revealed a low risk for mild neurological and cognitive sequelae, without hearing impairment. Recommendations for high-risk preterm infants diverged markedly. The current data report low rates of symptomatic disease after transmission of HCMV via breast milk to the preterm infant without evidence of certain long-term sequelae. The results of our review do not support a general approach, either by avoidance or pasteurization of breast milk, in high-risk preterm infants.

4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia

Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor-1 (PAI-1) is a characteristic feature of meningococcal sepsis. Previously, an association between mortality and the functional 4G/5G promoter polymorphism of the PAI-1gene in a cohort of UK and Dutch children with meningococcal sepsis was reported. We carried out a prospective, multicentre study to investigate the association of the 4G/5G PAI-1 polymorphism, diagnosis, and outcome in meningococcal disease in a Central European and UK population. Blood samples and clinical information of 347 previously healthy children with meningococcal infection were collected from 95 paediatric hospitals in Germany, Switzerland, Italy, the United Kingdom, and Austria from 2000 until 2002. Mortality was significantly associated with the 4G/4G genotype (12 of 90 (13%) vs. 15 of 240 (6%), P =0.037), resulting in an odds ratio of 2.31. The diagnosis of sepsis (independent of symptoms of meningitis) was significantly more frequent in carriers of the 4G/4G genotype (P =0.01), resulting in an odds ratio of 2.21 to develop sepsis. Meningitis was not associated with the PAI-1 4G/5G polymorphism, and allele frequencies were similar in patient and control groups. Conclusion:Our data show a correlation between the 4G/4G genotype in the plasminogen activator inhibitor-1 gene and poor outcome in children with meningococcal infection. In addition, 4G homozygous patients were prone to develop sepsis. We found no influence of the plasminogen activator inhibitor-1 polymorphism on the susceptibility to invasive meningococcal infection.

Neurodevelopmental outcome of hydrocephalus following intra-/periventricular hemorrhage in preterm infants: short- and long-term results

Over a 5-year period (1984–1988) intra- and periventricular hemorrhage (IVH/PVH) was observed in 299 preterm infants. Sixty-eight infants developed posthemorrhagic hydrocephalus (PH); of these, 23 infants died and 40 infants could be followed up for assessment of neurological development (5 patients were lost to follow-up). At 1 year of corrected age 15% (25% at 5 year follow-up) of the infants were determined to have developed normally, 35% (25% at 5-year follow-up) showed mild neurological symptoms and/or slight developmental delay, 32.5% (28% at 5-year follow-up) had handicaps and/or moderate mental retardation, and 17.5% (22% at 5-year follow-up) had severe handicaps and/or severe mental retardation. There was a significantly worse outcome in infants with grade 4 IVH/PVH (P<0.05) and a significantly worse outcome in the group requiring ventriculoperitoneal (VP) shunt (P<0.05). The results at 1 year of corrected age proved to be a quite realistic predictor of neurological functioning at 5 years of age (80% predicted correctly in the nonshunted-group — one patient lost to follow-up; 95% predicted correctly in the shunted group — four patients lost to follow-up). Cystic periventricular leukomalacia had been diagnosed in 7 (10%) patients and was associated with poor neurodevelopmental outcome. Gestational age, birth weight, time of shunt placement, and peripartum asphyxia had no significant influence on neurodevelopmental outcome. Infants with shunt infections and a high number of shunt revisions were found to have a significantly worse neurodevelopmental outcome (P<0.01).

Severe respiratory syncytial virus (RSV) infection in infants with neuromuscular diseases and immune deficiency syndromes

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection (LRTI) in infants and children. There is growing evidence of severe RSV disease in infants with neuromuscular diseases and immune deficiency syndromes. Factors predisposing to a more severe course of RSV disease in neuromuscular diseases include the impaired ability to clear secretions from the airways due to ineffective cough, respiratory muscle weakness, high prevalence of gastro-oesophageal reflux and swallowing dysfunction which leads to aspiration. Similarly, pulmonary disease is a common presenting feature and complication of T-cell immunodeficiency. Infants with severe congenital and acquired immune deficiency syndromes may demonstrate prolonged viral shedding in RSV LRTI and are reported to have increased morbidity and mortality associated with RSV infection. Although not indicated in most guideline statements, palivizumab prophylaxis for these uncommon underlying conditions is under consideration by clinicians. Prospective studies are needed to determine the burden of RSV disease in these children.

The Impact of Respiratory Syncytial Virus Infection: A Prospective Study in Hospitalized Infants Younger than 2 Years

AbstractBackground: We analyzed the influence of respiratory syncytial virus (RSV) on the clinical course and management of infants hospitalized due to viral upper and lower respiratory tract infections (U/LRTI). Patients and Methods: Infants younger than 2 years were prospectively tested for RSV infection by antigen detection in nasopharyngeal aspirates between November 1999 and October 2000. Results: Of 281 infants hospitalized during the study period, 58 (21%) tested RSV positive. Seasonal distribution of RSV infections showed a peak in March (45% of all U/LRTI). Infants with RSV infection (12% were preterm, 5% had congenital heart disease) were younger (p < 0.001), had more severe U/LRTI (p < 0.001), longer hospitalizations (p < 0.001), more days with oxygen requirement (p < 0.001) and respiratory support (p = 0016) and more frequent requirements for bronchoditators (p = 0.002) and corticosteroids (p = 0.02). Conclusion: RSV contributed to prolonged hospitalizations and more severe clinical courses of disease both in very young term and preterm infants.

Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life

Abstract Background: Our aim was to analyze C-reactive protein (CRP) values in term and preterm infants and correlate non-infection-associated increases with various neonatal disorders. Methods: Retrospective cohort study that included all newborns hospitalized at a tertiary care center between 2004 and 2007 with documented CRP values in the first 3 days of life. Analysis of differences in CRP values between term and preterm newborns and cases with CRP increases in sepsis negative newborns. Results: For diagnosis of blood culture proven sepsis (19 and 14 cases, respectively) in 353 preterm and 179 term newborns, CRP at a cut-off of 8 mg/L had sensitivities of 53% and 86% and specificities of 91% and 88%, respectively. The area under the receiver operating characteristics curves were 0.799 and 0.890, respectively. Preterm newborns had lower median values compared to term newborns in sepsis positive (9 vs. 18.5 mg/L, p<0.001) and negative newborns (0.5 vs. 2 mg/L, p<0.001). Increases in individuals without infection were correlated significantly with meconium aspiration syndrome and surfactant application in term newborns (p=0.009 and 0.025, respectively) and with surfactant application and higher birth weight in preterm newborns (p<0.001 and 0.031, respectively). Conclusions: CRP values were significantly lower in preterm compared to term newborns, and its application in the diagnosis of sepsis in preterm newborns was not as reliable as in term newborns. Meconium aspiration syndrome, surfactant application, and high birth weight were associated significantly with increased CRP values.