Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells.

Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0-60 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v/v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-κB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41-60. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-κB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.

Fetal inflammatory response syndrome (FIRS) and outcome of preterm neonates - a prospective analytical study.

OBJECTIVES: To estimate the incidence of fetal inflammatory response syndrome (FIRS) in preterm neonates and correlate it with immediate and one-year neurodevelopmental outcome. MATERIALS AND METHODS: This prospective observational analytical study, in preterm neonates with gestational age between 26 and 34 weeks was conducted from May 2014 to December 2015 in a tertiary care hospital in South India. FIRS was defined as the presence of either elevated levels of interleukin-6 (IL-6) in cord blood ≥11 pg/ml and/or the placental histopathology showing evidence of fetal inflammatory response. One hundred and twenty neonates were recruited. During delivery 2 ml cord blood for interleukin-6 and placenta were collected and stored appropriately. Based on presence/absence of FIRS (IL-6 in cord blood ≥11 pg/ml and or features of placental fetal inflammation), neonates were grouped into two groups. The neonatal and maternal characteristics between two groups were compared. The short-term outcome parameters during NICU stay and neurodevelopmental outcome at one year of corrected age was compared between groups. RESULTS: Among the 120 infants studied, 19 expired. Out of 101 babies discharged, 87 were followed up till corrected 1 year of age. On examination of placenta and cord blood, 50 neonates had evidence of FIRS (41.6%). So there were 50 neonates in FIRS and 70 in NO-FIRS group. The mean gestational age, birth weight, and gender distribution were comparable between the two groups. Mortality [OR: 2.44 (CI: 1.14-5.26)] and early hypotension [OR: 2.13 (CI: 1.1-4.2)] were significantly higher in the FIRS group. The neurodevelopmental assessment at corrected age of 1 year showed that infants with FIRS had lower mean motor developmental quotient by developmental assessment scale for Indian infants (DASII) [87.6 ± 9.15 versus 93.07 ± 9.3, p < .04]. CONCLUSIONS: FIRS has a significant role on survival and neurodevelopmental outcome of preterm infants.

The role of granulocyte colony-stimulating factor in the neutrophilia observed in the fetal inflammatory response syndrome.

OBJECTIVES: Fetal neutrophilia is present in two-thirds of cases with the fetal inflammatory response syndrome (FIRS). The mechanisms responsible for this finding have not been elucidated. Granulocyte colony-stimulating factor (G-CSF) is the primary physiologic regulator of neutrophil production and plays a key role in the rapid generation and release of neutrophils in stressful conditions (i.e., infection). The objective of this study was to determine: 1) whether FIRS was associated with changes in fetal plasma G-CSF concentrations; and 2) if fetal plasma G-CSF concentrations correlated with fetal neutrophil counts, chorioamnionitis, neonatal morbidity/mortality and cordocentesis-to-delivery interval. STUDY DESIGN: Percutaneous umbilical cord blood sampling was performed in a population of patients with preterm labor (n=107). A fetal plasma interleukin-6 (IL-6) concentration >11 pg/mL was used to define FIRS. Cord blood G-CSF was measured by a sensitive and specific immunoassay. An absolute neutrophil count was determined and corrected for gestational age. Receiver operating characteristic (ROC) curve, survival analysis and Cox proportional hazard model were employed. RESULTS: 1) G-CSF was detected in all fetal blood samples; 2) fetuses with FIRS had a higher median fetal plasma G-CSF concentration than those without FIRS (P<0.001); 3) a fetal plasma G-CSF concentration ≥134 pg/mL (derived from an ROC curve) was associated with a shorter cordocentesis-to-delivery interval, a higher frequency of chorioamnionitis (clinical and histological), intra-amniotic infection, and composite neonatal morbidity/mortality than a fetal plasma concentration below this cut-off; and 4) a fetal plasma G-CSF concentration ≥134 pg/mL was associated with a shorter cordocentesis-to-delivery interval (hazard ratio 3.2; 95% confidence interval 1.8-5.8) after adjusting for confounders. CONCLUSIONS: 1) G-CSF concentrations are higher in the peripheral blood of fetuses with FIRS than in fetuses without FIRS; and 2) a subset of fetuses with FIRS with elevated fetal plasma G-CSF concentrations are associated with neutrophilia, a shorter procedure-to-delivery interval, chorio-amnionitis and increased perinatal morbidity and mortality.

An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: implications for the understanding of the fetal inflammatory response syndrome.

OBJECTIVE: The fetal inflammatory response syndrome (FIRS) has been described in the context of preterm labor and preterm prelabor rupture of the membranes and is often associated with intra-amniotic infection/inflammation. This syndrome is characterized by systemic fetal inflammation and operationally defined by an elevated fetal plasma interleukin (IL)-6. The objective of this study was to determine if FIRS can be found in fetuses with activation of their immune system, such as the one observed in Rh alloimmune-mediated fetal anemia. METHODS: Fetal blood sampling was performed in sensitized Rh-D negative women with suspected fetal anemia (n=16). Fetal anemia was diagnosed according to reference range nomograms established for the assessment of fetal hematologic parameters. An elevated fetal plasma IL-6 concentration was defined using a cutoff of >11 pg/ml. Concentrations of IL-6 were determined by immunoassay. Non-parametric statistics were used for analysis. RESULTS: (1) The prevalence of an elevated fetal plasma IL-6 was 25% (4/16); (2) there was an inverse relationship between the fetal hematocrit and IL-6 concentration -- the lower the hematocrit, the higher the fetal IL-6 (r=-0.68, p=0.004); (3) fetuses with anemia had a significantly higher plasma IL-6 concentration than those without anemia (3.74 pg/ml, interquartile range (IQR) 1.18-2.63 vs. 1.46 pg/ml, IQR 1.76-14.7; p=0.02); (4) interestingly, all fetuses with an elevated plasma IL-6 concentration had anemia (prevalence 40%, 4/10), while in the group without anemia, none had an elevated fetal plasma IL-6. CONCLUSIONS: An elevation in fetal plasma IL-6 can be observed in a subset of fetuses with anemia due to Rh alloimmunization. This observation suggests that the hallmark of FIRS can be caused by non-infection-related insults. Further studies are required to determine whether the prognosis of FIRS caused by intra-amniotic infection/inflammation is different from that induced by alloimmunization.

Severe postnatally acquired cytomegalovirus infection presenting with colitis, pneumonitis and sepsis-like syndrome in an extremely low birthweight infant.

Few cases of severe postnatally acquired cytomegalovirus (CMV) infection are reported in premature infants. We report on an extremely low birthweight (ELBW) preterm infant who presented with a sepsis-like syndrome and multiple organ involvement, notably pneumonitis and colitis. The course of infection was assessed by repeated analysis of urine, tracheal aspirates and blood. The patient was given intravenous ganciclovir. The clinical course was rapidly favorable. Development of neutropenia led to the discontinuation of the antiviral treatment after 28 days. Follow-up showed moderate white matter anomalies on cerebral MRI, a transient hypoacusis and a mild developmental delay at 18 months of corrected age. To the best of our knowledge, this is the first description of a severe combination of pneumonitis and colitis in postnatal CMV infection. Many issues remain controversial and are discussed. We propose that antiviral treatment should be considered in severe postnatal CMV infection in ELBW patients.

[Procalcitonin and C-reactive protein as a markers of neonatal sepsis]. / Prokalcytonina oraz bialko C-reaktywne w rozpoznawaniu posocznicy u noworodków.

OBJECTIVES: Sensitive, reliable and early parameters of bacterial infection are extremely valuable in diagnosis of nosocomial infections in neonatal intensive care unit. In this study procalcitonin (PCT) and C-reactive protein (CRP) were evaluated for their diagnostic relevance in neonatal late onset sepsis. DESIGN: Clinical study MATERIALS AND METHODS: We analysed inflammatory parameters in 48 newborn infants admitted to the Intensive Care Unit of Institute of Paediatrics in Lodz who suffered from nosocomial sepsis. They were sampled for PCT and CRP levels at the time of the onset of signs and 24 hours later. CRP was determined by an nephelometric method and PCT was determined by an immunoluminometric assay. RESULTS: At the onset of Gram negative sepsis 14 from 17 contaminated newborns had significantly increased CRP levels and 15 of them had increased levels of PCT After 24 hours 100% of them had elevated PCT and CRP levels. At the onset of Gram positive sepsis only 18 from 31 neonates with positive blood culture had increased CRP levels and 28 of them had elevated concentrations of PCT. This difference was statistically significant. After 24 hours 26 of them had elevated CRP and 100% had increased PCT concentrations--this difference was not significant. CONCLUSION: Measurement of procalcitonin concentrations may be useful for early diagnosis of late onset sepsis in neonates.

[Evaluation of diagnostic value of procalcitonin (PCT) as a marker of congenital infection in newborns]. / Ocena wartosci oznaczania prokalcytoniny jako wykladnika zakazenia wrodzonego u noworodków.

UNLABELLED: Systemic bacterial infections still remain one of the major causes of neonatal morbidity and mortality. Early detection of neonatal sepsis can be difficult, because the first signs of the disease may be unspecific and similar to symptoms of other non-infectious processes. Procalcitonin became a new, sensitive marker of bacterial infections in newborns. The aim of our study was to assess the value of PCT as a diagnostic and prognostic tool of neonatal maternofetal infections. We also tried to estimate normal ranges of PCT in uninfected newborns. MATERIAL AND METHODS: 74 newborns, born in the Department of Obstetrics and Gynaecology, University of Medicine of Wroclaw, then hospitalized in the Department of Neonatology entered the study. They were divided into 2 groups: group 1-29 neonates with recognized materno-fetal infection, group 2-45 newborns without infection. In both groups blood samples to measure PCT concentrations were obtained by venipuncture on the 1st, 2nd, 3rd, 5th and between the 10th and 14th day of life (in the group of infected neonates) Sera were stored at -40 degrees C before analysis. PCT was determined using an immunoluminometric assay (BRAHMS Diagnostica). RESULTS: Serum procalcitonin values were significantly higher in the infected group than in the uninfected neonates (p < 0.001). The most significant differences were noted on the 2nd and 3rd day of life (p < 0.0001). After the treatment had been finished, the PCT levels in both groups were not statistically different. CONCLUSIONS: PCT is a useful tool in early diagnosing and monitoring the course of early-onset infections in neonates, particularly when blood cultures obtained from neonates remain negative. The decreasing concentrations of PCT level in children treated due to infection, indicate successful treatment and may help one to take a decision on termination of antibiotic therapy.