Ludo Mahieu

The role of inflammation in the development of chronic lung disease in neonates

Abstract Chronic lung disease (CLD) has been associated with chorioamnionitis and upper respiratory tract colonisation with Ureaplasma urealyticum. The aim of this review is to describe the increasing evidence that inflammation plays a critical role in the early stages of CLD of the neonate. Ongoing lung damage in the premature infant may be caused by failure to downregulate and control this inflammatory response. Tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and IL-8 are important pro-inflammatory cytokines of which IL-8 is an important chemotactic factor in the lung. Data suggest that preterm newborns with lung inflammation may be unable to activate the anti-inflammatory cytokine IL-10. Therefore, early post-natal anti-inflammatory therapy could help in preventing development of CLD. Prophylactic dexamethasone therapy cannot yet be recommended. There are a number of potential interactions between surfactant and cytokine effects on the preterm lung which have not been evaluated. Surfactant protein A may be an important modulator of the immune response to lung injury. The role of high-frequency ventilation in the prevention of CLD still remains unclear. Conclusion Many aspects of the pathogenesis of the inflammatory response in the development of chronic lung disease remain to be elucidated. Further research to identify preterm infants at highest risk for the development of this multifactorial and complex disease is needed.

Selecting neonates with congenital cytomegalovirus infection for ganciclovir therapy

ObjectiveThe objective of this study is to look for evidence based or scientific guidelines for selection of newborns with congenital cytomegalovirus (CMV) infection that might benefit from treatment with ganciclovir.Materials and methodsA literature search was conducted involving the MEDLINE database and the Cochrane Collaboration Library. Abstracts were reviewed to select pertinent articles dealing with ganciclovir therapy in neonates. References from selected articles as well as from reviews were screened for additional relevant articles. In total, 13 case reports (16 patients in all), three descriptive uncontrolled studies (20 patients in all), two randomized dose-comparative studies (54 patients in all) and one randomized controlled study (42 patients) were identified.ObservationsAll reported patients presented with central nervous system manifestation of CMV infection. Only the randomized controlled study showed a reduction of hearing deterioration in the treated group. Published predictors of hearing loss in congenitally CMV infected children allow identification of candidates that might benefit from treatment. Studies so far are promising but of insufficient number to make evidence based recommendations about indications for treatment of congenital CMV. As such, studies are very difficult to conduct and treatment of infants at high risk of hearing loss may appear justified. There is scientific data to help clinicians in selecting a subgroup of infants that is at higher risk of hearing deterioration and therefore might benefit the most from ganciclovir therapy.

Time to positivity of neonatal blood cultures: fast and furious?

The aim of this study was to determine the time to positivity (TTP) of neonatal blood cultures, to investigate differences between early onset versus late-onset sepsis, and non-proven versus proven sepsis, and to examine differences in TTP by organism type using a retrospective observational study at the Neonatal Intensive Care Unit, Antwerp University Hospital, Belgium. The subjects were 1828 neonates with suspected sepsis who were treated with antimicrobials for at least 3 days. The TTP was recorded for all episodes of suspected sepsis in an approximately 6.5 year period. A total of 2916 blood cultures were collected, of which 437 (15%) became positive. The overall TTP was 21.33 h (Q1-Q3 13.17-32.46). The difference between the median TTP in early onset versus late-onset sepsis was 0.83 h (22.00 versus 21.17 h, P=0.75). The median TTP for Gram-negative organisms was 11.17 h (Q1-Q3 8.84-15.67), whereas the median TTP for Gram-positive organisms was 23.59 h (Q1-Q3 15.29-34.58, P<0.001). In Gram-positive isolates, the median TTP for coagulase-negative staphylococci (CNS) was 26.67 h (Q1-Q3 19.00-38.17), whereas the median TTP for non-CNS was 12.83 h (Q1-Q3 10.50-18.17, P<0.001). The median TTP in proven sepsis was 20.17 h (Q1-Q3 13.00-30.37), whereas it was 29.67 h (Q1-Q3 21.17-50.63, P<0.001) in non-proven sepsis. TTP of neonatal blood cultures was significantly shorter for Gram-negative organisms. We suggest shortening the total incubation time of neonatal blood cultures to a maximum of 3 days. However, blood cultures collected in infants<72 h of age might require a longer incubation time. According to our results, it may be safe to narrow the antimicrobial spectrum to solely target Gram-positive bacteria when the culture is still negative after 48 h, and to cease antimicrobial therapy when the culture is still negative after 72 h in clinically well infants.

Relationship between histologic chorioamnionitis and early inflammatory variables in blood, tracheal aspirates, and endotracheal colonization in preterm infants

Histologic results of the placenta are usually not available within the first days of life. We identified inflammatory variables in tracheal aspirates and blood that were associated with histologic chorioamnionitis (HC). A derivation cohort consisted of 62 neonates and a validation cohort of 57 neonates with a gestational age < 31 wk and ventilated on d 1. Tracheal aspirates were taken on d 1 and on d 3, if the patient was still ventilated. HC was diagnosed by light microscopy. Logistic regression was used to identify independent factors in the derivation cohort associated with HC at d 1, 2, and 3. Model performance was studied using receiver operating characteristic curve analysis. Independent factors associated with HC were, at d 1, tracheal aspirate IL-8 ≥ 917 pg/mL (odds ratio, 60.7; 95% confidence interval, 11-328); at d 2, blood C-reactive protein ≥ 14 mg/L (odds ratio, 9.2; 95% confidence interval, 2-38), blood white blood cell count ≥ 10,400/mm3 (odds ratio, 7.4; 95% confidence interval, 2-28); and at d 3, blood neutrophil count ≥ 4968/mm3 (odds ratio, 14; 95% confidence interval, 3-57). The association with HC was less at d 3 (area under receiver operating characteristic curve, 0.77) when compared with the d 1 model (area under the curve, 0.88; p = 0.09). The models performed equally well in the validation cohort (goodness-of-fit test, p > 0.05). We conclude that the d 1 and d 2 models can be used as diagnostic factors for HC. Tracheal aspirate IL-8 taken immediately after birth was equally accurate in the diagnosis of HC as systemic inflammatory response at d 2 and better than on d 3.

Number of sites of perinatal Candida colonization and neutropenia are associated with nosocomial candidemia in the neonatal intensive care unit patient.

Objectives: To determine the role of perinatally acquired Candida colonization to invasive Candida infection (candidemia) and to assess risk factors associated with Candida colonization and candidemia in neonatal intensive care unit patients. Design: Retrospective case-control study. Setting: Neonatal intensive care unit of a teaching hospital. Patients: A total of 39 of 3219 (1.2%) who were positive for Candida colonization at birth were compared with 117 noncolonized controls. Interventions: Routine surveillance cultures for Candida of skin and meconium were performed at admission. All neonates with Candida colonization at birth during a 10-yr period were identified. Each case was matched to place of birth and date of admission with three noncolonized controls. Measurements and Main Results: Perinatal and neonatal variables were collected. Blood or skin culture was obtained when signs of sepsis or dermatitis were present. Patients with Candida colonization were compared with their noncolonized controls, whereas in this cohort, patients with candidemia were compared with those without by multivariate analysis. Vaginal candidiasis (odds ratio [OR] 15.8, 95% confidence interval [CI] 2.63, 94.77), birth weight below 1000 g (OR 8.1, 95% CI 1.22, 52.26), and vaginal delivery (OR 7.08, 95% CI 1.17, 42.70) were associated with Candida colonization. An increased risk for nosocomial candidemia was independently associated with the number of sites of Candida colonization (OR 24.02, 95% CI 1.89, 304), early neonatal neutropenia (OR 7.15, 95% CI 0.98, 80.95) and illness severity (clinical risk index for babies [CRIB]) score at day 1 (OR 1.38, 95%CI 1.065, 1.811). Conclusions: Maternal vaginal candidiasis and vaginal birth are risk factors for neonatal colonization. When controlling for illness severity, the number of sites colonized with Candida at birth contributes to neonatal nosocomial candidemia. Early neutropenia increases the risk further. These findings offer opportunities for prevention of Candida infection in neonatal intensive care unit patients.

Hepatic abscesses associated with umbilical catheterisation in two neonates

We describe two neonates with a liver abscess after umbilical venous catheterisation. The first case was a female neonate, born at 32 weeks of gestation. After persistance of elevated inflammatory parameters, an abscess in the right lobe of the liver was diagnosed. Percutaneous drainage under CT guidance was performed. The aspirated pus grew Staphylococcus epidermidis. Inflammatory parameters normalised after 27 days of antimicrobial therapy (vancomycin, cefotaxim, rifampicin). The second case was in a male neonate, born at 29 weeks of gestation. Percutaneously aspirated pus from the liver abscess was cultured and remained sterile. The patient received antimicrobial therapy (vancomycin, cefotaxim, amikacin) for 26 days and was cured with conservative treatment. Conclusion: hepatic abscess should be considered in any infant with an umbilical catheter-associated sepsis and persistent inflammatory response in spite of adequate antimicrobial therapy, especially when signs of abdominal infection are present.

Prediction models for neonatal health care-associated sepsis: a meta-analysis.

BACKGROUND AND OBJECTIVES: Blood culture is the gold standard to diagnose bloodstream infection but is usually time-consuming. Prediction models aim to facilitate early preliminary diagnosis and treatment. We systematically reviewed prediction models for health care–associated bloodstream infection (HABSI) in neonates, identified superior models, and pooled clinical predictors. Data sources: LibHub, PubMed, and Web of Science. METHODS: The studies included designed prediction models for laboratory-confirmed HABSI or sepsis. The target population was a consecutive series of neonates with suspicion of sepsis hospitalized for ≥48 hours. Clinical predictors had to be recorded at time of or before culturing. Methodologic quality of the studies was assessed. Data extracted included population characteristics, total suspected and laboratory-confirmed episodes and definition, clinical parameter definitions and odds ratios, and diagnostic accuracy parameters. RESULTS: The systematic search revealed 9 articles with 12 prediction models representing 1295 suspected and 434 laboratory-confirmed sepsis episodes. Models exhibit moderate-good methodologic quality, large pretest probability range, and insufficient diagnostic accuracy. Random effects meta-analysis showed that lethargy, pallor/mottling, total parenteral nutrition, lipid infusion, and postnatal corticosteroids were predictive for HABSI. Post hoc analysis with low-gestational-age neonates demonstrated that apnea/bradycardia, lethargy, pallor/mottling, and poor peripheral perfusion were predictive for HABSI. Limitations include clinical and statistical heterogeneity. CONCLUSIONS: Prediction models should be considered as guidance rather than an absolute indicator because they all have limited diagnostic accuracy. Lethargy and pallor and/or mottling for all neonates as well as apnea and/or bradycardia and poor peripheral perfusion for very low birth weight neonates are the most powerful clinical signs. However, the clinical context of the neonate should always be considered.

Microbiology and risk factors for catheter exit-site and -hub colonization in neonatal intensive care unit patients

OBJECTIVE To identify risk factors and describe the microbiology of catheter exit-site and hub colonization in neonates. DESIGN During a period of 2 years, we prospectively investigated 14 risk factors for catheter exit-site and hub colonization in 862 central venous catheters in a cohort of 441 neonates. Cultures of the catheter exit-site and hub were obtained using semiquantitative techniques at time of catheter removal. SETTING A neonatal intensive care unit at a university hospital. RESULTS Catheter exit-site colonization was found in 7.2% and hub colonization in 5.3%. Coagulase-negative staphylococci were predominant at both sites. Pathogenic flora were found more frequently at the catheter hub (36% vs 14%; P<.05). Through logistic regression, factors associated with exit-site colonization were identified as umbilical insertion (odds ratio [OR], 8.1; 95% confidence interval [CI95], 2.35-27.6; P<.001), subclavian insertion (OR, 54.6; CI95, 12.2-244, P<.001), and colonization of the catheter hub (OR, 8.9; CI, 3.5-22.8; P<.001). Catheter-hub colonization was associated with total parenteral nutrition ([TPN] OR for each day of TPN, 1.056; CI95, 1.029-1.083; P<.001) and catheter exit-site colonization (OR, 6.11; CI95, 2.603-14.34; P<.001). No association was found between colonization at these sites and duration of catheterization and venue of insertion, physicians experience, postnatal age and patients weight, ventilation, steroids or antibiotics, and catheter repositioning. CONCLUSION These data support that colonization of the catheter exit-site is associated with the site of insertion and colonization of the catheter hub with the use of TPN. There is a very strong association between colonization at both catheter sites.

Clinical Experience with Ceftriaxone Treatment in the Neonate

The safety of ceftriaxone has been evaluated in 80 neonates who were treated empirically for suspected infection with either ceftriaxone and ampicillin (group A, age 0-72 h) or ceftriaxone and vancomycin (group B, age greater than 72 h). Within 48 h after birth 2 group A patients died from sepsis (Haemophilus influenzae, Streptococcus pneumoniae, 1 case each); 1 group B patient died from sepsis (Pseudomonas aeruginosa). All bacterial isolates from group A patients were susceptible to ceftriaxone, but in 4 of the 8 group B patients with positive cultures a change in antibiotic therapy was required. Eosinophilia, thrombocytosis and an increase in serum alkaline phosphatases were observed in a limited number of patients during and after discontinuation of treatment. Direct hyperbilirubinemia ( > 2 mg/dl) occurred in 2 cases during treatment. Gallbladder sludge was sonographically diagnosed in 6 patients, but disappeared within 2 weeks after detection. One neonate had exanthema. Nurses rated ease of administration as very good. Ceftriaxone appears to be an interesting alternative in the empiric antibiotic treatment in the early neonatal period.

Diagnosis of catheter-related bloodstream infection in neonates: a study on the value of differential time to positivity of paired blood cultures.

Objective: Diagnosis of neonatal catheter-related bloodstream infection (CRBSI) is currently based on isolation of identical bacterial species from bloodstream and catheter tip cultures. This requires removal of the catheter followed by the insertion of a new catheter. The objective of this study was to investigate whether differential time to positivity (DTP) of blood cultures drawn from paired peripheral vein and central vascular catheter is useful for diagnosing neonatal CRBSI, avoiding removal of the catheter. Design: Retrospective observational study. Setting: Neonatal intensive care unit, University Hospital of Antwerp, Belgium. Patients: Neonates with probable and definite nosocomial bloodstream infection. Interventions: All episodes of nosocomial bloodstream infection (NBSI) in an approximately 7.5-yr period were identified retrospectively. Definite NBSI episodes in which paired blood cultures were obtained were retained to calculate DTP, to determine the optimal DTP cutoff for the diagnosis of CRBSI, and to assess the validity of DTP for the diagnosis of CRBSI. Measurements and Main Results: Of 32 NBSI episodes included in the study, 16 were CRBSI, seven were non-CRBSI, and nine were classified as “diagnosis uncertain.” In CRBSI, blood cultures drawn from a central vascular catheter were positive earlier than those drawn from a peripheral vein (median 9.67 hrs vs. 21.58 hrs, p < .01). Median DTP was 10.42 hrs in CRBSI and −0.33 hrs in non-CRBSI (p = .01). The optimal DTP cutoff for the diagnosis of CRBSI was ≥1 hr (area under the receiver operating characteristic curve = 0.84 ± 0.11), with a sensitivity of 94%, a specificity of 71%, a positive predictive value of 88%, and a negative predictive value of 83%. Conclusions: Differential time to positivity of paired blood cultures may have some potential in the diagnosis of catheter-related infections in neonatal intensive care unit patients and should be subjected to a prospective study.