Jozef De Dooy

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.

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.

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.

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.

Internal and external validation of the NOSEP prediction score for nosocomial sepsis in neonates.

Objective To evaluate the performance of a scoring system (NOSEP) to predict nosocomial sepsis in neonates at the hospital where the score was developed (internal validation) and in an independent data set from other centers (external validation). Design Multiple center prospective cohort study. Setting Six neonatal intensive care units from the Flanders in Belgium. Patients We analyzed two groups of patients: 62 episodes of presumed nosocomial sepsis in the internal validation cohort and 93 episodes of presumed nosocomial sepsis in a multiple center external validation cohort. Interventions Assessment of the predictive power of the NOSEP score 24 hrs preceding sepsis workup and the patients’ basic demographic characteristics and co-morbidity was performed. Diagnosis of nosocomial sepsis and the microbiology results were registered. Main results The NOSEP score’s discriminative capability was very good in the internal validation (area under receiver operating characteristic curve = 0.73 ± 0.08 [sem]). The NOSEP score performed satisfactory in the external validation (area under receiver operating characteristic curve = 0.66 ± 0.06). The calibration capability in both validation sets as measured by goodness-of-fit tests (internal validation, p = .56; external validation, p = .48) was good. An improvement of the NOSEP score was obtained for the external centers by redefining the cut-off of the items of the NOSEP score (area under receiver operating characteristic curve for NOSEP-NEW-I = 0.71 ± 0.05) or adding co-morbidity factors (area under receiver operating characteristic curve for NOSEP-NEW-II = 0.82 ± 0.04), with good calibration performance (goodness-of-fit test, p > .50). Finally, the fit of the NOSEP score demonstrated no significant variation across subgroups of patients. Conclusions The predictive power of the original NOSEP score is very good in neonates at the original neonatal intensive care unit. In other neonatal intensive care units, its discriminatory performance is satisfactory but could be improved after modification of the variables in the model or adding additional variables. To use such a NOSEP score in other neonatal intensive care units, its accuracy has to be validated and adjusted if necessary.

Implementation of a multi-parameter Point-of-Care-blood test analyzer reduces central laboratory testing and need for blood transfusions in very low birth weight infants.

Blood sampling for laboratory testing is a major cause of iatrogenic blood loss and anemia in neonatal intensive care unit [NICU] patients. The objective of the study was to assess whether the implementation of a multi-parameter Point of Care Test [POCT] (Roche, Cobas b221) analyzer affected blood loss for central laboratory testing and need for red blood cell transfusion in our NICU. This was a retrospective observational cohort study in a NICU with comparison of two serial cohorts of 2 years each. Implementation of a multi-parameter POCT decreased central laboratory performed testing for bilirubin (-32% per patient) and electrolytes (-36% per patient). On average, the net blood volume taken per admitted patient for electrolyte testing decreased with 23.7% and 22.2% for bilirubin testing in the second cohort. After implementation of POCT, fewer very low birth weight infants [VLBWI] required blood transfusion (38.9% vs. 50%, p<.05) as the number of transfusion/infants decreased by 48% (1.57 vs. 2.53, p<0.01). The implementation of POCT was cost-efficient for the Belgian national health insurance, cost reduction -8.3% per neonate. We conclude that implementation of a bedside multi-parameter POCT analyzer decreases transfusions among VLBWI by reducing iatrogenic blood loss for central laboratory testing.

Endotracheal colonization at birth is associated with a pathogen-dependent pro- and antiinflammatory cytokine response in ventilated preterm infants: a prospective cohort study.

The possible association between mediators of inflammation such as cytokines and perinatal colonization of the respiratory tract remains unclear. This prospective cohort study evaluated endotracheal colonization in 141 ventilated preterm infants at birth. The relation with cytokine response in the airways and C-reactive protein (CRP) in umbilical blood was investigated. Of the 141 preterm infants enrolled in this study, 37 (26%) were colonized. In addition to traditional pathogens (61%), commensal species (26%) and Mycoplasmataceae (13%) were isolated. Both the pro-inflammatory cytokines IL-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α as well as the antiinflammatory IL-10 are increased in colonized patients in a dose-dependent manner, with the strongest response in neonates colonized with Gram-negative organisms. There was no antimicrobial IL-12p70 response in colonized infants. Commensal flora is associated with the same inflammatory response as traditional pathogens. Although the umbilical cord blood CRP level was significantly higher in neonates with endotracheal colonization, it was highest in those colonized with Gram-negative organisms but still close to normal limits. Microorganisms in the endotracheal fluid of ventilated preterm infants are associated with a pathogen-specific and dose-dependent cytokine response in the airways and systemic CRP response.

Neonatal purpura due to Neisseria meningitidis serogroup C infection

Neisseria meningitidis sepsis should be considered in the differential diagnosis of neonatal purpura, especially during an epidemic of meningococcal disease in the community. Infection with Neisseria meningitidis is highest among infants aged <1 year with high mortality rates, but it is rare in the neonate. To the best of our knowledge, only two cases of purpura in the neonate, similar to that of meningococcaemia in older children, have been published [1, 5]. Both cases were due to N. meningitidis serogroup B. We present a neonate with meningococcaemia and a petechial and purpuric rash due to N. meningitidis serogroup C. A 12-day-old boy was admitted to a peripheral hospital with fever up to 40.7 C. At the end of the pregnancy, the 31-year-old mother experienced a urinary tract infection. The boys’ early neonatal history was unremarkable except for a left clubfoot. After a sepsis work-up including lumbar puncture, the boy was treated with intravenous cefotaxim, ampicillin and pooled human immunoglobulins. After developing a maculopapular rash on his trunk, he was transferred to our Neonatal Intensive Care Unit. On admission the boy was irritable with diffuse purpuric patches on the trunk and lower extremities. Besides a high pulse rate (171 beats/min), a high respiratory rate (68/min) and a prolonged capillary refill (6 s), clinical and neurological examination showed no abnormalities. Laboratory values revealed increased leukocyte count (20.2 g/l), increased C-reactive protein (CRP) (113 mg/l), low thrombocyte count (39 g/l) and diffuse intravascular coagulation (prothrombin time 17 s, activated partial thromboplastin time 100 s, fibrinogen 380 mg/l). A capillary blood sample showed a severe metabolic acidosis. All other investigations, including screening for congenital infection, lumbar puncture and X-rayfilms of the chest and abdomen were normal. Initial treatment consisted of ampicillin, netilmycin and cefotaxim. The boy required ventilation for respiratory failure, sodium bicarbonate and volume replacements to correct the metabolic acidosis, a platelet transfusion and low-dose dopamine for oliguria. On day 3, swelling, erythema and increased warmth of his left ankle were observed. Aspiration of joint fluid was not performed. X-ray films of both ankles revealed no evidence of osteomyelitis. N. meningitidis serogroup C, serotype 2a: subtype P1.5 was identified in the initial blood culture. Treatment was changed to penicillin G and was continued until CRP normalised (<10 mg/l) on day 18 of treatment, after which the child was discharged from the hospital. Eight months later the child’s development was normal but he showed two scars, one on the left ankle and one on his buttock, secondary to skin necroses. Purpura due to bacterial infections is very rare in the neonatal period. In this case, purpura reflected an underlying disseminated intravascular coagulation due to an infection. The differential diagnosis of a neonate with petechiae and purpura should include non-infectious [3] (Table 1) and infectious causes such as congenital infections with rubella, toxoplasmosis and cytomegalovirus and postnatal infections with herpes simplex virus, viral hepatitis, coxsackie-A virus, enterovirus and respiratory syncytial virus. Meningococcal infections are usually not considered. In contrast to two earlier published cases of neonatal purpura due to N. meningitidis serogroup B, we identified N. meningitidis serogroup C. Since 1997 there has been a steady increase in invasive meningoccal infections in Belgium reaching epidemic levels, in particular due to a 10-fold increase of serogroup C. The majority of the meningococcal infections with serogroup Eur J Pediatr (2003) 162: 283–284 DOI 10.1007/s00431-003-1163-5

Spontaneous spinal epidural hematoma in infancy: Review of the literature and the “seventh” case report

Spontaneous spinal epidural hematomas (SSEH) are a rare cause of spinal cord compression in childhood and especially in infancy. We reviewed the literature and describe a case of an 8-month-old boy with a large spontaneous cervico-thoracic epidural hematoma. With this review we want to detail the importance of early investigation, diagnosis and treatment in infants with SSEH. In our case the infant presented with irritability and crying and an ascending paralysis within four days. Magnetic resonance imaging (MRI) of the spine demonstrated an extensive epidural hematoma between C5 and L1, serious medullar compression and secondary cervical and thoracic medullar edema and hydromyelia. An emergency laminectomy was performed with evacuation of a well organized hematoma. There was a partial recuperation of the neurologic symptoms. Based on the scarce literature which only concerns seven case reports, SSEH is a rare cause of spinal compression in infancy. The presentation is often not specific and neurological symptoms are often lacking in the beginning. However early diagnosis with MRI and prompt neurosurgical intervention are important to improve outcome.

Vascular Complications of Varicella: Description of 4 Cases and a Review of Literature.

Stroke and deep venous thrombosis are rare complications of varicella zoster infection. We report 3 cases of children with a stroke and 1 case of a boy with a deep venous thrombosis after recent chicken pox.