Detection of Parechovirus (P) and Enterovirus (E) Among Infants Evaluated for Late-Onset Sepsis in the Neonatal Intensive Care Unit (NICU): The VIRIoN-P-E Study

Background: Limited data exist on the role of human parechoviruses (HPeV) and enteroviruses (EV) as causes of late-onset sepsis (LOS) in the NICU. Objective: To determine the frequency of detection of parechoviruses and enteroviruses among infants >72 hr of age who were evaluated for LOS in 2 academic NICUs (Parkland Memorial Hospital [PMH], Dallas -shared bays; Women & Infants Hospital [W&I], RI -single patient rooms) Design/Methods: Prospective cohort study of inborn infants hospitalized in the NICU at PMH and WIH from 1/2012 to 1/2013 and were enrolled in the Viral Respiratory Infections in the Neonatal Intensive Care Unit (VIRIoN-I; J Pediatr 2014:165:690). Eligible subjects were infants of all gestational ages (GA) and birth weights (BW) who were >72 hrs of age, remained in the NICU since birth, and underwent evaluation with initiation of antibiotic therapy for suspected LOS. Nasopharyngeal specimens were obtained within 72 hrs of the sepsis evaluation using flexible flocked nylon swabs that were placed in universal transport medium and frozen at -80\ub0C until tested for parechovirus and enterovirus RNA by polymerase chain reaction (PCR) assay (Virology Laboratory, Nationwide Children\u2019s Hospital, Columbus, OH). Demographic, clinical, laboratory, and radiographic data were obtained. Results: Of the 100 infants enrolled in the VIRIoN-I study, nasopharyngeal specimens were available from 65 (59, PMH; 6, WIH) for parechovirus and enterovirus PCR testing. These 65 infants (38, male; 27, female; 49, Hispanic; 6, white; 9, Black; 1, unknown) had a mean \ub1SD gestational age of 30 \ub1 5 wks and birth weight of 1619 \ub1 929 g, and received empirical antibiotics for possible LOS. Infants had a total of 94 sepsis evaluations (65, 1 evaluation; 16, 2; 8, 3; 4, 4) at a mean age of 20 days. Reasons for the sepsis evaluations included fever (9), hypothermia (65), apnea (50),feeding intolerance (51), seizure (1), irritabilitiy (5), emesis (20), diarrhea (1), bloody stool (5), rhinorrhea/congestion/cough (6), and lethargy (9). Four infants died. None of the infants had parechovirus or enterovirus detected in nasopharygeal specimens either at the first or subsequent sepsis evaluations. Conclusion(s): The burden of disease due to parechovirus and enteroviruses among inborn infants who remain in the NICU since birth appears to be low in those evaluated for LOS. Larger, prospective studies are needed to fully determine their contribution to \u201cculture-negative\u201d sepsis in the NICU. Publication Number: 3860.53

Update on vaccination of preterm infants: a systematic review about safety and efficacy/effectiveness. Proposal for a position statement by Italian Society of Pediatric Allergology and Immunology jointly with the Italian Society of Neonatology

Preterm infants (PIs) are at increased risk of vaccine-preventable diseases (VPDs). However, delayed vaccination start and low vaccine coverage are still reported. Areas covered: This systematic review includes 37 articles on preterm vaccination published in 2008-2018 in PubMed. Both live attenuated and inactivated vaccines are safe and well tolerated in PIs. Local reactions, apnea, and reactivity changes are the most frequently reported adverse events. Lower gestational age and birth weight, preimmunization apnea, longer use of continuous positive airway pressure (CPAP) are risk factors for apnea. The proportion of PIs who develop protective humoral and cellular immunity is generally similar to full terms although later gestational age is associated with increased antibody IgG concentrations (i.e. against certain pneumococcal serotypes, influenza, hepatitis B virus and poliovirus 1) and increased mononuclear cells proliferation (i.e. after inactivated poliovirus). Expert opinion: PIs can be safely and adequately protected by available vaccines with the same schedule used for full terms. Data at this regard have been retrieved by studies using a 3-dose primary series for pneumococcal and hexavalent vaccines. Further studies are needed regarding the 2 + 1 schedule. Apnea represents a nonspecific stress response in PIs, thus those hospitalized at 2 months should have cardio-respiratory monitoring after their first vaccination

Relationship between QT interval and cardiovascular risk factors in healthy young subjects

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Management of the mother-infant dyad with suspected or confirmed SARS-CoV-2 infection in a highly epidemic context

In the context of SARS-CoV-2 pandemic, the hospital management of mother-infant pairs poses to obstetricians and neonatologists previously unmet challenges. In Lombardy, Northern Italy, 59 maternity wards networked to organise the medical assistance of mothers and neonates with suspected or confirmed SARS-CoV-2 infection. Six "COVID-19 maternity centres" were identified, the architecture and activity of obstetric and neonatal wards of each centre was reorganised, and common assistance protocols for the management of suspected and proven cases were formulated. Here, we present the key features of this reorganization effort, and our current management of the mother-infant dyad before and after birth, including our approach to rooming-in practice, breastfeeding and neonatal follow-up, based on the currently available scientific evidence. Considered the rapid diffusion of COVID-19 all over the world, we believe that preparedness is fundamental to assist mother-infant dyads, minimising the risk of propagation of the infection through maternity and neonatal wards

Genetic polymorphisms and sepsis in premature neonates

Identifying single nucleotide polymorphisms (SNPs) in the genes involved in sepsis may help to clarify the pathophysiology of neonatal sepsis. The aim of this study was to evaluate the relationships between sepsis in pre-term neonates and genes potentially involved in the response to invasion by infectious agents. The study involved 101 pre-term neonates born between June 2008 and May 2012 with a diagnosis of microbiologically confirmed sepsis, 98 pre-term neonates with clinical sepsis and 100 randomly selected, otherwise healthy pre-term neonates born during the study period. During the study, 47 SNPs in 18 candidate genes were genotyped on Guthrie cards using an ABI PRISM 7900 HT Fast real-time and MAssARRAY for nucleic acids instruments. Genotypes CT and TT of rs1143643 (the IL1\u3b2 gene) and genotype GG of rs2664349GG (the MMP-16 gene) were associated with a significantly increased overall risk of developing sepsis (p = 0.03, p = 0.05 and p = 0.03), whereas genotypes AG of rs4358188 (the BPI gene) and CT of rs1799946 (the DEF\u3b21 gene) were associated with a significantly reduced risk of developing sepsis (p = 0.05 for both). Among the patients with bacteriologically confirmed sepsis, only genotype GG of rs2664349 (the MMP-16 gene) showed a significant association with an increased risk (p = 0.02). Genotypes GG of rs2569190 (the CD14 gene) and AT of rs4073 (the IL8 gene) were associated with a significantly increased risk of developing severe sepsis (p = 0.05 and p = 0.01). Genotype AG of rs1800629 (the LTA gene) and genotypes CC and CT of rs1341023 (the BPI gene) were associated with a significantly increased risk of developing Gram-negative sepsis (p = 0.04, p = 0.04 and p = 0.03). These results show that genetic variability seems to play a role in sepsis in pre-term neonates by influencing susceptibility to and the severity of the disease, as well as the risk of having disease due to specific pathogens. \ua9 2014 Esposito et al

Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged 44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating

Iatrogenic anetoderma of prematurity : a case report and review of the literature

Anetoderma is a skin disorder characterized by focal loss of elastic tissue in the mid dermis, resulting in localized areas of macular depressions or pouchlike herniations of skin. An iatrogenic form of anetoderma has been rarely described in extremely premature infants and has been related to the placement of monitoring devices on the patient skin. Because of the increasing survival of extremely premature infants, it is easy to foresee that the prevalence of anetoderma of prematurity will increase in the next future. Although it is a benign lesion, it persists over time and can lead to significant aesthetic damage with need for surgical correction. Sometimes the diagnosis can be difficult, especially when the atrophic lesions become evident after discharge. Here, we report on a premature infant born at 24 weeks of gestation, who developed multiple anetodermic patches of skin on the trunk at the sites where electrocardiographic electrodes were previously applied. The knowledge of the disease can encourage a more careful management of the skin of extremely premature babies and aid the physicians to diagnose the disease when anetoderma patches are first encountered later in childhood

Herpesviruses and breast milk.

Breast milk has always been the best source of nourishment for newborns. However, breast milk can carry a risk of infection, as it can be contaminated with bacterial or viral pathogens. This paper reviews the risk of acquisition of varicella-zoster virus (VZV) and cytomegalovirus (CMV), herpesviruses frequently detected in breastfeeding mothers, via breast milk, focusing on the clinical consequences of this transmission and the possible strategies for preventing it. Maternal VZV infections are conditions during which breastfeeding may be temporarily contraindicated, but expressed breast milk should always be given to the infant. CMV infection acquired through breast milk rarely causes disease in healthy term newborns; an increased risk of CMV disease has been documented in preterm infants. However, the American Academy of Pediatrics (AAP) does not regard maternal CMV seropositivity as a contraindication to breastfeeding; according to the AAP, in newborns weighing less than 1500 g, the decision should be taken after weighing the benefits of breast milk against the risk of transmission of infection. The real efficacy of the different methods of inactivating CMV in breast milk should be compared in controlled clinical trials, rigorously examining the negative consequences that each of these methods can have on the immunological and nutritional properties of the milk itself, with a view to establish the best risk-benefit ratio of these strategies before they are recommended for use in clinical practice

Interstitial lung disease in a newborn affected by mevalonic aciduria

Introduction: Mevalonic aciduria (MA) is the most severe phenotype of mevalonate-kinase deficiency (MKD), with a onset in early infancy and poor prognosis. MA diagnosis may be challenging in the neonatal period given its rarity and its unspecific symptoms that frequently recall those of other neonatal diseases. To our knowledge, interstial lung involvement has never been described as onset feature in a newborn with MKD. Objectives: We report the case of a newborn affected by MKD characterized by interstitial lung disease. Methods: The patient underwent laboratory and radiology evaluation as clinically indicated. Direct Sanger sequencing was used to screen the 10 exons of the MVK gene. Results: A female neonate born at term from consanguineous parents was referred to our hospital at 16 days of life (DOL) for mild hypotonia and persistent raised inflammatory markers despite antibiotic therapy. Infectious work-up was negative for both viral and bacterial infections. Chest x-ray revealed bilateral perihilar peribronchial thickening. Electroencephalography (EEG) reported moderate diffuse anomalies of background activity without major abnormalities. On DOL 20 the first episode of fever was recorded. Due to worsening tachypnea and persistent abnormal chest x-ray, a pulmonary CT scan was performed and showed diffuse ground-glass bilateral infiltrates consistent with alveolar-interstitial lung disease. On DOL 22 a palpable maculo-papular skin rash appeared on feet and hands, vanishing spontaneously 24 hours later. Bone marrow examination and levels of perforins, neuron-specific enolase and urinary catabolites of catecholamines were normal. A total body MRI was normal except for a mild cerebellar hypoplasia and the known interstitial lung disease. The patient kept presenting hypotonia, relapsing episodes of fever and skin rashes, developed anemia requiring blood transfusions and failure to thrive became evident. Type-I IFN signature was negative. A genetic test was requested, as well as quantification of urinary levels of mevalonic acid, which were markedly above the normal range. Direct Sanger sequencing allowed to detect a homozygous c.709A>T missense mutation in the exon 8 of the MVK gene, coding for a protein substitution p.T237S already classified as pathogenic in the INFEVERS database (http://fmf.igh.cnrs.fr/ISSAID/infevers/) and therefore consistent with the diagnosis of MKD. Both parents and her sister were found to be heterozygous carriers of the same mutation. On DOL 38 treatment with anakinra was started, with prompt regression of fever and skin rash, decrease in inflammatory markers, increase in reticulocytes count and weight gain. Hypotonia improved but persisted. The patient was discharged from hospital on DOL 56 in good clinical conditions, with acute phase reactants within the normal range and mild hypotonia. She is now 4 months old, still on anakinra treatment without adverse events. Conclusion: Autoinflammatory diseases in the neonatal period are a diagnostic challenge. Clinical suspicion is crucial in order to perform specific laboratory and genetic testing and start appropriate treatment. Interstitial lung involvement may be present in MKD and, together with increased inflammatory markers, could be the first manifestation of the disease

Usefulness of Presepsin (Soluble CD14 Subtype) in the Diagnosis of Neonatal Sepsis

Background: Sepsis is a major cause of morbidity and mortality in neonates. Recently, presepsin (soluble CD14 subtype) has been shown to be beneficial as sepsis marker in adults. Nevertheless, few data are available in neonates. Objective: To evaluate the diagnostic accuracy of presepsin as a marker of sepsis in the neonatal period. Design/Methods: All neonates with clinical signs of sepsis admitted to our Unit during a 18\uacmonths period were consecutively enrolled. CDC criteria were used to identify neonates with a suspected sepsis. The subjects enrolled in the study were then classified into 3 groups according to Goldstein's and Wynn's definitions: group 1, infection\u37e group 2, sepsis\u37e group 3, septic shock. To measure presepsin, 100 microliters of blood were collected at the following times: at the onset of clinical signs of sepsis (T0), every 12 h for the next 48 h (T1, T2, T3, T4), and at the end of antibiotic therapy (T5). C\uacreactive protein (CRP) was determined at the same times. Presepsin levels were determined using PathfastTM System (LSI Medience Corporation, Japan/Mitsubishi Chemical Europe). Results: We enrolled 110 neonates: 36 in group 1 (mean GA 34.6 wks, mean BW 2403 g), 59 in group 2 (mean GA 31 wks, mean BW 1615 g) and 15 in group 3 (mean GA 30.2 wks, mean BW 1441 g). Overall, median presepsin value was 1146 pg/ml at T0, higher than the values we previously reported in healthy neonates (PAS Meeting 2015), and decreased over time to 726 pg/ml at T5. Presepsin levels were significantly higher in neonates with sepsis and in those with septic shock than in the others at T0, T1, T2, T3, and T4 (p < .05). Additionally, neonates with septic shock had higher levels of presepsin than those with sepsis at all times. At enrollment, median presepsin value was 874 pg/ml, 1277 pg/ml, and 1928 pg/ml in group 1, 2, and 3 respectively. No significant difference was found in CRP values among the 3 groups at enrollment. The area under the ROC curve for presepsin at enrollment was 0.839 (95% CI: 0.79\uac0.88). Maximum Youden index was at a cut\uacoff value of 865 pg/ml, corresponding to 75% sensitivity and 80% specificity. Conclusions: According to our results, presepsin appears an accurate biomarker for the diagnosis of neonatal sepsis and it seems to be earlier than CRP in identifying sepsis and septic shock