Clinical Indicators of Late-Onset Sepsis Workup in Very Low-Birth-Weight Infants in the Neonatal Intensive Care Unit.

Background Late-onset sepsis (LOS) in very low-birth-weight (VLBW) infants is associated with significant morbidity and mortality. Objectives To determine the incidence of LOS workup, association, and predictive value of clinical indicators leading to culture-positive versus culture-negative sepsis workup. Methods All sepsis workups performed after 7 days of life, in neonates with birth weight of < 1,500 g were included. Each case (culture-positive workup) was matched with a control (culture-negative workup) for gestational age (GA), birth weight, corrected gestational age, and chronological age, at the time of workup. The clinical indicators leading to the performance of sepsis workup were compared between cases and controls. Results The incidence of culture-positive workup was 87/345 (25.2%) and that of LOS was 84/279 (30.1%). Among various clinical indicators, hypothermia and apnea were significantly associated with culture-positive sepsis workup (p = 0.015 and 0.004, respectively), with a positive predictive value of 81.2 and 71.4%, respectively. Conclusion In VLBW infants, one-fourth of sepsis workups resulted in a positive culture. Apnea and hypothermia were the most significant predictors of culture-positive workup after matching for GA, birth weight, chronological age, and corrected GA at the time of the workup.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza.

BACKGROUND: Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS: From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS: The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus, in a level III NICU: 2001 to 2008.

OBJECTIVE: To determine epidemiology and clinical characteristics of infants with methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) in a level III neonatal intensive care unit (NICU). STUDY DESIGN: All NICU admissions (2001 to 2008) with any positive S. aureus culture were included as cases. Cases were further characterized as either colonized or infected with invasive disease. RESULTS: Four thousand three hundred four infants were admitted; 273 (6.3%) had at least one culture positive for S. aureus, including 198 with MSSA and 75 with MRSA. Invasive disease occurred in 23.2% of MSSA cases versus 29.3% MRSA (p = 0.298). Between the study periods 2001 to 2005 versus 2006 to 2008, the incidence of all MSSA cultures (colonization and invasive disease) decreased from 53.6 to 38.9/1000 admissions (p = 0.044), and that of MRSA increased from 13.7 to 24.77/1000 admissions (p = 0.010). The incidence of invasive MSSA (p = 0.49) and MRSA (p = 0.38) disease between the two periods remained similar. Infants with invasive MRSA versus MSSA had a longer duration of positive cultures (55 versus 19 days, p = 0.009). None of five available isolates collected prior to 2006 was characterized as USA300, but 11/21 isolates collected subsequently were USA300 (p = 0.053). CONCLUSION: The incidence of MRSA (colonization and infection) nearly doubled during the study period coinciding with emergence of community-acquired MRSA USA300.

Evaluation of suspected neonatal herpes simplex virus infection in preterm versus term newborns in the neonatal intensive care unit.

BACKGROUND: While national guidelines are available for the evaluation and management of term infants at risk for herpes simplex virus (HSV) infection, such guidelines are lacking for preterm infants. We sought to determine the risk factors and clinical characteristics of preterm vs. term infants who were evaluated and treated empirically for HSV infection in the neonatal intensive care unit (NICU). METHODS: In a retrospective cohort study, medical records of all infants who were admitted to our NICU (2009-2016) and who were evaluated and empirically treated for HSV were reviewed for mothers' and infants' demographics, clinical characteristics, and laboratory findings. RESULTS: During the study period 4.2% (103/2,471) of all preterm infants, and 6.0% (112/1,865) of all term infants were evaluated and treated empirically for neonatal HSV. Among all infants who were evaluated and treated for HSV, 5.5% (12/215) had neonatal HSV disease, of whom 83.3% (10/12) were preterm infants. In comparison to term, preterm infants were more likely to be evaluated and treated, if they had a maternal history of HSV [OR 2.51 (95% CI: 1.41-4.48)], prolonged rupture of membranes [2.64 (1.221-5.73)], leukopenia [3.65 (1.94-6.87)] and thrombocytopenia [2.25 (0.85-5.89)]. HSV disease was associated with a higher mortality compared to those without disease [25% (3/12) vs. 4.4% (9/203) respectively; p = <0.05]. CONCLUSION: Preterm infants evaluated and empirically treated for HSV have a higher burden of HSV infection than term infants. HSV should be considered in the management of preterm infant with a maternal history of HSV, prolonged rupture of membranes, and thrombocytopenia.

Using Preventive Health Alerts in the Electronic Health Record Improves Hepatitis C Virus Testing Among Infants Perinatally Exposed to Hepatitis C.

BACKGROUND: Perinatal exposure to hepatitis C virus (HCV) is a major public health issue, and poor testing rates leave many children with infection unidentified. We sought to use the electronic health record (EHR) to promote guideline-directed HCV testing among infants born to mothers with HCV infection in an urban, safety-net hospital system. METHODS: Our study population was identified using our EHR database, Epic. Children were included in the study if they had perinatal HCV exposure, were 18 months to 18 years of age and had at least 1 encounter in a primary or urgent care clinic during the study period. Our study included retrospective (October 2011 to February 2015) and prospective (February 2015 to May 2018) arms. Our EHR-based intervention was initiated in the prospective arm and recommended a one-time HCV antibody test at or after the age of 18 months using a health maintenance reminder. The health maintenance reminder activated a point-of-care alert and a linked HCV testing order set in all prespecified encounters during the intervention period. RESULTS: Median time to appropriate HCV testing decreased from 96.2 months preintervention to 9.1 months postintervention (P < 0.0001), and rate of completed antibody testing increased from 14% to 61% (P < 0.0001). CONCLUSIONS: Among children with perinatal HCV exposure, using a point-of-care alert within the EHR significantly increased the HCV antibody testing rate in accordance with American Academy of Pediatrics (AAP) recommendations. More effective EHR-based interventions combined with increased provider awareness of appropriate HCV testing in perinatally exposed infants is imperative.

Hepatitis C Virus Screening Among Adolescents Attending a Drug Rehabilitation Center.

BACKGROUND: Hepatitis C virus (HCV) infection has a strong association with intravenous drug use (IVDU). IVDU is a growing public health concern, even in the adolescent population. To our knowledge, there are no published HCV screening studies targeting high-risk adolescents who attend drug rehabilitation centers.This study was designed to determine the seroprevalence of HCV infection utilizing point-of-care (POC) testing at an adolescent drug rehabilitation center and gain a preliminary understanding of the acceptance rate for HCV screening in this high-risk population. METHODS: This single-center, observational study was conducted at a major drug rehabilitation center in northeast Ohio from July 2016 to June 2017. The consented adolescents who presented at the center were recruited to participate in HCV screening. The participants were administered a survey to assess their demographics and risk behavior profile followed by HCV testing utilizing a POC test. RESULTS: During the study period, 150 adolescents were admitted to the drug rehabilitation center, of whom 100 were approached and 85 agreed to participate. Forty percent of the participants (34/85) were females, and 78% (66/85) were white. HCV prevalence among participants was 5% (4/85), all of whom were females. History of heroin use was reported by 15% (13/85) and it was associated with HCV seropositivity; 100% (4/4) of all HCV-positive individuals reported the use of heroin vs only 11% (9/81) of HCV-negative individuals (P = .0004). CONCLUSIONS: Our study showed a high prevalence of HCV among adolescents attending a drug rehabilitation center with high acceptance of POC HCV testing.

Pulmonary tuberculosis presenting as fever without source in a pediatric patient with acute lymphoblastic leukemia.

Children who undergo treatment for malignancies are at high for infection with both typical and opportunistic pathogens. Fever in these children prompts extensive evaluation and empiric treatment with broad-spectrum antimicrobials. In the United States (US), tuberculosis is an infrequently reported cause of fever in the pediatric cancer patient and has not been well described. In this report we describe a case of primary pulmonary tuberculosis (TB) in a boy with precursor B-cell acute lymphoblastic leukemia (ALL) and review the pertinent literature.

Multiple Pulmonary Nodules in an Immunocompetent Adolescent with Infectious Mononucleosis.

BACKGROUND: Infectious mononucleosis is usually a self-limiting illness, but can be rarely associated with complications. CASE CHARACTERISTICS: A 17-year-old boy with Epstein-Barr virus related infectious mononucleosis and cold antibody-mediated autoimmune hemolytic anemia with incidentally noted multiple pulmonary nodules. OBSERVATIONS: Nodules regressed over the next few weeks without specific therapy. MESSAGE: Pediatricians need to be aware of this rare clinical presentation of infectious mononucleosis so that further invasive testing can be avoided.

Nonimmune hydrops fetalis and hepatitis in a neonate with congenital human immunodeficiency virus infection.

We present a case report of a term neonate with congenital human immunodeficiency virus (HIV) infection born with nonimmune hydrops fetalis who developed hepatitis shortly after birth. Maternal HIV infection was diagnosed after delivery. An extensive evaluation for known causes of nonimmune hydrops, both infectious and noninfectious, was negative. After beginning highly active antiretroviral therapy, hepatitis resolved and the HIV viral load became undetectable. We believe this is the first report of nonimmune hydrops fetalis and hepatitis in an infant with congenital HIV infection.

Severe respiratory syncytial virus pneumonia associated with primary Epstein-Barr virus infection.

This is a case report of a child with severe respiratory syncytial virus (RSV) pneumonia and concurrent infection with Epstein-Barr virus. We hypothesize that immunosuppression due to EBV may have contributed to the severity of his RSV infection. The diagnosis of RSV infection was facilitated by bronchoalveolar lavage.

Interventions using electronic medical records improve follow up of infants born to hepatitis C virus infected mothers.

BACKGROUND: The American Academy of Pediatrics recommends hepatitis C virus (HCV) antibody testing for all HCV- exposed infants at age ≥ 18 months. However, many of these infants are not appropriately tested. In 2006, the pediatric infectious disease service (PIDS) at our institution implemented interventions using electronic medical records (EMR) to improve appropriate HCV testing for HCV-exposed infants. METHODS: Two-part study: During the first period (January 1, 1993, to December 31, 2005), medical records of all infants born to mothers with HCV were retrospectively reviewed for patient's demographics and infant's HCV testing. PIDS interventions included contacting the primary care physician through EMR requesting HCV testing for children without proper testing. During the second period (January 1, 2006, to December 31, 2011), interventions using EMR were implemented prospectively, including PIDS consultations during birth hospitalization for all HCV-exposed infants, addition of HCV exposure to the EMR problem list and communication with PCPs via the EMR to assure appropriate HCV testing. RESULTS: About 67,112 infants were born during the study period; 280 had maternal HCV infection and 193 continued to receive medical care at our institution. PIDS interventions using EMR resulted in a significant improvement of appropriate HCV testing among HCV-exposed infants from 8% (10/121) to 50% (36/72); P <0.0001. It also resulted in the identification of 5 new HCV-infected children; 3 of them were born before 2006 and previously undiagnosed. CONCLUSIONS: Interventions using EMR improved the identification and appropriate HCV follow up of infants born to HCV-infected mothers.

Tuberculous radiculomyelitis presenting in a toddler with lower extremity weakness and seizure.

Tuberculous radiculomyelitis is an uncommon but serious complication of tuberculosis that can lead to considerable morbidity and mortality. We present the case of a 21-month-old male Congolese refugee diagnosed with tuberculous radiculomyelitis who presented with gradual motor and speech regression, and likely an infection-related seizure 2 months before diagnosis.

Safety and immunogenicity of a live attenuated RSV vaccine in healthy RSV-seronegative children 5 to 24 months of age.

UNLABELLED: Despite substantial morbidity associated with respiratory syncytial virus (RSV) infection, there is no licensed vaccine. MEDI-559 is a live attenuated intranasal vaccine candidate being developed for prevention of lower respiratory illness due to RSV in young children. This randomized, placebo-controlled study evaluated safety of MEDI-559 in healthy, RSV-seronegative children. MEDI-559 or placebo was administered on 3 occasions, 2 months apart. Primary safety was based on solicited symptoms (SSs) and adverse events (AEs) collected for 28 days after each dose. Nasal wash samples were collected 3 times after each dose (days 7-10, 12-18, 28-34) and at sick visits. Serum was collected for measuring antibody immune responses to RSV prior to first vaccination and 28 days post final dose. Long-term safety was monitored for 365 days from first dose. SSs were mild and frequent (MEDI-559 84%; placebo 91%); most common SSs were runny/stuffy nose, cough, and irritability/fussiness. AEs occurred in 67% MEDI-559 and 57% placebo recipients: most common AE was upper respiratory tract infection (MEDI-559 35%; placebo 23%). Higher incidence of medically attended lower respiratory illness within 28 days after dosing occurred in the MEDI-559 arm compared to placebo (none associated with vaccine virus shedding). There was no evidence of enhanced RSV disease. Vaccine virus was detected only in MEDI-559 recipients; shedding occurred in 56%subjects, primarily post dose 1. A functional immune response was observed in 59% and 9% MEDI-559 and placebo recipients, respectively, by an RSV microneutralization assay. Vaccine take, assessed by proportion that shed vaccine-type virus or had a seroresponse against RSV, was seen in 95% MEDI-559 subjects. MEDI-559 is therefore biologically active and immunogenic in this seronegative pediatric population. Although the frequency of SSs and AEs was not considered clinically significant, the increase in medically attended lower respiratory illnesses in the vaccine group warrants expanded safety studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00767416.

Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children.

BACKGROUND: Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are important causes of lower respiratory tract illness and hospitalization in young children. Currently, there is no licensed vaccine against RSV or PIV3. METHODS: In this randomized, phase 1, double-blind, placebo-controlled, dose-escalating study, 49 healthy RSV/PIV3-seronegative children 6 to <24 months of age were randomized 2:1 to receive 3 doses (at 10, 10, or 10 median tissue culture infective dose [TCID50]) of MEDI-534 (a live, attenuated RSV/PIV3 chimeric virus vaccine candidate) or placebo at 2-month intervals. Solicited adverse events (SEs) and unsolicited adverse events (AEs) were recorded during days 0 to 28 after each dose. Nasal wash samples were collected 3 times (days 7-10, 12-18, and 28-34) after each dose and at unscheduled illness visits. Blood for antibody response was collected at baseline and 28 days after each dose. Subjects were followed for 180 days after the last dose or to the end of the RSV season. RESULTS: Overall, there was no difference in the incidence of SEs and AEs between the RSV/PIV3 vaccine and placebo arms. Runny/stuffy nose was the most commonly reported SE. Medically attended lower respiratory illness rates were balanced between treatment arms, and there was no evidence of enhanced RSV disease or vaccine-related serious AEs. Vaccine virus was detected in most vaccinees on days 7 to 10 after dose 1 in a dose-dependent manner. Seroresponse to RSV and PIV3 was highest in subjects receiving the 10 dosage. CONCLUSIONS: The safety profile and vaccine take as measured by shedding and/or seroresponse in this RSV/PIV3-seronegative pediatric population support the continued development of this RSV/PIV3 pediatric vaccine candidate.

Immunogenicity and safety of an inactivated hepatitis A vaccine when coadministered with measles-mumps-rubella and varicella vaccines in children less than 2 years of age.

BACKGROUND: Hepatitis A vaccination in early childhood has reduced hepatitis A transmission. Coadministration of hepatitis A vaccine with other childhood vaccines may assist completion of the age-appropriate immunization schedule. We assessed the immunogenicity and safety of an inactivated hepatitis A virus vaccine when coadministered with measles-mumps-rubella (MMR) and varicella vaccines in children less than 2 years of age. METHODS: In this open-label, randomized, multicenter study, 3 groups of healthy children 15 months of age received either 2 doses of hepatitis A vaccine 6 to 9 months apart (n = 324), hepatitis A vaccine coadministered with MMR and varicella vaccines and a second dose of hepatitis A vaccine 6 to 9 months later (n = 462), or MMR and varicella vaccines followed 6 weeks later by 2 doses of hepatitis A vaccine 6 to 9 months apart (n = 455). Immune responses were evaluated at baseline, 31 days after the second dose of hepatitis A vaccine, and 42 days after MMR and varicella vaccine administration. Solicited, unsolicited, and serious adverse events were collected. RESULTS: After 2 doses of hepatitis A vaccine, nearly all subjects in all groups were seropositive (≥99%). Coadministration of hepatitis A vaccine with MMR and varicella vaccines did not impact the immunogenicity of any of the vaccines and was well tolerated. CONCLUSIONS: The immune response to hepatitis A vaccine and US-licensed MMR and varicella vaccines is not adversely affected when coadministered in children 15 months of age.

Safety of oseltamivir compared with the adamantanes in children less than 12 months of age.

BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.

Recognition and treatment of neonatal community-associated MRSA pneumonia and bacteremia.

Community-associated strains of methicillin-resistant Staphylococcus aureus (CA-MRSA) have recently emerged as a major cause of serious infections among older children and are now being seen in NICU patients. We present the case of a preterm infant with CA-MRSA necrotizing pneumonia and secondary bacteremia.