Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.

OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.

Using Clinical History Factors to Identify Bacterial Infections in Young Febrile Infants.

OBJECTIVE: To develop a novel predictive model using primarily clinical history factors and compare performance to the widely used Rochester Low Risk (RLR) model. STUDY DESIGN: In this cross-sectional study, we identified infants brought to one pediatric emergency department from January 2014 to December 2016. We included infants age 0-90 days, with temperature ≥38°C, and documented gestational age and illness duration. The primary outcome was bacterial infection. We used 10 predictors to develop regression and ensemble machine learning models, which we trained and tested using 10-fold cross-validation. We compared areas under the curve (AUCs), sensitivities, and specificities of the RLR, regression, and ensemble models. RESULTS: Of 877 infants, 67 had a bacterial infection (7.6%). The AUCs of the RLR, regression, and ensemble models were 0.776 (95% CI 0.746, 0.807), 0.945 (0.913, 0.977), and 0.956 (0.935, 0.975), respectively. Using a bacterial infection risk threshold of .01, the sensitivity and specificity of the regression model was 94.6% (87.4%, 100%) and 74.5% (62.4%, 85.4%), compared with 95.5% (87.5%, 99.1%) and 59.6% (56.2%, 63.0%) using the RLR model. CONCLUSIONS: Compared with the RLR model, sensitivities of the novel predictive models were similar whereas AUCs and specificities were significantly greater. If externally validated, these models, by producing an individualized bacterial infection risk estimate, may offer a targeted approach to young febrile infants that is noninvasive and inexpensive.

Measuring the Severity of Respiratory Illness in the First 2 Years of Life in Preterm and Term Infants.

OBJECTIVE: To develop a valid research tool to measure infant respiratory illness severity using parent-reported symptoms. STUDY DESIGN: Nose and throat swabs were collected monthly for 1 year and during respiratory illnesses for 2 years in a prospective study of term and preterm infants in the Prematurity, Respiratory Outcomes, Immune System and Microbiome study. Viral pathogens were detected using Taqman Array Cards. Parents recorded symptoms during respiratory illnesses using a Childhood Origins of Asthma (COAST) scorecard. The COAST score was validated using linear mixed effects regression modeling to evaluate associations with hospitalization and specific infections. A data-driven method was also used to compute symptom weights and derive a new score, the Infant Research Respiratory Infection Severity Score (IRRISS). Linear mixed effects regression modeling was repeated with the IRRISS illness data. RESULTS: From April 2013 to April 2017, 50 term, 40 late preterm, and 28 extremely low gestational age (<29 weeks of gestation) infants had 303 respiratory illness visits with viral testing and parent-reported symptoms. A range of illness severity was described with 39% of illness scores suggestive of severe disease. Both the COAST score and IRRISS were associated with respiratory syncytial virus infection and hospitalization. Gestational age and human rhinovirus infection were inversely associated with both scoring systems. The IRRISS and COAST scores were highly correlated (r = 0.93; P < .0001). CONCLUSIONS: Using parent-reported symptoms, we validated the COAST score as a measure of respiratory illness severity in infants. The new IRRISS score performed as well as the COAST score.

Viral Respiratory Infections in Preterm Infants during and after Hospitalization.

OBJECTIVE: To determine the burden of viral respiratory infections in preterm infants both during and subsequent to neonatal intensive care unit (NICU) hospitalization and to compare this with term infants living in the community. STUDY DESIGN: From March 2013 through March 2015, we enrolled 189 newborns (96 term and 93 preterm) into a prospective, longitudinal study obtaining nose/throat swabs within 7 days of birth, weekly while hospitalized and then monthly to 4 months after hospital discharge. Taqman array cards were used to identify 16 viral respiratory pathogens by real-time polymerase chain reaction. Demographic, clinical, and laboratory data were gathered from electronic medical records, and parent interview while hospitalized with interval histories collected at monthly visits. The hospital course of all preterm infants who underwent late-onset sepsis evaluations was reviewed. RESULTS: Over 119 weeks, we collected 618 nose/throat swabs from at risk preterm infants in our level IV regional NICU. Only 4 infants had viral respiratory infections, all less than 28 weeks gestation at birth. Two infants were symptomatic with the infections recognized by the clinical team. The daily risk of acquiring a respiratory viral infection in preterm infants in the NICU was significantly lower than in the full term cohort living in the community. Once discharged from the hospital, viral respiratory infections were common in all infants. CONCLUSIONS: Viral respiratory infections are infrequent in a NICU with strict infection prevention strategies and do not appear to cause unrecognized illness. Both preterm and term infants living in the community quickly acquire respiratory viral infections.

Observational trial of a 48-hour gentamicin dosing regimen derived from Monte Carlo simulations in infants born at less than 28 weeks' gestation.

OBJECTIVE: To develop and validate a 48-hour gentamicin dosing regimen for infants born at <28 weeks' gestation. STUDY DESIGN: Using previously published pharmacokinetic data, we performed Monte Carlo simulations for several candidate gentamicin dosing regimens. On the basis of these simulations, we changed dosing for infants born at <28 weeks to 4.5 mg/kg every 48 hours. We then conducted an observational study of 30 infants on this new regimen and compared serum gentamicin levels with 60 historical control subjects who received 2.5 mg/kg every 24 hours. RESULTS: Infants in the 48-hour group achieved higher gentamicin peaks (mean 9.43 microg/mL vs 6.0 microg/mL, P < .001) and lower gentamicin troughs (mean 1.08 microg/mL vs 1.54 microg/mL, P < .001) compared with the 24-hour group. Seven percent of the 48-hour group infants had a gentamicin peak <6 microg/mL versus 43% in the 24-hour group. With a goal for peaks of 6 to 12 microg/mL and for troughs of <1.5 microg/mL, infants in the 48-hour group required fewer adjustments of their dosing regimens compared with the 24-hour group (26.7% vs 78.3%). CONCLUSIONS: Gentamicin given every 48 hours to infants born at <28 weeks achieves optimal blood concentrations more frequently than does once-daily dosing. Monte Carlo simulations on the basis of pharmacokinetic modeling are useful to optimize drug dosing in premature infants.

Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7).

OBJECTIVE: To examine whether: (1) congenital human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) infections occur; whether (2) their manifestations differ from postnatal infections; and whether (3) HHV6 and HHV7 infections differ despite their close relatedness. STUDY DESIGN: HHV6 and HHV7 infections acquired congenitally and postnatally in normal children were compared using viral isolation, serology, reverse-transcription polymerase chain reaction (RT-PCR) and nested DNA-PCR for HHV6 variant A (HHV6A), HHV6 variant B (HHV6B), and HHV7. RESULTS: HHV6 DNA was detected in 57 (1%) of 5638 cord bloods. HHV7 DNA, however, was not detected in 2129 cord bloods. Congenital HHV6 infections differed from postnatal infections, which were acute febrile illnesses. Congenital infections were asymptomatic, 10% demonstrated reactivation at birth, and HHV6 DNA persistence in follow-up blood samples was significantly more frequent. One-third of congenital infections were HHV6A, whereas all postnatal infections were HHV6B. CONCLUSIONS: Congenital HHV6 infections occurred in 1% of births, similar to the rate for cytomegalovirus infection. Congenital infections were clinically and virologically distinct from postnatal infections. Congenital HHV7 infections, however, were not detected, suggesting considerable differences in transmission and pathogenesis in these closely related beta-herpesviruses.

Human herpesvirus 6 (HHV6) DNA persistence and reactivation in healthy children.

OBJECTIVE: To determine in healthy children after primary infection the persistence of human herpesvirus 6 (HHV6) DNA, the presence and frequency of HHV6 re-activation or re-infection, and the relationship of both to illness and the presence of human herpesvirus 7 (HHV7) infection. STUDY DESIGN: Children 1 to 12 years of age with previous HHV6 infection were prospectively evaluated by HHV6 and HHV7 DNA polymerase chain reaction (PCR) and reverse transcription (RT)-PCR for HHV6. HHV6 plasma antibody titers were measured. Illnesses were recorded by diary, and physician records were reviewed. RESULTS: HHV6 DNA was detected in >or=1 peripheral blood mononuclear cell (PBMC) samples in 89% of children. HHV6 reactivation and re-infection were detected by RT-PCR in 1.1% of samples. Detection of HHV6 DNA was intermittent in 76% of children and was not associated with cumulative rates of illness. Illness at a study visit was significantly associated with the absence of HHV6 and HHV7 DNA in PBMC samples and was not associated with HHV6 antibody titer or the presence of HHV6 DNA in saliva. CONCLUSIONS: HHV6 DNA persists in most children intermittently following primary infection and is unrelated to illness. Reactivation of HHV6 occurs in healthy children without apparent illness.