Impact of human coronavirus infections on paediatric patients at a tertiary paediatric hospital: a retrospective study of the prepandemic era.

BACKGROUND: Human coronaviruses (HCoVs) are important respiratory pathogens in humans and animals. Most HCoVs are emerging pathogens, with five known human pathogens identified in the last two decades. AIM: To examine the clinical course of HCoV infection in children to improve understanding of severity and outcomes. METHODS: A retrospective review was undertaken of all encounters of children with known HCoV infection at a tertiary paediatric hospital from January 2015 to January 2018. Electronic medical records were reviewed for demographic data, HCoV type, viral co-pathogens, time to testing, need for hospitalization, requirement for higher-level care (HLC) including intensive care unit management and requirement for oxygen support, radiographic findings suggestive of lower respiratory tract (LRT) disease, and length of stay (LOS). FINDINGS: In total, 450 encounters for 430 different patients were identified, with the majority (85%) being inpatient. OC43 was the most common HCoV. Younger patients (age <5 years) had higher probability of hospitalization [adjusted odds ratio (aOR) 2.2, 95% confidence interval (CI) 1.2-4.1], requirement for HLC (aOR 1.8, 95% CI 1.0-3.1) and presence of LRT findings on chest radiographs (aOR 1.7, 95% CI 1.01-2.9). Clinical outcomes did not differ between HCoV types, except LOS which was longer for 229E. Fifty-two (11%) encounters were detected after 3 days of hospitalization (median 25.5 days), suggesting possible nosocomial infection. CONCLUSION: HCoVs are important respiratory pathogens in the paediatric population, especially among patients aged <5 years who are at increased risk for severe disease. The role of HCoVs as hospital-acquired pathogens may be underappreciated.

The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach.

Infants are at increased risk for morbidity and mortality due to influenza. Until recently, few data were available with which to optimize oseltamivir dosing in this high-risk population. Here, data for 133 infants were pooled from two prospective pharmacokinetic/pharmacodynamic safety studies to develop a population pharmacokinetic model. A three-compartment model with allometric scaling of all clearance and volume parameters described the disposition of oseltamivir and its carboxylate metabolite (OC). Weight dependence, OC clearance, and volume of distribution increased linearly with age. Analyses showed no association between OC exposure and viral clearance, the development of resistance (phenotypic/genotypic), normalization of body temperature, or safety endpoints. Pharmacokinetic bridging showed that a 3 mg/kg dose yielded acceptable OC exposure and good tolerability while minimizing the risk of underexposure and resistance/treatment failure. These pharmacological analyses formed the basis of the US Food and Drug Administration's recent approval of oseltamivir treatment for infants with influenza aged as young as 2 weeks.

Determination of appropriate dosing of influenza drugs in pediatric patients.

Dose-finding studies of influenza antiviral drugs are challenging because it is difficult to enroll subjects in pediatric interventional studies and also because of the lack of concentration (or toxicity)­response relationships, the short duration of antiviral therapy, and the continually developing metabolic profiles of infants and young children. The evaluation of influenza antiviral agents in premature infants adds even more complexity. Recent advances in exposure-targeted study designs and modeling and simulations have aided in addressing some of these challenges.

Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates.

The effect of the increasing prevalence of maternal obesity on perinatal morbidity.

OBJECTIVE: In this study, we assessed the temporal trends and relative and attributable perinatal risks of maternal obesity over a 20-year period. STUDY DESIGN: We conducted a retrospective cohort study between 1980 and 1999 by using a computerized perinatal database of all women who received prenatal care and delivered their infants within a regional health care system. The main outcome measures were as follows: (1) annual mean body weight and the percentage of women classified as obese at the first prenatal visit (primary definition > or = 200 lb; secondary definitions > or = 250 lb, > or = 300 lb, body mass index > 29 kg/m(2)); and (2) relative and attributable risks of obesity for selected maternal and perinatal morbidities in successive 5-year periods. RESULTS: From 1980 to 1999, the mean maternal weight of women at the first prenatal visit increased 20% (144-172 lb), as did the percentage of women > or = 200 lb (7.3-24.4), the percentage > or = 250 lb (1.9-10.7), the percentage > or = 300 lb (0.5-4.9), and the percentage with a body mass index > 29 kg/m(2) (16.3-36.4), P < .01 for all. Controlling for maternal age, race, and smoking status, obese women were at increased risk at each period for cesarean delivery (range of adjusted relative risk, 1.5-1.8), gestational diabetes (range, 1.8-2.9), and large (> 90th percentile) for gestational age infants (range, 1.8-2.2). From the earliest 5-year period (1980-1984) to the most recent (1995-1999), the percentage of obesity-attributable cesarean deliveries more than tripled from 3.9 to 11.6. Similar percentage increases were observed for the obesity-attributable risks for gestational diabetes (12.8-29.6) and large for gestational age infants (6.5-19.1). Trends for secondary obesity definitions were similar, although the magnitude of the increased attributable risks was smaller. CONCLUSIONS: Efforts to reduce the frequency of certain perinatal morbidities will be constrained unless effective measures to prevent, or limit the risks of, maternal obesity are developed and implemented.

Natural history of neonatal herpes simplex virus infections in the acyclovir era.

OBJECTIVE: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made. DESIGN/METHODS: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported. RESULTS: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy. CONCLUSION: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.

Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections.

OBJECTIVE: The objective of this investigation was to establish the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes simplex virus (HSV) disease. In addition, an estimate of therapeutic efficacy was sought, both with respect to mortality and to morbidity. Virologic efficacy of HD acyclovir was also assessed. PARTICIPANTS: Infants who were

Advances in the treatment of neonatal herpes simplex infections.

Neonatal HSV disease is a potentially devastating illness with significant mortality and morbidity. Collaborative research efforts over the past 25 years have provided therapeutic options that were beyond hope just a generation ago. The use of high-dose acyclovir for the treatment of acute neonatal HSV disease has reduced mortality rates to their lowest level ever. Application of PCR to clinical specimens from neonates suspected of having neonatal HSV infection largely has eliminated the need to perform invasive brain biopsies, while at the same time providing a new tool with which to re-define the natural history of neonatal HSV disease. A limitation of PCR is the lack of standardisation in methodologies from laboratory to laboratory, which can impede a clinician's ability to interpret the PCR results. As such, all test results, including those from PCR, must be evaluated in the context of the patient's medical condition. Areas for continued research for further means of improvement in disease outcome include raising awareness of neonatal HSV disease so that the time between disease onset and the initiation of antiviral therapy can be shortened, as well as the evaluation of monoclonal antibodies as adjunctive therapy to high-dose acyclovir. Utilisation of suppressive oral acyclovir following acute neonatal disease is another therapeutic option under clinical investigation with the potential to improve morbidity outcomes of neonatal HSV disease survivors.

Juvenile onset recurrent respiratory papillomatosis: possibilities for successful antiviral therapy.

Recurrent respiratory papillomatosis (RRP) is a potentially devastating disease that can have significant morbidity, and can even result in mortality due to airway compromise or, less commonly, malignant transformation. Two distinct types of RRP exist: adult-onset RRP (AO-RRP) and juvenile-onset RRP (JO-RRP). Acquisition of human papillomavirus (HPV), the causative agent of RRP, is believed to occur in the peripartum period in the case of JO-RRP, with disease symptoms (primarily hoarseness) becoming apparent during the first several years of life. Treatment currently consists of surgical debulking of the papillomas to relieve airway obstruction. However, numerous antiviral therapies have also been evaluated, albeit primarily under uncontrolled settings. This article will review the biology, natural history and management of HPV infection, with particular emphasis on JO-RRP.

Indicated versus spontaneous preterm delivery: An evaluation of neonatal morbidity among infants weighing

OBJECTIVE: The aim of the study was to determine whether infants weighing 20 weeks who were not produced as the result of an induced abortion were included. Our analysis was further limited to infants without major congenital anomalies who survived >2 days, were deemed potentially viable by the obstetrician, and would have undergone a cesarean delivery for fetal indications (N = 411). The primary reason for delivery was categorized as indicated delivery, spontaneous preterm labor, or spontaneous preterm premature rupture of membranes. Selected neonatal outcomes were evaluated among infants born to women in each of these groups. Logistic regression analyses were used to control for the effects of other potentially confounding variables. RESULTS: A total of 156 of the 411 infants were born to women who underwent an indicated preterm delivery, whereas 160 were born after spontaneous preterm labor and 95 were delivered after preterm premature rupture of membranes. Univariate analyses revealed significantly lower incidences of grade III or IV intraventricular hemorrhage, grade III or IV retinopathy of prematurity, and seizure activity among infants born in an indicated preterm delivery than among those born after spontaneous preterm labor or preterm premature rupture of membranes. However, infants of women who underwent indicated preterm delivery had a more advanced mean gestational age at birth than did those born after spontaneous preterm labor or preterm premature rupture of membranes (28 +/- 2 weeks, 26 +/- 2 weeks, and 26 +/- 1 weeks, respectively, P <.001). Multiple logistic regression analysis was therefore used to control for the disparity in gestational age. Multivariate analyses did not confirm the apparent improvement in neonatal outcome in the indicated delivery group. CONCLUSION: In this population of infants weighing

Human herpesvirus-6: neurologic implications of a newly-described viral pathogen.

Discovered only 12 years ago, human herpesvirus-6 (HHV-6) has been associated with central nervous system (CNS) findings such as febrile seizures, encephalitis, meningitis, and possibly multiple sclerosis. These manifestations have been reported in both immunocompetent and immunocompromised individuals. The applications of such sophisticated laboratory tools as polymerase chain reaction, in situ hybridization, immunohistochemical staining, and representational difference analysis have expanded knowledge of the spectrum of CNS disease attributable to HHV-6 while delineating pathogenic mechanisms of both primary HHV-6 infection and reactivation from latency. This article reviews existing knowledge of the CNS manifestations of HHV-6, focusing on both clinical aspects of HHV-6 infection and its pathogenesis on neurologic diseases.

Burkitt lymphoma in pregnancy.

BACKGROUND: Burkitt lymphoma during pregnancy is a rare event, and outcomes have been poor. However, few patients were treated by current standards, with nearly half receiving single-agent cyclophosphamide or no chemotherapy. CASE: A patient with Burkitt lymphoma presenting at 11 6/7 weeks' gestation was treated with surgical resection of all visible disease and cytotoxic combination chemotherapy. The patient was disease free at 1 year after diagnosis. CONCLUSION: When Burkitt lymphoma is encountered in pregnancy, immediate cytotoxic combination chemotherapy is indicated.

Fetal heart rate characteristics at 25 to 28 weeks' gestation.

The objective of this article is to define normative fetal heart rate (FHR) tracing characteristics between 25-28 weeks' gestation in a low-risk population with normal pregnancy outcomes and to determine which criteria best determine FHR reactivity. Continuous FHR tracings were reviewed from 188 low-risk women participating in a trial of the Mammary Stimulation Test (MST) at 25-28 weeks' gestation. A reactive tracing required the presence of > or =two accelerations in 20 min. Different acceleration criteria were evaluated based upon the width of the acceleration (short vs. long) and the amplitude of the acceleration (10 vs. 15 bpm). Seventy-one percent of the FHR tracings were reactive using the higher amplitude (15 bpm), short criteria. This number increased significantly to 92% when the lower amplitude (10 bpm), short criteria were used (p <0.01). As gestational age advanced, there was a trend toward increased reactivity irrespective of which criteria were used, but these differences were not significant. Reducing the acceleration amplitude criteria to 10 bpm in preterm pregnancies will maximize the number of reactive nonstress tests. This is advantageous because it would improve test specificity and decrease the false-positive rate. Our findings need to be prospectively validated in a high-risk population.

Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy.

OBJECTIVE: The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir. STUDY DESIGN: In a prospective, double-blind trial, 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were randomly assigned at 36 weeks' gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amniotic fluid samples were obtained during labor and simultaneous umbilical cord and maternal plasma samples were collected at delivery. Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants. RESULTS: Peak acyclovir plasma concentrations (mean +/- standard deviation) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose (3.14 +/- 0.7 microg/mL vs 0.74 +/- 0.6 microg/mL, P < .0001) and at steady state (3.03 +/- 1.0 microg/mL vs 0.94 +/- 0.7 microg/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose (17.8 +/- 3.6 h x microg/mL vs 7.71 +/- 2.5 h x microg/mL, P < .001) and at steady state (19.65 +/- 6.4 h x microg/mL versus 11.0 +/- 4.5 h x microg/mL, P = .009). There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no significant laboratory or clinical evidence of toxicity was detected. CONCLUSION: In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels, with significantly higher peak concentrations and daily area under the curve values, than did acyclovir therapy. Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy.

Bacterial vaginosis: association with adverse pregnancy outcome.

Bacterial vaginosis is the most common lower genital tract infection encountered among women of reproductive age. This condition can best be considered as a vaginal syndrome associated with an alteration of the normal vaginal flora rather than an infection specific to any one microorganism. Bacterial vaginosis is a clinical condition with a complex microbiology that is characterized by a reduced concentration of a normally abundant Lactobacillus species along with high concentrations of gram-negative and anaerobic bacteria, particularly, Gardnerella vaginalis and Mobiluncus, Bacteroides, Prevotella, and Mycoplasma species. The exact make up of the microorganisms and their relative concentration vary among women who have this condition. Although it was previously regarded as a harmless condition, recent work has linked bacterial vaginosis to numerous upper genital tract complications such as preterm labor and preterm delivery, preterm premature rupture of the membranes, chorioamnionitis, and postpartum endometritis. The findings from recent prospective randomized trials suggest that treatment of bacterial vaginosis in certain women who are at high risk for preterm delivery decreases the rate of preterm birth.

The effect of maternal magnesium sulfate treatment on neonatal morbidity in < or = 1000-gram infants.

We evaluated the effect of maternal magnesium sulfate treatment on selected neonatal outcomes in < or =1000-g infants. In a 1-year (1992-1993) observational study, the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units collected outcome data for 799 infants whose birth weights were < or =1000 g. Only singleton infants, with a gestational age >20 weeks who were not the product of an induced abortion were included. Our analysis was further limited to those infants without major congenital anomalies, who were deemed potentially viable by the obstetrician, whose mother would have undergone a cesarean delivery for fetal indications, and who survived greater than 2 days. Outcomes were compared in infants whose mothers did and did not receive magnesium sulfate for labor tocolysis. Among the 124 women who did and the 184 who did not receive magnesium sulfate tocolytic therapy, the frequencies of grade III or IV intraventricular hemorrhage (16 vs. 20%, p = 0.34), seizure activity (7 vs. 10%, p = 0.35), grade III or IV retinopathy of prematurity (21 vs. 18% p = 0.59), abnormal neurological exam (28 vs. 28%, p = 0.91), intact survival to 120 days or to discharge (48 vs. 44%, p = 0.54), and infant mortality (23 vs. 31%, p = 0.10) were similar. Multiple logistic regression analysis was used to control for the effect of potential confounders (specifically, gestational age) and confirmed the lack of a significant association between maternal magnesium sulfate treatment for tocolysis and selected neonatal outcomes in this population of < or =1000-gram infants.