Neonatal Herpes Simplex Virus Infection: Epidemiology and Outcomes in the Modern Era.

BACKGROUND: Over the past several decades, there have been advances in diagnosis and treatment of neonatal herpes simplex virus (HSV) disease. There has been no recent comprehensive evaluation of the impact of these advances on the management and outcomes for neonates with HSV. METHODS: Clinical data for initial presentation, treatment, and outcomes were abstracted from medical records of neonates with HSV treated at Seattle Children's Hospital between 1980 and 2016. RESULTS: One hundred thirty infants with a diagnosis of neonatal HSV were identified. Between 1980 and 2016, high-dose acyclovir treatment for neonatal HSV infection increased from 0% to close to 95%, with subsequent decrease in overall HSV-related mortality from 20.9% to 5.6%. However, even among infants treated with high-dose acyclovir, mortality was 40.9% for infants with disseminated (DIS) disease, and only 55% of infants with central nervous system (CNS) disease were without obvious neurologic abnormalities at 24 months. Over the study period, the time between initial symptoms and diagnosis decreased. Skin recurrences were more common with HSV-2 than HSV-1 (80% vs 55%; P = .02) and in infants with lesions at initial diagnosis (76% vs 47%; P = .02). CONCLUSION: Changes in the standard of care for management of neonatal HSV disease have led to improvements in timeliness of diagnosis and outcome but mortality in infants with DIS disease and neurologic morbidity in infants with CNS disease remain high. Future research should focus on prevention of perinatal infection and subsequent recurrences.

Interrater and Test-Retest Reliability of the Beery Visual-Motor Integration in Schoolchildren.

PURPOSE: To assess interrater and test-retest reliability of the 6th Edition Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) and test-retest reliability of the VMI Visual Perception Supplemental Test (VMIp) in school-age children. METHODS: Subjects were 163 Native American third- to eighth-grade students with no significant refractive error (astigmatism <1.00 D, myopia <0.75 D, hyperopia <2.50 D, anisometropia <1.50 D) or ocular abnormalities. The VMI and VMIp were administered twice, on separate days. All VMI tests were scored by two trained scorers, and a subset of 50 tests was also scored by an experienced scorer. Scorers strictly applied objective scoring criteria. Analyses included interrater and test-retest assessments of bias, 95% limits of agreement, and intraclass correlation analysis. RESULTS: Trained scorers had no significant scoring bias compared with the experienced scorer. One of the two trained scorers tended to provide higher scores than the other (mean difference in standardized scores = 1.54). Interrater correlations were strong (0.75 to 0.88). VMI and VMIp test-retest comparisons indicated no significant bias (subjects did not tend to score better on retest). Test-retest correlations were moderate (0.54 to 0.58). The 95% limits of agreement for the VMI were -24.14 to 24.67 (scorer 1) and -26.06 to 26.58 (scorer 2), and the 95% limits of agreement for the VMIp were -27.11 to 27.34. CONCLUSIONS: The 95% limit of agreement for test-retest differences will be useful for determining if the VMI and VMIp have sufficient sensitivity for detecting change with treatment in both clinical and research settings. Further research on test-retest reliability reporting 95% limits of agreement for children across different age ranges is recommended, particularly if the test is to be used to detect changes due to intervention or treatment.

Visual Motor and Perceptual Task Performance in Astigmatic Students.

Purpose. To determine if spectacle corrected and uncorrected astigmats show reduced performance on visual motor and perceptual tasks. Methods. Third through 8th grade students were assigned to the low refractive error control group (astigmatism < 1.00 D, myopia < 0.75 D, hyperopia < 2.50 D, and anisometropia < 1.50 D) or bilateral astigmatism group (right and left eye ≥ 1.00 D) based on cycloplegic refraction. Students completed the Beery-Buktenica Developmental Test of Visual Motor Integration (VMI) and Visual Perception (VMIp). Astigmats were randomly assigned to testing with/without correction and control group was tested uncorrected. Analyses compared VMI and VMIp scores for corrected and uncorrected astigmats to the control group. Results. The sample included 333 students (control group 170, astigmats tested with correction 75, and astigmats tested uncorrected 88). Mean VMI score in corrected astigmats did not differ from the control group (p = 0.829). Uncorrected astigmats had lower VMI scores than the control group (p = 0.038) and corrected astigmats (p = 0.007). Mean VMIp scores for uncorrected (p = 0.209) and corrected astigmats (p = 0.124) did not differ from the control group. Uncorrected astigmats had lower mean scores than the corrected astigmats (p = 0.003). Conclusions. Uncorrected astigmatism influences visual motor and perceptual task performance. Previously spectacle treated astigmats do not show developmental deficits on visual motor or perceptual tasks when tested with correction.

Assessment of Grating Acuity in Infants and Toddlers Using an Electronic Acuity Card: The Dobson Card.

PURPOSE: To determine if testing binocular visual acuity in infants and toddlers using the Acuity Card Procedure (ACP) with electronic grating stimuli yields clinically useful data. METHODS: Participants were infants and toddlers ages 5 to 36.7 months referred by pediatricians due to failed automated vision screening. The ACP was used to test binocular grating acuity. Stimuli were presented on the Dobson Card. The Dobson Card consists of a handheld matte-black plexiglass frame with two flush-mounted tablet computers and is similar in size and form to commercially available printed grating acuity testing stimuli (Teller Acuity Cards II [TACII]; Stereo Optical, Inc., Chicago, IL). On each trial, one tablet displayed a square-wave grating and the other displayed a luminance-matched uniform gray patch. Stimuli were roughly equivalent to the stimuli available in the printed TACII stimuli. After acuity testing, each child received a cycloplegic eye examination. Based on cycloplegic retinoscopy, patients were categorized as having high or low refractive error per American Association for Pediatric Ophthalmology and Strabismus vision screening referral criteria. Mean acuities for high and low refractive error groups were compared using analysis of covariance, controlling for age. RESULTS: Mean visual acuity was significantly poorer in children with high refractive error than in those with low refractive error (P = .015). CONCLUSIONS: Electronic stimuli presented using the ACP can yield clinically useful measurements of grating acuity in infants and toddlers. Further research is needed to determine the optimal conditions and procedures for obtaining accurate and clinically useful automated measurements of visual acuity in infants and toddlers.

Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection.

OBJECTIVE: To evaluate the utility of quantitative herpes simplex virus (HSV) polymerase chain reaction (PCR) levels for prognosis and management of neonatal HSV disease. STUDY DESIGN: Clinical and virologic data were abstracted by medical record review from neonatal HSV cases treated at Seattle Children's Hospital between 1993 and 2012. HSV PCR results from plasma (n = 47), cerebrospinal fluid (n = 56), or both (n = 40) at the time of diagnosis were available from 63 infants; 26 with skin-eye-mouth (SEM), 18 with central nervous system (CNS), and 19 with disseminated (DIS) disease. RESULTS: Plasma HSV PCR was positive in 78% of the infants with SEM, 64% with CNS and 100% with DIS disease. Mean plasma viral level was 2.8 log10 copies/mL in SEM, 2.2 log10 copies/mL in CNS, and 7.2 log10 copies/mL in DIS infants. The HSV levels were higher among infants who died compared with surviving infants, 8.1 log10 copies/mL (range 7.7-8.6) vs 3.8 log10 copies/mL (range 0.0-8.6), P = .001, however, level of HSV DNA in the cerebrospinal fluid or in plasma did not correlate with neurologic outcome. Dynamics of HSV clearance from plasma during high-dose acyclovir treatment showed single-phase exponential decay with a median viral half-life of 1.26 days (range: 0.8-1.51). CONCLUSIONS: Plasma HSV levels correlate with clinical presentation of neonatal HSV disease and mortality, but not neurologic outcome.

Primary Maternal Herpes Simplex Virus-1 Gingivostomatitis During Pregnancy and Neonatal Herpes: Case Series and Literature Review.

BACKGROUND: Neonatal herpes simplex virus (HSV) is a serious, life-threatening infection that is usually acquired during birth from contact with infected maternal genital secretions. Primary maternal HSV gingivostomatitis is a rare occurrence during pregnancy, and HSV type 1 (HSV-1) neonatal disease after primary maternal HSV gingivostomatitis during pregnancy has not been reported in detail. METHODS: We reviewed the medical records of neonates (≤28 days of age) with a confirmed diagnosis of neonatal HSV-1 at a single pediatric center from January 1981 to January 2010 to identify cases in which the mother had primary gingivostomatitis during pregnancy or at term. RESULTS: Seven neonates whose mothers had primary HSV-1 gingivostomatitis during pregnancy were identified from a review of 48 neonates with laboratory-proven HSV-1 neonatal disease. Of the 7 women, 2 presented with symptoms of primary HSV-1 gingivostomatitis during the first trimester and 5 in the third trimester. Three of the neonates developed skin, eye, and mucous membrane disease, 2 developed central nervous system disease, and 2 developed disseminated disease. One of the neonates with disseminated HSV-1 disease died. CONCLUSIONS: Primary maternal HSV gingivostomatitis during pregnancy may lead to HSV-1 transmission to the neonate. Physicians caring for pregnant women should communicate the diagnosis of HSV gingivostomatitis to the neonate's primary provider to ensure proper surveillance, early evaluation, and prompt treatment.

Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses.

OBJECTIVE: Low-level HIV-1 replication may occur during antiretroviral therapy (ART) that suppresses plasma HIV-1 RNA to less than 50 copies/ml (suppressive ART). Antiretroviral drugs appear less effective in macrophages and monocytes compared with lymphocytes, both in vitro and as implied in vivo by greater viral evolution observed during suppressive ART. Our objective was to examine sputum, which is rich in macrophages, for evidence of increased HIV-1 replication compared with that in the blood during suppressive ART. DESIGN: A cross-sectional study during suppressive ART was performed, and HIV-1 DNA sequences derived from induced sputa and peripheral blood mononuclear cells were compared. METHODS: Multiple sequences encoding HIV-1 reverse transcriptase, protease, and envelope were generated using single-genome sequencing. Reverse transcriptase and protease sequences were analyzed for genotypic drug resistance. The evolutionary distances of env sequences from the inferred most recent common ancestor of infection were calculated, and CXCR4 usage was predicted. RESULTS: Nine hundred seventy bidirectional sequences from 11 individuals were analyzed. HIV-1 env and pol derived from sputa had greater frequency of drug-resistance mutations (P = 0.05), evolutionary divergence (P = 0.004), and tendency for CXCR4 usage (P = 0.1) compared with viruses derived from peripheral blood mononuclear cells. CONCLUSION: The greater frequency of HIV-1 drug-resistance mutations and divergence of HIV-1 env in sputa-derived viruses compared with peripheral blood mononuclear cell-derived viruses suggests greater HIV-1 replication in the respiratory tract compared with the blood. Characterization of viral evolution over time and by cell-type could identify cells that provide a sanctuary for low-level viral replication in the respiratory tract during suppressive ART.

Measured visual field extent varies with peripheral stimulus flicker rate in very young children.

PURPOSE: The purpose of this article is to describe measured visual field extent in very young children in response to variation in peripheral stimulus flicker rate. METHODS: Binocular visual field extent was measured using a black, double-arc perimeter and an LED static perimetry procedure in 120 11-month-old, 120 17-month-old, and 120 30-month-old children and 40 adults. Each subject was tested with one of four flicker rates: 1 Hz, 10 Hz, 20 Hz, or 40 Hz. An interpolated estimate of the eccentricity at which 50% of subjects detected the peripheral stimulus and the mean of the farthest eccentricity at which subjects detected the peripheral stimulus were calculated for each flicker rate for each age group. RESULTS: In 11-, 17-, and 30-month-old children, but not in adults, measured visual field extent (eccentricity at which the stimulus was detected) varied significantly with rate of stimulus flicker. The largest measured visual field extent was produced by a 10-Hz stimulus and the smallest was produced by 1-Hz and 40-Hz stimuli. Measured visual field extent in children was similar to that of adults for 10-Hz flicker, but smaller than that of adults for 1-Hz, 20-Hz, and 40-Hz flicker. CONCLUSIONS: These results underscore the importance of standardizing stimulus parameters when developing tests for clinical assessment of visual fields in children. Furthermore, for longitudinal assessment of young patients, use of a 10-Hz flicker rate, in combination with the other parameters used in the present study, would help to avoid difficulties in interpretation that could arise from an interaction between age-related and disease-related changes that might occur if other stimulus flicker rates were used.

Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.

Episodes of low-level viremia (LLV), with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels ranging from 50 to 400 copies (c)/ml, occur commonly during highly active antiretroviral therapy (HAART). LLV has been associated with virologic failure of HAART in some studies, while in others LLV did not appear to affect the clinical outcome. To understand the processes leading to LLV, genetic analyses were used to determine whether plasma virions emanated from archived or from newly evolved viral genomes. Episodes of LLV (plasma HIV-1 RNA, 50 to 379 [median, 77] c/ml) were detected in 21/37 (57%) HIV-1-infected children with median plasma HIV-1 RNA levels of <50 c/ml during 79 patient years of HAART. Viral sequences were derived by direct sequencing of PCR products from 21 plasma specimens diluted to end point. In phylogenetic analysis, LLV viral sequences grouped with virus from early in the course of infection in 8/11 subjects. Six specimens had multiple identical viral sequences, suggesting origin from clonally expanded infected cells. LLV plasma virus evolved over time, indicating viral replication, in 3/11 subjects. Two of these had frequent LLV, including the selection of drug-resistant mutants. In summary, plasma virus from episodes of LLV during effective HAART appeared to originate from two distinct processes, (i) clonal outgrowth from long-lived HIV-1-infected cells, presumably following activation and proliferation of these cells, and (ii) ongoing viral replication that included the selection of new drug-resistant mutants. These observations provide a plausible explanation for the divergent clinical outcomes previously associated with LLV.

The effect of flicker rate on nasal and temporal measured visual field extent in infants.

PURPOSE: To explore the effect of peripheral stimulus flicker rate on measured visual field extent (MVFE) in young infants. METHODS: Three hundred sixty infants (180 each at 3.5 and 7 months of age) were tested monocularly with a light-emitting diode static perimetry procedure using a double-arc perimeter with arms at 45 degrees , 135 degrees , 225 degrees , and 315 degrees . Each subject was tested with one of six flicker conditions: no flicker, 1 Hz, 3 Hz, 10 Hz, 20 Hz, and 40 Hz. An interpolated estimate of the location at which 50% of subjects detected the peripheral stimulus (corrected for spontaneous eye movements) and the mean location of the farthest spot seen were calculated across subjects for each perimeter arm for each flicker condition for each age group. RESULTS: Nasally, MVFE was larger for 7-month-old than for 3.5-month-old infants. Across both ages, infants showed larger MVFE for 10-Hz stimuli than for nonflickering stimuli, but MVFE did not differ between any other flicker conditions. Temporally, response to flicker varied with age. For 3.5-month-old infants, MVFE was smaller for the no flicker condition than for the 3-Hz, 10-Hz, and 20-Hz conditions, but there were no other differences across flicker conditions. For 7-month-old infants, MVFE was larger for 3-Hz stimuli than for the no flicker, 1-Hz, 20-Hz, and 40-Hz conditions, but there were no other differences across flicker conditions. Additional analyses showed that the effect of flicker rate on the percentage of subjects looking at a peripheral stimulus at a single eccentricity (29 degrees ) was similar to the effect of stimulus flicker across eccentricities, as reflected in MVFE. CONCLUSIONS: Peripheral stimulus flicker can enhance the MVFE in 3.5- and 7-month-old infants. However, the effect depends on flicker rate and is consistent with previous data indicating that 10 Hz and perhaps 3 Hz are especially effective in enhancing MVFE in older infants and young children.

The influence of stimulus size on measured visual field extent in infants.

PURPOSE: To compare measured visual field extent for a 6 degrees stimulus (typical size used in studies of infants) with a 1.5 degrees stimulus (similar to the largest size used in Goldmann perimetry) in young infants. METHODS: A total of 120 infants (60 each at 3.5 months and 7 months of age) and 24 adults were tested monocularly with a kinetic perimetry procedure using a black double-arc perimeter. Each subject was tested with either a 6 degrees or 1.5 degrees white sphere, which was mounted on a black wand and moved smoothly toward the intersection of the perimeter arms at 3.4 degrees /s. Visual field extent along each perimeter arm was defined as the median of 2 to 3 measurements of the position of the leading edge of the stimulus when the subject made an eye movement toward the stimulus. RESULTS: The 6 degrees stimulus produced larger measured visual field extent than the 1.5 degrees stimulus in 3.5-month olds (temporal field only) and in 7-month olds (nasal and temporal field), but not in adults. CONCLUSIONS: Using the testing conditions of the present study, increasing stimulus size beyond the largest used in a Goldmann perimeter (approximately 2 degrees) increases measured visual field extent in young infants, but not in adults. This may relate to differences in peripheral summation areas or to differences in attentional factors between infants and adults.

Response to immunization with measles, tetanus, and Haemophilus influenzae type b vaccines in children who have human immunodeficiency virus type 1 infection and are treated with highly active antiretroviral therapy.

OBJECTIVE: To assess the level of immunity to measles, tetanus, and Haemophilus influenzae type b (Hib) in previously immunized children who have human immunodeficiency virus (HIV) infection and were treated with highly active antiretroviral therapy (HAART) and to determine the response to reimmunization. METHODS: Retrospective review of clinical data from children who have HIV-1 infection and were treated with HAART. Children were included in the analysis when they had a history of immunizations before treatment with HAART; had specific immunoglobulin G levels to tetanus, measles, or Hib measured after starting HAART but before the receipt of additional immunizations; were reimmunized while on HAART; and had postimmunization immunoglobulin G levels available. RESULTS: Nineteen children (median age: 7 years; range: 3-14 years) who were treated with 3 to 5 drug HAART regimens for a median of 20 months (range: 8-37) met the criteria for at least 1 antigen and were included in this review. Fifteen (79%) of the 19 had plasma RNA levels <50 copies/mL. The median CD4% before HAART was 26% (range: 1-41) and at the time of immunization, 35% (range: 20-54). Before reimmunization, 1 (5%) of 18 children had detectable antibody levels to measles, 6 (35%) of 17 had detectable antibody levels to tetanus, and 14 (78%) of 18 had detectable antibody levels to Hib. After immunization, 15 (83%) of 18, 10 (90%) of 11, and 3 (75%) of 4 seroconverted to measles, tetanus, and Hib, respectively. Antibody levels remained detectable after 1 year in the majority of children tested. CONCLUSIONS: Consideration should be given to readministering childhood immunizations to children who have HIV infection and are treated successfully with combination antiretroviral therapy.

Amblyopia in astigmatic preschool children.

Best-corrected acuity was measured for vertical and horizontal gratings and for recognition acuity optotypes (Lea Symbols) in a group of three- to five-year-old children with a high prevalence of astigmatism. Results showed meridional amblyopia (MA) among children with simple/compound myopic or mixed astigmatism, due to reduced acuity for horizontal gratings. Children with simple/compound hyperopic astigmatism showed no MA, but did show reduced acuity for both grating orientations. Reduced best-corrected recognition acuity was shown by both myopic/mixed and hyperopic astigmats. These results suggest that optical correction of astigmatism should be provided prior to age three to five years, to prevent development of amblyopia.

Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy.

To evaluate human immunodeficiency virus type 1 (HIV-1) replication and selection of drug-resistant viruses during seemingly effective highly active antiretroviral therapy (HAART), multiple HIV-1 env and pol sequences were analyzed and viral DNA levels were quantified from nucleoside analog-experienced children prior to and during a median of 5.1 (range, 1.8 to 6.4) years of HAART. Viral replication was detected at different rates, with apparently increasing sensitivity: 1 of 10 by phylogenetic analysis; 2 of 10 by viral evolution with increasing genetic distances from the most recent common ancestor (MRCA) of infection; 3 of 10 by selection of drug-resistant mutants; and 6 of 10 by maintenance of genetic distances from the MRCA. When four- or five-drug antiretroviral regimens were given to these children, persistent plasma viral rebound did not occur despite the accumulation of highly drug-resistant genotypes. Among the four children without genetic evidence of viral replication, a statistically significant decrease in the genetic distance to the MRCA was detected in three, indicating the persistence of a greater number of early compared to recent viruses, and their HIV-1 DNA decreased by > or =0.9 log(10), resulting in lower absolute DNA levels (P = 0.007). This study demonstrates the variable rates of viral replication when HAART has suppressed plasma HIV-1 RNA for years to a median of <50 copies/ml and that combinations of four or five antiretroviral drugs suppress viral replication even after short-term virologic failure of three-drug HAART and despite ongoing accumulation of drug-resistant mutants. Furthermore, the decrease of cellular HIV-1 DNA to low absolute levels in those without genetic evidence of viral replication suggests that monitoring viral DNA during HAART may gauge low-level replication.

Efficacy and toxicity of antiretroviral therapy using 4 or more agents: application of a strategy for antiretroviral management in human immunodeficiency virus-infected children.

OBJECTIVE: To characterize the long-term tolerance and virologic efficacy of combination antiretroviral therapy consisting of 4 or more agents in a clinical setting. METHODS: An observational review of 36 children infected with human immunodeficiency virus 1 (HIV-1) treated with 4 or 5 antiretroviral agents in 2 university hospital clinics between April 1, 1996, and October 31, 2000. Highly active antiretroviral therapy regimens were chosen with regard to the child's past antiretroviral exposure or results of genotypic resistance data. Plasma HIV-1 RNA levels were monitored weekly to monthly after initiation of highly active antiretroviral therapy, and adherence efforts were actively supported and monitored. MAIN OUTCOME MEASURE: Number of children with undetectable plasma HIV-1 RNA levels at longest follow-up. RESULTS: Four- or 5-drug highly active antiretroviral therapy reduced plasma HIV-1 RNA levels to less than 50 copies/mL in 32 (89%) of 36 children. After a median of 28.7 months of observation, 28 children (78%) remained at this level of suppression. Adverse reactions were limited to mild neutropenia and mild transient or persistent elevations in alanine aminotransferase levels in 11% of children. CONCLUSIONS: Treatment with 4 or 5 antiretroviral agents was well tolerated in HIV-1-infected children and resulted in a high degree of viral suppression, even in children with previous antiretroviral drug experience.