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Biomedical subjects

H A Rotbart

Publications and source records attributed to H A Rotbart.

At least 37 records · Page 2Linked to original sources

Enteroviral infections of the central nervous system.

Infections of the CNS with the nonpolio enteroviruses are common and important causes of morbidity in both children and adults. Studies have recently defined the short-term and long-term outcomes of aseptic meningitis due to the enteroviruses. Focal encephalitis is increasingly recognized as a complication of enterovirus infection. Patients at greatest risk for sequelae of CNS enteroviral disease include neonates and those who are immunocompromised. The clinical presentation may mimic that of bacterial or other viral CNS infections, a circumstance making laboratory diagnosis of paramount importance for reducing unnecessary hospitalization and therapy. Recent advances in PCR technology, including its adaptation to a colorimetric microwell plate format, promise to greatly facilitate diagnosis of enteroviral infections. Promising antiviral drugs for CNS disease and other serious manifestations of enteroviral infections are under development.

Adult↗

Neonatal enterovirus infection: virology, serology, and effects of intravenous immune globulin.

A prospective study of the virology of and serological responses to enterovirus infection in 16 neonates (< or = 2 weeks of life) and their mothers was performed. At study entry, 11 neonates did not have detectable serum neutralizing antibody to their own viral isolates, despite the presence of neutralizing antibody in 9 of 11 mothers of these infants. Viremia and viruria were demonstrated in 8 and 7 neonates, respectively, with maximal detected titers of 6.3 x 10(3) 50% tissue culture infective dose per mL (TCID50) and 6.8 x 10(1) TCID50/mL, respectively. Viremia was associated with onset of illness in the first 5 days of life, low initial serum neutralization titer, and the presence of echovirus serotypes. Randomized administration of intravenous immune globulin (IVIG; 750 mg/kg) to nine neonates overall modestly increased serum neutralization titers but did not reduce the daily incidence of viremia and viruria compared with that of controls. However, receipt of IVIG containing a neutralization titer of > or = 1:800 to the patients' own viral isolates was associated with significantly higher serum neutralization titers and more rapid cessation of viremia and viruria. Future trials of IVIG for neonatal enterovirus disease should assess the efficacy and safety of higher or repeated doses of this agent and/or of IVIG selected for their high titers to frequently circulating and/or particularly virulent enterovirus serotypes.

Antibodies, Viral↗

Sequence analysis of the downstream 5' nontranslated region of seven echoviruses with different neurovirulence phenotypes.

The downstream 5' nontranslated regions of seven echoviruses with different neurovirulent phenotypes were amplified and sequenced. Neurovirulent echovirus serotypes 4, 6, 9, 11, and 30 were identical to the putative poliovirus in 18S rRNA binding sequence and the flanking conserved sequences. Less neurovirulent echoviruses, serotypes 2 and 12, exhibited variations within these regions.

Base Sequence↗

Diagnosis of enteroviral meningitis by using PCR with a colorimetric microwell detection assay.

A 5-h, user-friendly PCR assay for the diagnosis of enteroviral meningitis was developed. Reverse transcription and amplification were performed in a one-step reaction using rTth polymerase. Carryover contamination was prevented with dUTP and uracil N-glycosylate. Detection was performed colorimetrically on a microwell titer plate. Sensitivity, specificity, positive predictive value, and negative predictive value were 94.7, 97.4, 94.7, and 97.4%, respectively.

Base Sequence↗

Diagnosis of enterovirus brain disease in hypogammaglobulinemic patients by polymerase chain reaction.

CSF samples taken from three patients with primary hypogammaglobulinemia and chronic brain disease were positive for enterovirus RNA by use of a technique based on the polymerase chain reaction (PCR) to amplify viral genomic sequences. Repeated attempts to culture viruses from the CSF from these patients were unsuccessful, possibly because the patients were treated regularly with intravenous immunoglobulin, which may have contained enough specific antibody to partially neutralize the viruses. Our data suggest that enteroviruses are responsible for diverse CNS features in patients with primary hypogammaglobulinemia and that for these patients the diagnosis should be pursued using PCR technology.

Adult↗

Immune responses to varicella zoster virus infections in healthy children.

The immune responses to varicella zoster virus were studied in 67 otherwise normal children participating in a placebo-controlled trial of acyclovir for the treatment of chickenpox. No differences were observed between acyclovir and placebo groups. Children were studied longitudinally, at onset of chickenpox, and at 1 month, 3 months, 1 year, and 3 years after infection. These data help define the natural history of the immune response to chickenpox in children.

Acyclovir↗

Profile of enterovirus disease in the first two weeks of life.

We studied 57 infants < or = 14 days of age referred for possible enterovirus (EV) infection to assess the accuracy of that clinical diagnosis and describe the natural history of neonatal EV infection. Twenty-nine neonates proved to have EV infection, 23 had illnesses compatible with (but not proven to be) EV infection, and 5 had alternative diagnoses: bacterial infections (2); herpes simplex virus infection (1); and metabolic disorders (2). Neonates with proved EV infection were generally full term and had uncomplicated immediate postnatal periods but high percentages of ill contacts. Neonatal symptoms and signs included fever, irritability, anorexia, lethargy, hypoperfusion, rash, jaundice and respiratory findings. Laboratory abnormalities included cerebrospinal fluid (CSF) pleocytosis, chest radiograph infiltrates, abnormal urinalyses and elevated transaminases. EVs were most commonly isolated from CSF and rectum/stool but also frequently from serum and urine. Five EV-infected patients had severe multisystem disease (pneumonitis, hepatitis, thrombocytopenia, bleeding and meningitis), requiring supportive care and lengthy hospitalizations. All survived, 2 with residual hepatic dysfunction. Markers of severe disease included: early age of illness onset (especially Day 1 of life); maternal viral symptoms at delivery; absence of fever and irritability; tachypnea; lethargy; abdominal distension; hepatomegaly; and positive serum viral culture. These data support conservative management of ill infants < or = 2 weeks of age and suggest that antiviral therapy for neonatal EV infection would be optimally targeted at infants with early onset illness, multisystem disease and/or viremia.

Cerebrospinal Fluid↗

Acyclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Acyclovir Varicella Study Group.

STUDY OBJECTIVE: To determine whether orally administered acyclovir is of therapeutic benefit for varicella in otherwise healthy adolescents, and to compare the severity of the disease in adolescents with that in younger children. DESIGN: Multicenter, randomized, placebo-controlled, double-blind trial. SETTING: Patients' homes and university hospital clinics. PATIENTS: Sixty-eight adolescents between 13 and 18 years of age with varicella entered the study. Of the 62 adolescents with laboratory-confirmed varicella who were included in the final analysis, 31 received acyclovir and 31 received placebo. INTERVENTIONS: Placebo or an 800 mg acyclovir tablet was given orally four times daily for 5 days, beginning within 24 hours of onset of rash. MEASUREMENTS AND MAIN RESULTS: Acyclovir recipients had significant reductions in times to cessation of new lesion formation (p less than 0.001), maximum number of lesions (p = 0.019), and defervescence (p = 0.045). Mean constitutional illness score was significantly reduced on day 4 (0.5 vs 1.5, p = 0.05), as was the mean number of residual hypopigmented lesions present on 28-day follow-up examination (22.7 vs 92.7, p = 0.018). Two complications, both bacterial superinfections, occurred in placebo recipients. Adverse experiences and varicella-zoster virus antibody titers measured 28 days after enrollment were similar in both treatment groups. Comparison of placebo recipients with children 2 to 12 years of age participating in a companion study indicated that varicella is more severe in adolescents: mean maximum total lesions (421 vs 347, p = 0.003), mean maximum constitutional illness score (3.1 vs 2.2, p = 0.032), and mean number of residual lesions (92.7 vs 33.2, p = 0.01) were all greater in the adolescent population. CONCLUSIONS: Oral acyclovir therapy is safe and effective for treatment of varicella in otherwise healthy adolescents; this may be an appropriate subgroup for treatment with antiviral drugs because the disease is more severe in them than in younger children.

Acyclovir↗

Immune response of elderly individuals to a live attenuated varicella vaccine.

The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu. One cohort received 3000 pfu with a 3000 pfu booster 3 months later. The vaccine was well tolerated. VZV-specific immunologic responses were evaluated over a 24-month period. The mean anti-VZV antibody level was significantly increased for 12 months after vaccination. Interferon-gamma production in vitro by peripheral blood mononuclear cells (PBMC) of vaccinees was also increased for 6 months after vaccination. Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000. This vaccine-enhanced frequency of VZV-responding T cells is similar to the frequency observed in 35- to 40-year-old adults. Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response. The data indicate that VZV immunity in the elderly can be boosted by active immunization. If the increased incidence of herpes zoster that accompanies aging results from the natural waning of immunity, active immunization may prevent or attenuate zoster in the elderly.

Aged↗

A controlled trial of acyclovir for chickenpox in normal children.

BACKGROUND: Chickenpox, the primary infection caused by the varicella-zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications. METHODS: To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multicenter, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered by the oral route in a dose of 20 mg per kilogram of body weight four times daily for five days. RESULTS: The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs 347; P less than 0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P less than 0.001). In over 95 percent of the recipients of acyclovir no new lesions formed after day 3, whereas new lesions were forming in 20 percent of the placebo recipients on day 6 or later. The recipients of acyclovir also had accelerated progression to the crusted and healed stages, less itching, and fewer residual lesions after 28 days. In the children treated with acyclovir the duration of fever and constitutional symptoms was limited to three to four days, whereas in 20 percent of the children given placebo illness lasted more than four days. There was no significant difference between groups in the distribution of 11 disease complications (10 bacterial skin infections and 1 case of transient cerebellar ataxia). Acyclovir was well tolerated, and there was no significant difference between groups in the titers of antibodies against varicella-zoster virus. CONCLUSIONS: Acyclovir is a safe treatment that reduces the duration and severity of chickenpox in normal children when therapy is initiated during the first 24 hours of rash. Whether treatment with acyclovir can reduce the rare, serious complications of chickenpox remains uncertain.

Acyclovir↗

Evolution of the placental barrier to fetal infection by murine enteroviruses.

A murine model that demonstrated a placental barrier to fetal enterovirus infection in late pregnancy was extended to middle and early gestation. Inoculation with Theiler's murine encephalomyelitis virus (TMEV) in middle and early gestation infected 73% and 90% of placentas and 7% and 78% of fetuses, respectively. In situ hybridization (ISH) of tissues obtained after middle-gestation inoculation revealed TMEV in the placental decidua and spongiotrophoblast layers but generally not in the labyrinth (the layer adjacent to the fetus) or fetus (similar to late gestation). In contrast, ISH of placentas harvested after early-gestation inoculation identified TMEV predominantly in the labyrinth, in which vasculature was often replaced by hyalinized hemorrhagic tissue and small cell infiltrates; fetuses contained virus in heart, pericardium, great vessels, lung, pleura, brain, and liver. The placental barrier to enterovirus transmission appears to develop between early and middle gestation. Enterovirus infection before this time may induce placental damage, fetal infection, or both.

Animals↗

Nucleic acid detection systems for enteroviruses.

The enteroviruses comprise nearly 70 human pathogens responsible for a wide array of diseases including poliomyelitis, meningitis, myocarditis, and neonatal sepsis. Current diagnostic tests for the enteroviruses are limited in their use by the slow growth, or failure to grow, of certain serotypes in culture, the antigenic diversity among the serotypes, and the low titer of virus in certain clinical specimens. Within the past 6 years, applications of molecular cloning techniques, in vitro transcription vectors, automated nucleic acid synthesis, and the polymerase chain reaction have resulted in significant progress toward nucleic acid-based detection systems for the enteroviruses that take advantage of conserved genomic sequences across many, if not all, serotypes. Similar approaches to the study of enteroviral pathogenesis have already produced dramatic advances in our understanding of how these important viruses cause their diverse clinical spectra.

Animals↗

Incidence of nonbacterial intraamniotic infections in abnormal pregnancies.

Amniotic fluids from 41 abnormal and 47 control pregnancies were examined for viruses, Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma hominis. Abnormal pregnancies included those with fetal abnormalities, maternal complications, suspected chorioamnionitis and premature labor. Two percent of cultures were positive, including cytomegalovirus from one case of fetal growth retardation and U urealyticum from two patients with chorioamnionitis and from two controls. The abnormal pregnancies studied generally were not associated with nonbacterial intraamniotic infections.

Amniocentesis↗