Harley A. Rotbart

Human enterovirus infections.

Introduction Section I: Scientific Principles Epidemiology Enterovirus genetics Early events in infection Viral replication Transplantation and host cell shutoff Packaging and assembly Cell biology of enterovirus infections Host immune response to enterovirus infections Section II: Clinical Manifestations Poliomyelitis and vaccine strategies Perinatal enterovirus infections The febrile infant syndrome Respiratory infections Aseptic meningitis and encephalitis Myocarditis and dilated cardiomyopathy The possible role of enteroviruses in diabetes mellitus The possible role of enteroviruses in chronic neuromuscular diseases Section III: Diagnosis and Treatment Laboratory diagnosis Development of antiviral agents

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.

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.

Treatment of picornavirus infections.

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infections of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens-the enteroviruses (including polioviruses, coxsackieviruses, and echoviruses), the rhinoviruses, and the hepatoviruses (including hepatitis A). Recently, the parechoviruses (formerly, echoviruses 22 and 23) have been classified as a fourth genus of human picornaviruses. This article will focus on the enteroviruses and rhinoviruses agents, for which substantial effort has been expended and recent successes reported towards the development of safe and effective antiviral therapy.

Impact of rapid polymerase chain reaction results on management of pediatric patients with enteroviral meningitis

Background. Enterovirus (EV) infections can be rapidly detected by PCR. However, several studies suggest that results must be available early in the management of the patient to impact significantly on patient care. We evaluated this hypothesis directly during an outbreak of EV aseptic meningitis. Methods. From June through November, 1998, EV PCR was performed 5 days a week on cerebrospinal fluid specimens from pediatric patients evaluated for meningitis. We compared antibiotic use, length of stay and hospital charges in a group of patients with EV meningitis whose positive EV PCR results were available within 24 h of specimen collection, to a group of similar patients whose results were available >24 h after collection. Results. Cerebrospinal fluid specimens were submitted for EV PCR from 113 patients with suspected EV meningitis, and 50 of 113 (44%) were positive. Of these 50 EV-PCR-positive patients, 17 of 50 (34%) had EV PCR results available in ≤24 h and 33 of 50 (66%) had results available in >24 h. Patients with EV-positive results reported ≤24 h after specimen collection had 20 h less of antibiotic use (P = 0.006) and

Diagnosis of neonatal enterovirus infection by polymerase chain reaction

2798 less in hospital charges (P = 0.001) than patients with positive results available in >24 h. Hospitalized patients who received positive results rapidly did not have significantly less antibiotic therapy or shorter length of stay, but hospital charges were reduced by

Clinical significance of enteroviruses in serious summer febrile illnesses of children

2331 (P = 0.009). Conclusion. Rapid reporting of PCR results can have a significant impact on several outcome measures for patients with EV meningitis.

Neonatal rotavirus-associated necrotizing enterocolitis: Case control study and prospective surveillance during an outbreak

A 5-hour colorimetric polymerase chain reaction (PCR) assay was more sensitive than viral culture in identifying viral infection in initial serum (13/16 vs 5/16; p = 0.008) and urine (10/16 vs 5/16; p = 0.2) specimens from 16 enterovirus-infected newborn infants, and remained more sensitive throughout their illnesses. Combined sensitivity of serum and urine PCR was 14 of 16 (88%). Results of all acute-phase PCR assays of serum and urine from four neonates with cultures negative for enterovirus were also negative. PCR assay of serum and urine facilitates rapid, accurate diagnosis of neonatal enterovirus infections.

An outbreak of rotavirus-associated neonatal necrotizing enterocolitis*

BACKGROUND Enteroviruses are common causes of aseptic meningitis and nonspecific febrile illnesses in young children. During the summer-fall months, enterovirus-infected children are frequently evaluated in emergency room settings to rule out bacterial sepsis and/or meningitis. OBJECTIVES We sought to determine the clinical significance of enterovirus infections in children evaluated for serious febrile illnesses in pediatric emergency rooms during the summer-fall season. METHODS Children admitted to emergency rooms at four university teaching hospitals during a single summer-fall season who required blood culture and/or lumbar puncture to rule out bacterial sepsis/meningitis were prospectively studied. An extensive questionnaire was administered, and specimens of cerebrospinal fluid, serum, urine and throat were tested for enteroviruses by viral culture and PCR. Patients were followed to determine the duration, management and outcome of their illnesses. RESULTS Of 203 patients studied 173 had no apparent explanation for their illness (e.g. bacterial sepsis, bacterial urinary tract infection, etc.). Of those 173 patients 79 (46%) were infected with enteroviruses, including 33 of 47 (70%) patients with aseptic meningitis, 13 of 25 (52%) patients with nonspecific febrile episodes and 33 of 101 (33%) patients with fever and focal findings (P < 0.0001 for aseptic meningitis vs. fever and focal findings; P = 0.0001 for aseptic meningitis vs. combined nonspecific febrile episodes and fever/focal patients). Among 119 hospitalized patients 65 (55%) were enterovirus-infected. Children < or =90 days of age were more likely to be enterovirus-infected (66 of 122; 54%) than children older than 90 days (13 of 51; 25%) (P = 0.0001). Enterovirus-infected children were more likely to be hospitalized as a result of the current emergency room visit (65 of 79 vs. 54 of 94; P = 0.0005) and were more likely to have had an additional hospitalization for the same illness (10 of 79 vs. 1 of 94; P = 0.003). Enterovirus-infected patients also had a shorter period from illness onset to presentation. Enterovirus-infected children were indistinguishable from those without enterovirus infection in their symptoms at onset, signs at presentation and total duration of illness (>7 days in both groups). Enterovirus-infected children were almost all treated with antibiotics (78 of 79; 99%), with 74 of 79 (94%) receiving parenteral antibiotics for a mean of 3.6 days. CONCLUSIONS During the summer-fall months, 39% (79 of 203) of children for whom blood cultures and/or lumbar punctures were performed for suspected bacterial infection had enterovirus infection identified as the only explanation for their illness. Of those patients with no alternative diagnosis, enterovirus infection was confirmed in 46% (79 of 179). The majority of those patients requiring hospitalization were infected with enteroviruses. The use of PCR increases the number of children for whom a specific etiology of illness can be determined and may in the future reduce the hospitalization and use of unnecessary antibiotics in patients with enterovirus infections.

Antiviral therapy for enteroviruses and rhinoviruses.

After the death of a premature infant from rotavirus-associated necrotizing enterocolitis, we instituted prospective surveillance for this disease in our neonatal intensive care unit. During the 4-month study period an additional six cases of necrotizing enterocolitis and eight cases of hemorrhagic gastroenteritis occurred. Rotavirus infection was documented in 11 of these 15 symptomatic infants, in comparison with only eight rotavirus infections in 147 asymptomatic or minimally symptomatic bables (P<0.0001). Stools from 110 nursery personnel tested during the outbreak did not contain rotavirus. However, 12 of 59 staff members had serum IgM antibody against rotavirus, suggesting recent infection. In a case-control study we compared babies with severe gastrointestinal illness with a control group randomly selected from asymptomatic babies in the nursery during the time of the outbreak. Univariate analysis found six categorical variables and nine continuous variables that were significantly associated with disease. Multivariate logistic regression analysis, however, found only birth weight (P<0.0001), rotavirus infection (P<0.0001), and age at time of first nonwater feeding (P<0.02) to be associated with gastrointestinal illness. This study provides further evidence for the role of infection in some cases of neonatal necrotizing enterocolitis and hemorrhagic gastroenteritis.