Christine E. Long

Human Herpesvirus-6 Infection in Children -- A Prospective Study of Complications and Reactivation

BACKGROUND Infection with human herpesvirus-6 (HHV-6) is nearly universal in infancy or early childhood. However, the course of this infection, its complications, and its potential for persistence or reactivation remain unclear. METHODS We studied infants and children under the age of three years who presented to our emergency department with acute illnesses. Infants and young children without acute illness were studied as controls. HHV-6 infection was identified by blood-mononuclear-cell culture, serologic testing, and the polymerase chain reaction (PCR). RESULTS No primary HHV-6 infection was found among 582 infants and young children with acute nonfebrile illnesses or among 352 controls without acute illness. Of 1653 infants and young children with acute febrile illnesses, 160 (9.7 percent) had primary HHV-6 infection, as documented by viremia and seroconversion. They ranged in age from 2 weeks to 25 months; 23 percent were under the age of 6 months. HHV-6 infections accounted for 20 percent of 365 visits to the emergency department for febrile illnesses among children 6 to 12 months old. Of the 160 infants and young children with acute HHV-6 infections, 21 (13 percent) were hospitalized, and 21 had seizures. Often the seizures appeared late and were prolonged or recurrent. HHV-6 infections accounted for one third of all febrile seizures in children up to the age of two years. In follow-up studies over a period of one to two years, the HHV-6 genome persisted in blood mononuclear cells after primary infection in 37 of 56 children (66 percent). Reactivation, sometimes with febrile illnesses, was suggested by subsequent increases in antibody titers in 16 percent (30 of 187) and by PCR in 6 percent (17 of 278). No recurrent viremia was detected. Of 41 healthy newborns studied, 12 (29 percent) had the HHV-6 genome in their blood mononuclear cells; nevertheless, 6 of these newborns subsequently had primary HHV-6 infections. CONCLUSIONS In infants and young children HHV-6 infection is a major cause of visits to the emergency department, febrile seizures, and hospitalizations. Perinatal transmission may occur, with possible asymptomatic, transient, or persistent neonatal infection.

Primary human herpesvirus 6 infection in young children.

BACKGROUND Human herpesvirus 6 (HHV-6) is a recently discovered virus that, on the basis of serologic evidence, appears to infect most children by the age of three years. However, the clinical manifestations of primary HHV-6 infection have not been well defined. METHODS We studied consecutive children two years old or younger who presented to an emergency ward with febrile illnesses. Our evaluation included the isolation of HHV-6 from peripheral-blood mononuclear cells, an immunofluorescent-antibody assay, the detection of HHV-6 by the polymerase chain reaction (PCR), and restriction-endonuclease-fragment profiles of HHV-6 isolates. RESULTS HHV-6 was isolated from 34 of 243 acutely ill children (14 percent). The children with viremia had irritability, high temperatures (mean, 39.7 degrees C), and inflammation of tympanic membranes (in 21), but few other localizing signs. Two children were hospitalized, but all 34 recovered after an average of four days of fever. The rash characteristic of roseola, which has been associated with HHV-6 infection, was noted in only three children. In 29 children (85 percent), serum samples obtained during convalescence had at least a fourfold increase in IgG antibody titers; 4 infants less than three months old who presumably had maternal antibody did not have this increase. HHV-6 was isolated from blood obtained during convalescence in only one child, but in two thirds of the children the virus could be detected by PCR. The isolates had genomic heterogeneity, indicating the presence of multiple strains. CONCLUSIONS Primary infection with HHV-6 is a major cause of acute febrile illness in young children. Such infection is associated with varied clinical manifestations, viremia, and the frequent persistence of the viral genome in mononuclear cells.

Persistence of Human Herpesvirus 6 According to Site and Variant: Possible Greater Neurotropism of Variant A

Little is known of the persistence and pathogenicity of human herpesvirus 6 (HHV-6) after primary infection, including the role of strain variant. Over 2 to 5 years, 2,716 children and 149 families were studied. Peripheral blood mononuclear cell (PBMC), saliva, and cerebrospinal fluid (CSF) specimens were examined for HHV-6 DNA and variant. Ninety-nine percent of isolates causing primary infection were HHV-6 variant B (HHV-6B), which predominated in 95%-98% of the variants persisting in PBMC and saliva specimens from children and adults. Of 668 CSF samples, 13% contained HHV-6 DNA; of 77 children examined after primary infection, 61% had HHV-6 DNA detected only in their CSF and 39% had HHV-6 DNA in both CSF and PBMCs. HHV-6 variant A (HHV-6A) was detected significantly (P = .0001) more frequently in CSF than in PBMCs or saliva. In children for whom HHV-6 was identified in both CSF and PBMCs, PBMCs contained only HHV-6B, while CSF contained HHV-6A or HHV-6B, not both. Thus, in patients with dual infection, only HHV-6A persisted in CSF, which suggests that HHV-6A has greater neurotropism. Findings for adults indicate that dual infection occurs; variant persistence is similar to that for children. The frequency of HHV-6A infection increased little with age, thereby indicating that HHV-6A infection remains uncommon into adulthood. This study suggests that HHV-6 variants have different immunobiologic courses and neurotropism.

Severity of Respiratory Syncytial Virus Infection Is Related to Virus Strain

The relationship between respiratory syncytial virus (RSV) strain and disease severity was assessed in 265 hospitalized infants over a 3-year period (1988-1991). A severity index of clinical and physiologic parameters was used to grade illness severity. Multivariate analysis of 134 infants infected with group A RSV strains and 131 infants infected with group B strains indicated that prematurity, underlying medical conditions, group A RSV infection, and age < or =3 months were independently associated with severe disease. Odds ratios for severe disease for these risk factors were 1.83, 2.84, 3.26, and 4.39, respectively. Among infants without underlying medical conditions, group B RSV infection rarely required ventilatory support, in contrast to group A infections (1/90 vs. 13/107; P < .006), and had significantly lower severity indices (mean +/- SD, 0.6 +/- 9 vs. 1.3 +/- 1.9; P = .05). Results confirm earlier findings that group A RSV infection results in greater disease severity than group B infection among hospitalized infants.

Primary human herpesvirus 7 infection : a comparison of human herpesvirus 7 and human herpesvirus 6 infections in children

OBJECTIVE To define the clinical and virologic characteristics of primary human herpesvirus 7 (HHV-7) infection and to compare these characteristics with those of primary human herpesvirus 6 (HHV-6) infection. STUDY DESIGN A prospective convenience sample study of 496 children < or =3 years old. HHV-7 and HHV-6 infections were identified by viral isolation. Polymerase chain reaction and serology for HHV-7 and HHV-6 were performed. Clinical and laboratory characteristics of patients were obtained from medical records and follow-up interviews. RESULTS Children with primary HHV-7 infection (n = 8) were identified and compared with children with primary HHV-6 infection (n = 29) detected during the same time period. All children were febrile (mean temperature 39.8 degrees C) with no difference in the degree of fever, frequency of rash, or gastrointestinal complications between the groups. The median age of children with primary HHV-7 infection was 26 months, significantly older than that of children with primary HHV-6 infection (median, 9 months). Children with primary HHV-7 infection were also more likely than those with primary HHV-6 infection to have seizures associated with the illness (P = .004). CONCLUSION Primary infection with HHV-7 can cause a highly febrile illness in childhood, complicated by seizures. The serologic diagnosis of primary HHV-6 and HHV-7 infections may be confounded by cross-reacting antibodies.

Parainfluenza viral infections in pediatric outpatients: seasonal patterns and clinical characteristics.

Parainfluenza types 1, 2 and 3 were studied in a pediatric outpatient population from 1976 to 1992 to compare seasonal patterns over time and to define better the spectrum of illness in all ages of children caused by these viruses. Parainfluenza type 1 occurred in the fall of odd numbered years; parainfluenza type 2 was less predictable; and parainfluenza type 3 appeared yearly with peak activity in spring or summer. The parainfluenza viruses were the major cause of croup and also accounted for one-half of the cases of laryngitis and over one-third of all lower respiratory tract illness in children from whom a virus was isolated. The major clinical manifestations of infection with parainfluenza types 1 and 2 were croup, upper respiratory infections and pharyngitis; for parainfluenza type 3 upper respiratory tract infection was predominant in all age groups. The parainfluenza viruses cause appreciable respiratory morbidity each year among infants and young children. They are the major cause of croup but also produce a spectrum of diseases ranging from mild upper respiratory tract infection to bronchiolitis and pneumonia. Most studies have focused on the morbidity of parainfluenza viruses in infants and young children who are hospitalized. Less appreciated is the impact of parainfluenza viral infections in outpatients and in older children. The parainfluenza viruses have a striking epidemiologic pattern which has evolved over the past 30 years. In the early 1960s parainfluenza types 1, 2 and 3 were all reported to be endemic.(ABSTRACT TRUNCATED AT 250 WORDS)

Predicting deterioration in previously healthy infants hospitalized with respiratory syncytial virus infection

Objective. To estimate the incidence of clinical deterioration leading to intensive care unit transfer in previously healthy infants with respiratory syncytial virus (RSV) infection hospitalized on a general pediatric unit and, to assess the hypothesis that history, physical examination, oximetry, and chest radiographic findings at time of presentation can accurately identify these infants. Study Design. A virology database was used to identify and determine the disposition of all children ≤1 year of age admitted to the Childrens Hospital at Strong (CHaS) with RSV infection during the 1985 to 1994 respiratory seasons. Index patients were all previously healthy, full-term infants admitted initially to the general inpatient services at CHaS or Rochester General Hospital, a second University of Rochester teaching hospital, whose clinical deterioration led to transfer to the pediatric intensive care unit (PICU). These infants were matched retrospectively (for year and date of infection, sex, chronologic age, and race) with two hospitalized controls who did not require PICU transfer. Chest radiographic findings, respiratory rate (RR), O2 saturation, and presence of wheezing at time of presentation to the emergency department (ED) were compared. Results. During the study years, 542 previously healthy, full-term infants were admitted to the general pediatric unit at CHaS with proven RSV infection. Ten (1.8%; 95% confidence interval, 0.9%, 3.4%) were transferred subsequently to the PICU, primarily for close monitoring of progressive respiratory distress. Data for these patients and 7 patients transferred from Rochester General Hospital to the PICU at the CHaS were compared with those for control patients. The mean RR in the ED (63 vs 50), and O2 saturation in the ED (88% vs 93%) were modestly abnormal in cases compared with controls. Wheezing on examination at time of presentation and chest radiographic findings did not differ between the two groups. A RR >80 and an O2saturation <85% at time of presentation each had a specificity >97% for predicting subsequent deterioration. Each parameter, however, had a sensitivity ≤30%. Conclusion. Clinical deterioration requiring PICU admission is an uncommon occurrence in previously healthy infants admitted to a general pediatric inpatient unit with RSV infection. Extreme tachypnea and hypoxemia were both associated with subsequent deterioration; however, only a small proportion of patients who clinically deteriorated presented in this way. The clinical usefulness of these parameters, therefore, is limited. respiratory syncytial virus, deterioration, healthy infants, prediction.

Sequelae of respiratory syncytial virus infections. A role for intervention studies.

The association between respiratory syncytial virus (RSV) infections in infancy and respiratory abnormalities later in life has been attributed both to a direct effect of the infection itself and to an inherent susceptibility. Observational studies do not allow a rigorous test of these hypotheses. Respiratory syncytial virus infection is universal in the first years of life and no uninfected control group exists. Randomized, controlled trials using new prophylactic agents such as vaccines or specific therapeutic agents will provide a powerful test of the relationship between RSV infection and long-term respiratory sequelae.

Preventability of Invasive Pneumococcal Disease and Assessment of Current Polysaccharide Vaccine Recommendations for Adults: United States, 2001–2003

UNLABELLED BACKGROUND. To prevent Streptococcus pneumoniae infection among persons at highest risk for invasive pneumococcal disease (IPD), the pneumococcal polysaccharide vaccine (PPV) is currently recommended for persons >or=65 years old and persons 2-64 years old with certain underlying conditions. Policymakers have considered expanding recommendations for PPV to include persons who are 50-64 years old and additional populations at risk for IPD. Our objectives were to determine the proportion of IPD cases that might have been prevented if all persons with vaccine indications had been vaccinated and to evaluate new indications. METHODS From 2001 to 2003, we performed a case series study of IPD in adults at 6 sites of the Active Bacterial Core surveillance-Emerging Infections Program Network. A case of IPD was defined as isolation of pneumococcus from a normally sterile site from a resident of 1 of the surveillance areas. RESULTS Among 1878 case patients, 1558 (83%) had at least 1 current vaccine indication; of these, 968 case patients (62%) were unvaccinated. Adherence to existing vaccine recommendations would have prevented 21% of all cases. The proportions of all cases potentially prevented by each new indication were as follows: lowering the universal age of recommended vaccination to 50 years, 5.0%-7.0%; adding new risk-based indications to include current smoking, 1.5%-2.5%; former smoking, 0.4%-0.7%; black race, 1.0%-1.4%; and asthma, 0.3%-0.4%. CONCLUSIONS Increasing vaccine coverage rates among persons with a current indication may prevent more cases than expanding existing indications. Of the potential new indications studied, the strategy that may prevent most cases is lowering the recommended age for universal vaccination to 50 years.

Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo.

PURPOSE To determine the long term effects of ribavirin therapy in children hospitalized for respiratory syncytial virus (RSV) lower respiratory tract infection. METHODS Fifty-four of 60 children in randomized trials of ribavirin therapy were enrolled in a prospective follow-up study. Subjects were examined annually and had age-appropriate pulmonary function tests; interim histories were obtained from families and personal physicians. RESULTS Recurrent lower respiratory tract illness was reported at least once for 79% of the ribavirin and 73% of placebo group. In the first 5 years after RSV, 54% of the ribavirin group and 50% of the placebo group reported wheezing. There were no significant differences between the groups in annual rates, timing, or severity of recurrent lower respiratory tract illness. No significant differences in pulmonary function were detected by tests of oxygen saturation, peak expiratory flow and spirometry. CONCLUSIONS Children in the ribavirin treatment group did not have exacerbated respiratory symptoms compared with those in the control group, and their pulmonary function measurements were equal to those of the placebo-treated group, suggesting no long term adverse effect or benefit of ribavirin therapy.