During 1975-1995, a total of 2960 healthy adults, 18-60 years of age, were prospectively evaluated for respiratory virus infections. Of these subjects, 211 (7%) acquired respiratory syncytial virus (RSV) infection. The infections were symptomatic in 84% of subjects, involved only the upper respiratory tract in 74%, and included lower respiratory tract symptoms in 26%. Overall, 40% of the subjects were febrile. Lower respiratory tract signs developed in 26%. RSV illnesses were more prolonged than non-RSV respiratory illnesses. Compared with influenza, RSV infections were less frequently associated with fever and headache, but were associated significantly more often with nasal congestion, ear and sinus involvement, and productive cough. Absence from work during the acute phase of the illness resulted from 38% of RSV infections and 66% of influenza cases. The mean duration of RSV illness (9.5 days), however, was significantly longer than that of influenza (6.8 days). The occurrence of annual epidemics of RSV, the virus' potential to reinfect all age groups, and the morbidity associated with these reinfections suggest that RSV infections in working adults may result in appreciable costs for medical visits and absence from work.

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 less than or equal to 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.

Objective. To determine the safety and efficacy of prophylaxis with palivizumab in reducing the incidence of hospitalization because of respiratory syncytial virus (RSV) infection in high-risk infants. Methods. A randomized, double-blind, placebo-controlled trial was conducted at 139 centers in the United States, the United Kingdom, and Canada. During the 1996 to 1997 RSV season, 1502 children with prematurity (less than or equal to 35 weeks) or bronchopulmonary dysplasia (BPD) were randomized to receive 5 injections of either palivizumab (15 mg/kg) or an equivalent volume of placebo by intramuscular injection every 30 days. The primary endpoint was hospitalization with confirmed RSV infection. Children were followed for 150 days (30 days from the last injection). Those with hospitalization as a result of RSV infection were evaluated for total number of days in the hospital, total days with increased supplemental oxygen, total days with moderate or severe lower respiratory tract illness, and incidence and total days of intensive care and mechanical ventilation. The incidence of hospitalization for respiratory illness not caused by RSV and the incidence of otitis media were also evaluated. The placebo and palivizumab groups were balanced at entry for demographics and RSV risk factors. Ninety-nine percent of children in both groups completed the protocol and similar to 93% received all five scheduled injections. Results. Palivizumab prophylaxis resulted in a 55% reduction in hospitalization as a result of RSV (10.6% placebo vs 4.8% palivizumab). Children with prematurity but without BPD had a 78% reduction in RSV hospitalization (8.1% vs 1.8%); children with BPD had a 39% reduction (12.8% vs 7.9%). When gender, entry age, entry weight, BPD, and gestational age were included in a logistic regression model, the effect of prophylaxis with palivizumab remained statistically significant. The palivizumab group had proportionally fewer total RSV hospital days, fewer RSV hospital days with increased oxygen, fewer RSV hospital days with a moderate/severe lower respiratory tract illness, and a lower incidence of intensive care unit admission. Palivizumab was safe and well tolerated. No significant differences were observed in reported adverse events between the two groups. Few children discontinued injections for related adverse events (0.3%). Reactions at the site of injection were uncommon (1.8% placebo vs 2.7% palivizumab); the most frequent reaction was mild and transient erythema. Mild or moderate elevations of aspartate aminotransferase occurred in 1.6% of placebo recipients and 3.6% of palivizumab recipients; for alanine aminotransferase these percentages were 2.0% and 2.3%, respectively. Hepatic and renal adverse events related to the study drug were similar in the two groups. Conclusions. Monthly intramuscular administration of palivizumab is safe and effective for prevention of serious RSV illness in premature children and those with BFD.

Objective. To test the hypothesis that children experiencing first febrile seizures caused by human herpesvirus 6 (HHV-6) have an increased risk for recurrent seizures when compared with children experiencing first febrile seizures attributed to other illnesses.Design and participants, Descriptive prospective study of 36 HHV-6 culture-positive children and a matched subgroup of 86 HHV-6 culture-negative children, all of whom had their first febrile seizures evaluated in a tertiary care emergency department and were followed for at least 12 months, with an average follow-up of 35.7 months,Primary outcome measure. The recurrence of seizures among HHV-6 culture-positive and HHV-6 culture-negative children with no known previous neurologic deficits.Results. A decreased incidence of recurrent seizures occurred in children whose first febrile seizures were caused by HHV-6. Twenty percent of HHV-6 culture-positive children and 40% of HHV-6 culture-negative children (P < 0.038) experienced a recurrent seizure within 1 year of their first febrile seizure. The mean time to recurrence within 12 months was 8.6 months for children with HHV-6 infection and 3.8 months (P < 0.001) for children without HHV-6 infection. Most recurrent seizures occurred within 12 months of a first febrile seizure for both HHV-6-positive and HHV-6-negative children (88 and 91%).Conclusions. Children who had their first febrile seizures caused by primary HHV-6 infection did not demonstrate an increased risk for recurrent seizures when compared with children whose first febrile seizures were from other etiologies.

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.

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.

BACKGROUND:Acute respiratory illnesses (ARIs) are the leading cause of medical visits for community-dwelling patients of all ages, but virologic and clinical descriptions of these illnesses in older adults are infrequent.OBJECTIVES:To determine the feasibility of influenza surveillance in a population of community-dwelling elderly, to compare the patterns of influenza infection in elderly persons with that observed in young populations in which surveillance is usually conducted, and to describe the clinical presentation of influenza infection in elderly outpatients who seek medical attention for ARI.DESIGN:Prospective clinical and viral surveillance of ARIs among ambulatory patients during 3 consecutive winter seasons.SETTING:Nine internal medicine and 3 pediatric practices in Upstate New York in cooperation with the Medicare Influenza Vaccine Demonstration Project.PATIENTS:Elderly (n=808) and pediatric (n=2080) outpatients with ARI office visits.MEASUREMENTS:Frequency of influenza and other respiratory virus isolates and clinical profile of influenza among older adults and children with ARIs.RESULTS:Influenza virus was the viral agent recovered most often from specimens obtained from patients in both age groups with ARI symptoms, especially those with fever. Influenza accounted for 11% of ARIs in adults (87 isolates) and 20% in children (408 isolates). At the initial illness visit, influenza infection was equally common in elderly individuals with or without underlying cardiopulmonary conditions. Lower respiratory tract signs occurred in 13% of the adults and in 7% of the children with influenza documented by laboratory studies. Other respiratory viruses were recovered from specimens obtained from 20 adults and from 259 children.CONCLUSIONS:Viruses are important agents of ARIs in elderly outpatients. Children and older adults experience similar patterns of influenza infection and other epidemic respiratory pathogens, such as parainfluenza and respiratory syncytial viruses. Viral identification is feasible in older adults seen in physicians' offices and may contribute to improved measures of effects of influenza and other respiratory viruses on ARIs.

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.

OBJECTIVE:To evaluate the safety and efficacy of respiratory syncytial virus immune globulin (RSVIG) in the prevention of severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in infants born prematurely with or without bronchopulmonary dysplasia (BPD).METHODS:Data from a prospective, blinded, randomized, multicenter trial during three consecutive RSV seasons involving 249 children. This analysis comprises 162 preterm children, of whom 102 had BPD. The 87 children with congenital heart disease (CHD) were excluded from this analysis. Children were randomized to receive monthly infusions of RSVIG 750 mg/kg (high dose), RSVIG 150 mg/kg (low dose), or no RSVIG: Results from the preterm infants with and without BPD who received RSVIG 750 mg/kg are contrasted with control infants who did not receive RSVIG:RESULTS:As compared with controls, high-dose RSVIG administration significantly reduced the incidences of RSV LRTI (P = .01) and moderate-to-severe LRTI (P = .006). RSV-associated hospitalization also was decreased (P = .06) as well as were total RSV-associated days in the intensive care unit (P = .05). Significantly fewer preterm infants developed severe RSV LRTI in the RSVIG group compared with controls (4/58 [7%] vs 14/58 [24%], respectively; P = .01). Adverse reactions occurred in 5% of RSVIG infusions. These were generally mild and included reversible fluid overload, transient fever, and decreases in oxygen saturation. There was one death unrelated to either RSV or RSVIG administration.CONCLUSIONS:Prophylaxis with RSVIG is safe and is currently the only effective means to prevent severe RSV LRTI in high-risk preterm infants.

We collected surveillance data as part of the Medicare Influenza Vaccine Demonstration to describe communitywide epidemiology of influenza, focusing on the elderly. Laboratory-based surveillance was established in medical practices, hospitals, and nursing homes in a two-county demonstration in upstate New York. Time course and intensity of epidemic influenza were compared between counties, between influenza A and B epidemics, and among several levels of surveillance involving elderly persons as well as children during the years 1989-1992. The counties experienced parallel epidemics during each of the three demonstration years. Influenza A/H3N2, predominant in 1989-1990 and 1991-1992, was equally intense among young and old, accounted for 11%-28% of acute cardiopulmonary hospitalizations of older persons, and caused focal outbreaks in 30%-40% of nursing homes in the respective epidemics. Influenza B, predominant in 1990-1991, showed modest impact among the elderly as compared with children. Influenza A/H1N1 occurred among children each year but was virtually absent among the elderly. Systematic surveillance during the "influenza season" consistently confirms widespread infection among older patients, both in the community and in institutions. However, much febrile respiratory illness in this age group during periods of epidemic influenza is culture-negative for influenza virus and thus may be caused by other respiratory pathogens.

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.

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)

Objectives. To evaluate the efficacy of high-titer intravenous respiratory syncytial virus immune globulin (RSVIG) in the treatment of children at high risk for severe RSV infection who were hospitalized with proven RSV.Methods. Infants and young children younger than 2 years with bronchopulmonary dysplasia, chronic lung disease, congenital heart disease, or prematurity (<32 weeks' gestational age), hospitalized with a history of lower respiratory tract infection (LRI) of less than 4 days, were enrolled in this study. Patients were randomized in a blinded fashion to receive either 1500 mg/kg RSVIG or placebo in equal volumes. They were evaluated daily for safety and respiratory scores and for RSV nasal shedding.Results. One hundred seven high-risk children were randomized-54 in the RSVIG group and 53 in the placebo group. Of these children, 51 in each group were considered evaluable. Children with pulmonary disease, congenital heart disease, or prematurity were equally distributed between the two treatment groups. However, two important differences were found in baseline variables between the two groups: there were more patients in the placebo group who had histories of previous LRI and there was a trend toward more severe disease at study entry in the RSVIG group. This was manifested by a higher entry respiratory score in the RSVIG group than in the placebo group (3.4 +/- 0.2 vs 3.1 +/- .01). A higher proportion of children in the RSVIG group (47%) than in the placebo group (28%) required intensive care at entry and mechanical ventilation at study entry (31% RSVIG-treated vs 18% placebo-treated patients). No significant difference was found between groups in the mean unadjusted duration of hospitalization (RSVIG group, 9.10 +/- 1.18 days; control group, 8.17 +/- 1.08 days), When the mean was adjusted for entry respiratory score, likewise, no difference was observed between each group (8.41 +/- 0.97 vs 8.89 +/- .99 days), The lack of efficacy observed in the study primary endpoint was observed in all diagnostic groups. No differences between the RSVIG and placebo groups were observed in the following secondary endpoints: duration of intensive care unit stay, duration of intensive care unit stay for RSV, mechanical ventilation, or supplemental oxygen. No significant differences in adverse events were reported in the RSVIG group (16 children) when compared with the control group (10 children).Conclusion. RSVIG treatment was safe but not efficacious in the treatment of children with bronchopulmonary dysplasia, congenital heart disease, or premature gestation who were hospitalized with RSV LRI.

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.

To better understand the duration of immunity against respiratory syncytial virus (RSV) and the role of serum antibodies to the surface glycoproteins, F and G, in susceptibility to reinfection, 15 adults with previous natural RSV infection were challenged with RSV of the same strain group (A) at 2, 4, 8, 14, 20, and 26 months after natural infection. By 2 months about one-half and by 8 months two-thirds of the subjects became reinfected. Each challenge resulted in infection in at least one-fourth of the subjects. Within 26 months 73% had two or more and 47% had three or more infections. The duration of immunity tended to increase after two closely spaced infections. Higher neutralizing, F and GA antibody levels before challenge correlated significantly with protection against infection. However, even in subjects with the highest antibody levels, the risk of reinfection was 25%. Specific nasal IgA antibody titers did not correlate significantly with protection. This suggests that humoral neutralizing, F, and G antibodies correlate with resistance to reinfection, but protection is far from complete and is of short duration.

Infants with cardiopulmonary disease develop severe illness from respiratory syncytial virus (RSV) infection. Safety, feasibility, and pharmacokinetics of intravenous gamma globulin (IVIG) to prevent RSV illness were studied in 23 high-risk infants in a phase I trial. IVIG with an RSV neutralizing antibody titer of 1:1,100 in 5% solution was given monthly over a 2- to 4-h period in a clinical setting during the RSV season. The first group (n = 7) received 500 mg/kg of body weight, the second group (n = 9) received 600 mg/kg, and the third group (n =7) received 750 mg/kg. Serum was drawn prior to infusion and 2, 14, and 30 days after infusion. Total immunoglobulin G and RSV A2 and RSV B neutralizing antibody levels were obtained after the first IVIG infusion. Two children developed mild reversible pulmonary edema (group receiving 600 mg/kg per dose), and one developed hives and wheezing during one infusion (group receiving 500 mg/kg per dose). Twelve children developed subsequent RSV infection during two RSV seasons (November to April) over a 2-year follow-up period; 9 of 12 developed infection during the infusion year. Eleven illnesses were mild; one child died of progressive RSV illness (group receiving 500 mg/kg per dose). A cumulative infusion effect was not observed. IVIG appears safe and feasible in an outpatient setting, and at 750 mg/kg per dose, a target RSV antibody level of greater than or equal to 1:100 was achieved.

Over 15 years respiratory syncytial virus (RSV) isolates from 1209 hospitalized and ambulatory children were examined for strain group and in a subset for subgroup to determine the associated epidemiologic and clinical characteristics. Three patterns of yearly outbreaks existed: (1) strong predominance of group A strains (9 years with 83%-100% A strains), (2) relatively equal proportions of group A and B strains (4 years), and (3) strong predominance of group B strains (78%-85%) in 2 years, separated by a decade. The first pattern of highly dominant A strains occurred in cycles of 1 or 2 consecutive years with a single intervening year in which B strains were greater than or equal to 40% of the isolates. Subgroups A1 and A2 predominated, while B2, 3, and 4 occurred almost equally. A greater clinical severity for Group A strains was suggested by children with group A infections requiring intensive care significantly more often (15.4 vs. 8.3%, P = .008). Further, strongly dominant A strain years were associated with higher proportions of RSV admissions requiring intensive care (16.6% vs. 5.5%, P less than .01). Strains of subgroups A2 and B4 were more frequently found in hospitalized patients and A1 in outpatients, and the 2 years with the highest rates of intensive care admissions were those in which subgroup A2 dominated.