Incidence and viral aetiologies of acute respiratory illnesses (ARIs) in the United States: a population-based study.

We conducted prospective, community-wide surveillance for acute respiratory illnesses (ARIs) in Rochester, NY and Marshfield, WI during a 3-month period in winter 2011. We estimated the incidence of ARIs in each community, tested for viruses, and determined the proportion of ARIs associated with healthcare visits. We used a rolling cross-sectional design to sample participants, conducted telephone interviews to assess ARI symptoms (defined as a current illness with feverishness or cough within the past 7 days), collected nasal/throat swabs to identify viruses, and extracted healthcare utilization from outpatient/inpatient records. Of 6492 individuals, 321 reported an ARI within 7 days (4·9% total, 5·7% in Rochester, 4·4% in Marshfield); swabs were collected from 208 subjects. The cumulative ARI incidence for the entire 3-month period was 52% in Rochester [95% confidence interval (CI) 42-63] and 35% in Marshfield (95% CI 28-42). A specific virus was identified in 39% of specimens: human coronavirus (13% of samples), rhinovirus (12%), RSV (7%), influenza virus (4%), human metapneumovirus (4%), and adenovirus (1%). Only 39/200 (20%) had a healthcare visit (2/9 individuals with influenza). ARI incidence was ~5% per week during winter.

Respiratory syncytial virus infections in previously healthy working adults.

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.

Circulation patterns of genetically distinct group A and B strains of human respiratory syncytial virus in a community.

Human respiratory syncytial virus (HRSV) is classified into two major groups, A and B, each of which contains multiple variants. To characterize the molecular epidemiology of HRSV strains over time, sequencing studies of a variable region of the attachment protein gene from a single community in the United States during 5 successive years were performed. Phylogenetic analysis revealed distinct clades (genotypes) that were further classified in subtypes based on > or = 96% nucleotide similarity. Five genotypes and 22 subtypes among 123 group A HRSV isolates, and four distinct genotypes and six subtypes among 81 group B HRSV isolates were identified. One to two genotypes or subtypes accounted for > or = 50% of isolates from a given year. A shift in the predominant genotype or subtype occurred each year such that no genotype or subtype predominated for more than 1 of the 5 study years. The consistency in the displacement of the predominant strain suggests that a shift, even within the same group, is advantageous to the virus. It was hypothesized that the 'novel' strain is better able to evade previously induced immunity in the population and consequently either circulates more efficiently or is more pathogenic. The yearly shift in HRSV strains may contribute to the ability of HRSV to consistently cause yearly outbreaks of HRSV disease. These results also suggest that isolates may need to be characterized as to both group and genotype to fully understand protective immunity after natural infection and efficacy studies of candidate vaccines.

Risk of recurrent seizures after a primary human herpesvirus 6-induced febrile seizure.

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.

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.

Influenza surveillance in community-dwelling elderly compared with children.

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.

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.

Immunity to and frequency of reinfection with respiratory syncytial virus.

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.

Occurrence of groups A and B of respiratory syncytial virus over 15 years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children.

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.

Risk of secondary bacterial infection in infants hospitalized with respiratory syncytial viral infection.

Because infants hospitalized with respiratory syncytial virus (RSV) infection frequently receive antibiotics, our study was undertaken to determine what the actual risk of secondary bacterial infections in patients with RSV infection is and what effect antibiotic treatment might have on the course of illness. In a 9-year prospective study of 1706 children hospitalized with acute respiratory illnesses, 565 children had documented RSV infections. A subsequent bacterial infection rarely developed in those with RSV lower respiratory tract disease. The rate of subsequent bacterial infection was 1.2% in the total group of children infected with RSV, and 0.6% in the 352 children who received no antibiotics. A significantly greater proportion (4.5%) of subsequent bacterial infections occurred in infants who received parenteral antibiotics (p = 0.01), and especially in a subgroup who received parenteral antibiotics for 5 or more days (11%, p less than 0.001). We conclude that the risk of secondary bacterial infection appears to be low for most infants with RSV infection. In a few infants given parenteral broad-spectrum antibiotics the risk may be greater, but whether this is related to the antibiotic therapy or to other risk factors is not clear.

The use of eye-nose goggles to control nosocomial respiratory syncytial virus infection.

We evaluated an eye-nose goggle to determine its usefulness in reducing nosocomial RSV infection in patients and staff members on our infant ward. During a community outbreak of RSV in 1984, infection was assessed by biweekly routine viral cultures on all ward personnel and patients and also by seroconversion in personnel. For three weeks staff members wore the goggles; two (5%) adults and one (6%) child acquired nosocomial infection. During the subsequent three-week study period, goggles were not used and 34% of personnel and 43% of susceptible infants became infected. The use of the disposable eye-nose goggles was associated with a significant decrease in nosocomial RSV infections (P less than .003 for staff and P less than .05 for contact infants).

Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease.

Aerosolized ribavirin was evaluated in the treatment of respiratory syncytial virus lower respiratory tract disease in 53 infants, 36 of whom had underlying diseases. Of the total infants, 26 were studied in a double-blind, placebo-controlled manner; 14 received ribavirin and 12 received placebo, a water aerosol, for an average of five days. When the infants with bronchopulmonary dysplasia and congenital heart disease treated with ribavirin were compared with those receiving placebo, the treated infants showed a significantly faster rate of improvement in their illness severity score. The degree of improvement in the total group of infants receiving ribavirin compared with those receiving placebo was similarly greater, and at the end of therapy significantly greater improvement was also demonstrated in their arterial blood gas values and in the amount of virus shed from their nasal washes. No toxic or adverse effects of the aerosol therapy were observed in any of the 53 infants studied, and resistance to ribavirin did not develop in any of the respiratory syncytial virus strains isolated, despite prolonged treatment in some of the more ill infants.

Rapid detection of respiratory syncytial virus with a monoclonal antibody.

We developed an indirect fluorescent-antibody test employing a mouse monoclonal antibody directed against the nucleoprotein of RSV for rapid detection of respiratory syncytial virus (RSV). This test demonstrated distinctive fluorescent inclusions in HEp-2 cells infected with 24 RSV isolates collected during 6 previous years but not in cells infected with 13 other respiratory viruses. Examination of nasal cells of 100 infants with acute respiratory illness showed that the indirect fluorescent-antibody test employing the monoclonal antibody was 79% sensitive and 100% specific, as compared with the combination of both culturing and a similar indirect fluorescent-antibody test with commercial anti-RSV serum. This monoclonal antibody is an easily produced, well-characterized, sensitive, and specific reagent for the rapid detection of RSV antigen.

Infectivity of respiratory syncytial virus by various routes of inoculation.

To understand the transmission of respiratory syncytial virus, we examined the frequency of infection in volunteers after inoculation by different routes with varying doses of virus. Thirty-two adult volunteers received serial dilutions of a safety-tested live strain of respiratory syncytial virus instilled into nose, eye, or mouth. The highest inoculum, 5.2 log10 50% tissue culture infective dose (TCID50), was administered to four groups of four subjects each, by nose to one group, by eye to one group, and by mouth to two groups. Subsequently, 1:100 and 1:1,000 dilutions of this inoculum were administered by nose and eye. At the highest inoculum, infection occurred in three of four subjects inoculated by nose and in three of four subjects inoculated by eye. Infection occurred in one of eight subjects inoculated by mouth, but this subject most likely was infected by secondary spread. With an inoculum of 3.2 log10 TCID50, the proportion of subjects infected by either route diminished to 25%. When the inoculum was further reduced to 2.2 log10 TCID50, no infections occurred by either route. Infections after the highest inoculum were characterized by earlier and greater shedding. These findings suggest that respiratory syncytial virus may infect by eye or nose and that both of these routes appear equally sensitive. In comparison, the mouth appears to be an insensitive route of inoculation. This is of potential import in infection control procedures and in the development of vaccines or other prophylactic measures.

Respiratory syncytial virus serology by a simplified enzyme-linked immunosorbent assay.

A simplified enzyme-linked immunosorbent assay (ELISA) which utilized commercially available reagents was developed for respiratory syncytial virus (RSV)-specific immunoglobulin G. An analysis of the inherent variation of the assay allowed the setting of strict criteria for determining a significant change in RSV antibodies. The ELISA was more sensitive than the standard complement fixation or microneutralization tests in a carefully studied group of 32 RSV-infected adults. The ELISA correlated closely with complement fixation serological testing in 25 patients. The use of purified antigens might allow the development of a more sensitive ELISA.