Background Respiratory syncytial virus (RSV) is an increasinglyrecognized cause of illness in adults. Data on the epidemiologyand clinical effects in community-dwelling elderly persons andhigh-risk adults can help in assessing the need for vaccinedevelopment.
Methods During four consecutive winters, we evaluated all respiratoryillnesses in prospective cohorts of healthy elderly patients(65 years of age) and high-risk adults (those with chronic heartor lung disease) and in patients hospitalized with acute cardiopulmonaryconditions. RSV infection and influenza A were diagnosed onthe basis of culture, reverse-transcriptase polymerase chainreaction, and serologic studies.
Results A total of 608 healthy elderly patients and 540 high-riskadults were enrolled in prospective surveillance, and 1388 hospitalizedpatients were enrolled. A total of 2514 illnesses were evaluated.RSV infection was identified in 102 patients in the prospectivecohorts and 142 hospitalized patients, and influenza A was diagnosedin 44 patients in the prospective cohorts and 154 hospitalizedpatients. RSV infection developed annually in 3 to 7 percentof healthy elderly patients and in 4 to 10 percent of high-riskadults. Among healthy elderly patients, RSV infection generatedfewer office visits than influenza; however, the use of healthcare services by high-risk adults was similar in the two groups.In the hospitalized cohort, RSV infection and influenza A resultedin similar lengths of stay, rates of use of intensive care (15percent and 12 percent, respectively), and mortality (8 percentand 7 percent, respectively). On the basis of the diagnosticcodes of the International Classification of Diseases, 9th Revision,Clinical Modification at discharge, RSV infection accountedfor 10.6 percent of hospitalizations for pneumonia, 11.4 percentfor chronic obstructive pulmonary disease, 5.4 percent for congestiveheart failure, and 7.2 percent for asthma.
Conclusions RSV infection is an important illness in elderlyand high-risk adults, with a disease burden similar to thatof nonpandemic influenza A in a population in which the prevalenceof vaccination for influenza is high. An effective RSV vaccinemay offer benefits for these adults.
Respiratory syncytial virus (RSV) was first recognized in 1957as a cause of bronchiolitis in infants and is the most commonlyidentified cause of lower respiratory tract infection in youngchildren.1 Mild illness in young adults with reinfection wasdescribed and confirmed in subsequent family studies.2,3 However,RSV was not recognized as a potentially serious problem in olderadults until the 1970s, when outbreaks of the virus occurredin long-term care facilities.4,5,6,7 Since then, additionalstudies in hospitalized adults have suggested that RSV may bean important cause of illness in community-dwelling elderlypeople.8,9 Most previous studies used insensitive viral cultureor retrospective serologic studies for diagnosis, a practicethat led to widely variable assessments of the incidence andeffects of the disease. Recent estimates of the disease burdenof RSV in adults have been based on mathematical models linkingviral activity in children with hospitalization and death inadults,10,11,12,13,14 and Thompson et al. have estimated thatRSV accounts for approximately 10,000 deaths annually in theUnited States in persons over the age of 65 years.14 Althoughthese estimates are useful, their accuracy is confounded bycocirculation of other respiratory viruses with indistinguishableclinical syndromes and is limited by the assumption that viralactivity in infants reflects events in elderly populations.15,16,17These results have stimulated interest in vaccines and othertreatments for RSV in adults.15,18,19 However, additional dataregarding virus-specific epidemiology and disease effects, particularlyin community-dwelling elderly persons and high-risk adults,are needed before embarking on costly vaccine trials.
Therefore, we identified RSV infections during four consecutivewinters in prospective cohorts of community-dwelling elderlypeople and high-risk adults and in persons hospitalized withacute cardiopulmonary conditions. Identical techniques of diagnosingRSV infection and influenza A were used to assess the diseaseburden and to provide a direct comparison of RSV infection withinfluenza A, which is a universally recognized cause of seriousdisease in the populations mentioned above.
Methods
Study Design
The study spanned four consecutive winters, from late 1999 throughearly 2003 in Rochester, New York. Three groups of patientswere recruited: two prospective cohorts (healthy elderly personsand high-risk adults) and a hospitalized cohort of patientswho were admitted each winter with cardiopulmonary illnesses.Enrollees or their guardians provided written informed consent.The University of Rochester Research Subjects Review Board andthe Rochester General Hospital Clinical Investigation Committeeapproved the study.
Enrollment of Prospective Cohorts
Persons who were 65 years of age or older and did not have disablingunderlying illnesses (i.e., healthy elderly persons) and persons21 years of age or older with physician-diagnosed congestiveheart failure or chronic pulmonary disease (i.e., high-riskadults) were enrolled in the late summer and fall (from July15 to November 15) and were followed for a maximum of two winters.To be considered high risk, patients with cardiac disease wererequired to have at least class II symptoms according to theNew York Heart Association's classification, and patients withpulmonary disease were required to have activity-restrictingsymptoms or use long-term medications.20 Advertisements andmailings were used to recruit patients from health maintenanceorganizations and from cardiac and pulmonary rehabilitationprograms.
At enrollment, data on the patients' demographic status, medicalhistory, and functional performance were recorded. Functionalstatus was assessed with the use of a modified Katz Activitiesof Daily Living (ADL) Scale and the Instrumental Activitiesof Daily Living (IADL) Scale.21,22 Baseline blood samples werecollected from the prospective groups before the RSV season(from July 15 to November 15) and postseason blood samples werecollected the following spring (from April 15 to June 15).
Illness Evaluation
Prospective Cohorts
Patients notified study personnel regarding symptoms of respiratoryillness or worsening of baseline cardiopulmonary symptoms fromNovember 15 through April 15 of each year. Symptoms includednasal congestion, sore throat, hoarseness, new or worseningcough, sputum production, and dyspnea with or without fever.During home visits, investigators conducted a physical examination,collected nasopharyngeal swabs and blood samples, and obtaineda history of the illness. Four to six weeks later, patientswere questioned about their functional status and use of healthcare services (including telephone consultations, office visits,emergency room visits, and hospitalizations). Events relatedto the use of health care services were recorded as unique ifthe events were isolated, whereas the highest level of carewas counted if the events were directly related.
Hospital Cohort
During the same surveillance periods, all adults 65 years ofage or older or with underlying cardiopulmonary diseases whowere admitted to Rochester General Hospital with acute respiratorysymptoms were evaluated within 48 hours after admission. Enrollmentwas performed Monday through Friday, so patients who were admittedon Friday were not eligible. Patients with admission diagnosesof pneumonia (International Classification of Diseases, 9thRevision, Clinical Modification [ICD-9-CM] codes 480 to 486),upper respiratory infection (ICD-9-CM code 465), bronchitis(ICD-9-CM code 466), influenza (ICD-9-CM code 487), chronicobstructive pulmonary disease (ICD-9-CM codes 490 to 492 and496), asthma (ICD-9-CM code 493), viral illness (ICD-9-CM code79.9), or congestive heart failure (ICD-9-CM code 428) wereeligible and underwent identical evaluations as prospectivecohorts. Patients' functional activity scores before their illnesswere determined by a review of records of social workers andnurses plus interviews with patients and their families. Patientswere followed until discharge from the hospital. Follow-up visitswere made at home or in the hospital four to six weeks afterthe initial assessment to collect data on functional activityand convalescent-phase blood samples.
Laboratory Studies
Samples from nasopharyngeal swabs were inoculated into tubesof HEp-2 cells and rhesus monkey kidney cells within four hoursafter collection, and the remainder were frozen at –80°C.Cultures were examined daily for cytopathic effects in the clinicalmicrobiology laboratory, and viral growth was confirmed by indirectimmunofluorescence with the use of monoclonal antibodies specificfor RSV and influenzavirus A and B.
Reverse-transcriptase polymerase chain reaction (RT-PCR) forRSV and influenza was performed on 250-µl aliquots ofsamples from nasopharyngeal swabs with the use of single-tubenested reactions with primers from the conserved region of theRSV fusion and influenza A matrix genes.23,24 The limit of detectionfor each assay was 0.1 plaque-forming unit.25 RSV subgroupsA and B were identified by a strain-specific RT-PCR assay.26
Enzyme immunoassay was used to measure serum IgG responses topurified RSV glycoproteins according to established methods.27The serum IgG responses to influenza A and B antigens were determinedwith the use of whole-cell lysate assays infected with influenzavirus,as previously described.24,28 An increase by a factor of fouror more in the IgG titer in response to any RSV antigen or influenzaantigen was considered diagnostic.
Definitions of Illness
Symptomatic RSV or influenza infections were defined as illnesseswith a positive viral culture, a positive RT-PCR assay, or adiagnostic serologic result. Asymptomatic RSV infection wasdefined as an increase by a factor of four or more in RSV IgGtiters in samples obtained after the winter season as comparedwith those obtained before the winter season in persons withoutillness or in asymptomatic intervals between illnesses. Interpretationof the serologic results was occasionally complicated by vaccination.During the four years of the study, the timing of influenzavaccination was highly variable because of vaccine shortagesor delays. For illnesses that occurred within four weeks aftervaccination, the antibody response alone was not sufficientto define influenza infection. Asymptomatic influenza infectionwas defined as an antibody rise occurring more than four weeksafter vaccination during an illness-free interval.
Statistical Analysis
The chi-square test and Fisher's exact test were used to compareproportions. For data with a normal distribution, means werecompared with Student's t-test; for skewed data, the Mann–Whitneytest was used. The Poisson regression model and McNemar's testwere used to compare the rates of illness and viral infection.29
Results
Populations
A total of 608 healthy elderly persons and 540 high-risk adultswere enrolled in the prospective surveillance. During the sameperiod, 1483 hospitalized patients were eligible for study,of whom 1388 (94 percent) agreed to participate. Demographiccharacteristics and admission diagnoses were not significantlydifferent for those who declined to participate in the study.
Characteristics of the study populations are summarized in Table 1.The average age in each group was at least 70 years. Of thehigh-risk patients, 73 percent were 65 years of age or older,17 percent were between the ages of 55 and 64 years, and 10percent were 54 years of age or younger. The percentage of personswith exposure to children was higher in the high-risk groupthan in either the healthy elderly group or the hospitalizedgroup (P=0.008), although living situations were similar forthe three groups (Table 1). There were significantly lower ratesof chronic disease and the use of medication in the healthyelderly cohort than in the high-risk and hospitalized groups.Despite having substantial cardiopulmonary disease, the high-riskgroup was only slightly less functional than the healthy elderlygroup. In contrast, the hospitalized group had significantlyworse functional scores before hospitalization than did bothprospective cohorts (P<0.001).
During the four winter seasons studied, 2514 cases of illnesswere evaluated (1043 in prospective patients and 1471 in hospitalizedpatients). Although the numbers of illnesses in the two prospectivegroups were similar, rates expressed as cases of illness per100 person-months were higher in high-risk subjects than inhealthy elderly patients because of a greater attrition rate(14.3 cases vs. 10.4, P<0.001; relative risk, 1.39; 95 percentconfidence interval, 1.23 to 1.57).
During the four winters, the activity of both influenzavirusA and B varied considerably, whereas annual RSV activity wasrelatively constant (Table 2). The circulating influenzavirusstrains varied considerably during the years of study.30 The1999–2000 season was dominated by influenzavirus A H3N2(99.5 percent) in the mid-Atlantic region. During subsequentyears, the circulating strains were as follows: 2000–2001,37 percent influenzavirus A (97 percent H1N1) and 63 percentinfluenzavirus B; 2001–2002, 88 percent influenzavirusA (98 percent H3N2) and 12 percent influenzavirus B; 2002–2003,86 percent influenzavirus A (70 percent H1N1) and 14 percentinfluenzavirus B.
Table 2. Rates of Illness and Infection According to Year of Study.
RSV infection was identified in 102 cases of illness involvingpatients in the prospective cohorts and in 142 cases involvinghospitalized patients. Influenza A was diagnosed in 44 casesof illness involving patients in the prospective cohorts andin 154 cases involving hospitalized patients (Table 2). Giventhe low number of influenza B infections, subsequent discussionwill be limited to influenza A and RSV infection. RSV infectiondeveloped annually in 3 to 7 percent of the healthy elderlygroup and in 4 to 10 percent of the high-risk group. There wasno significant difference in the rates of RSV infection or influenzaA among patients in their first year of surveillance as comparedwith their second year. Two patients in the prospective cohortshad two cases of RSV infection each, and four patients had influenzaA and RSV infection at different times. The number of patientswith RSV infection in the prospective cohorts was approximatelytwice that of patients with influenza A (97 vs. 39, P<0.001).There were 1.5 RSV infections per 100 person-months in the high-riskgroup and 0.9 in the healthy elderly group (P=0.02; relativerisk, 1.61; 95 percent confidence interval, 1.09 to 2.39). InfluenzaA rates were identical in the two prospective cohorts: 0.5 infectionper 100 person-months. Despite higher rates of RSV infectionin the prospective cohorts, the overall numbers of patientswho had RSV infection and influenza in the hospital cohort weresimilar. Data on the hospital cohort do not include those forpatients from the prospective cohorts who were subsequentlyadmitted to the hospital.
Viral Diagnosis
Most illnesses (76 percent) were evaluated with all three diagnosticmethods (Table 3). Serum from convalescent patients was notavailable in 18 percent of cases, and nasal specimens were unobtainablein 6 percent. RSV infection was diagnosed with more than onetest in 47 percent of cases, RT-PCR alone was used in 20 percent,and serologic testing alone was used in 33 percent. Eleven hospitalizedpatients had dual infections and were excluded from clinicalanalyses (nine patients with both RSV infection and influenzaA, one with RSV infection and influenza B, and one with influenzaA and influenza B). The RSV strain was group A in 73 cases (45percent) and group B in 89 (55 percent). Both RSV strains circulatedeach year without significant differences in the percentagesof group A and B viruses among mildly ill outpatients and severelyill hospitalized patients.
Clinical Effects of Infection in Prospective Cohorts
Eighty-nine percent of RSV infections were symptomatic in theprospective cohorts. Five patients in the healthy elderly groupand six patients in the high-risk group had serologic evidenceof infection without reported illnesses. Similarly, 91 percentof patients with influenza were symptomatic. The symptoms andsigns of RSV infection and those of influenza were not substantiallydifferent (data not shown).
The effects of RSV infection were considerable in both the healthyelderly group and the high-risk group (Table 4). Fifteen percentof patients in the healthy elderly group called their physicianand 17 percent made office visits, although none of them requiredemergency room or inpatient services. The use of medical carewas significantly greater in the high-risk group: 23 percentcalled the doctor, 29 percent made office visits, 9 percentvisited the emergency room, and 16 percent required hospitalization.Two high-risk patients with RSV infection (4 percent) died.The mean duration of illness was approximately two weeks inboth groups, and 39 percent of patients in the healthy elderlygroup and 45 percent in the high-risk group were unable to performthe normal activities of daily living for at least one day.The proportion of patients with acute functional impairmentwas substantially greater in the high-risk group with RSV infectionthan in the healthy elderly group.
Table 4. Infections in Healthy Elderly Patients and High-Risk Patients.
Among the healthy elderly patients, influenza A infection generateda greater percentage of office visits than did RSV infection(42 percent vs. 17 percent, P=0.04) and a higher rate of antibioticuse (33 percent vs. 9 percent, P=0.02). Among high-risk patients,the use of medical care was similar in the RSV and influenzaA subgroups, although office visits were more common in theinfluenza A subgroup (60 percent vs. 29 percent, P=0.02). However,because RSV infection occurred more frequently than influenzaA, the total number of health care visits (office visits, emergencyroom visits, and hospitalizations) was similar for the two viruses,at 38 and 30, respectively. Acute functional impairment in thehealthy elderly group was also greater with influenza than itwas with RSV infection, with 67 percent of patients housebound(P=0.005) and 25 percent confined to bed (P=0.05). None of thepatients in the healthy elderly group with influenza were hospitalizedor died, whereas 20 percent of high-risk patients were hospitalized.
Clinical Effects of Infection with RSV and Influenza A in Hospitalized Patients
Demographic and clinical characteristics of patients with RSVinfection and patients with influenza requiring hospitalizationwere not significantly different (Table 5). Twelve percent ofpatients with RSV infection and 10 percent of patients withinfluenza were residents of long-term care facilities, a findingthat was similar to that of the hospital cohort in general (8percent). The clinical effects of RSV infection and influenzain the hospitalized cohorts were also similar, as assessed bythe length of stay; whether the patient had pneumonia, was inintensive care, or required mechanical ventilation; and mortality.The mortality among patients with RSV infection was higher inthe group admitted from long-term care facilities (38 percent)than in the group admitted from the community (3 percent, P<0.001),whereas among patients with influenza, there was no significantdifference between the two groups. Five percent of patientswith RSV infection and 6 percent of patients with influenzarequired a higher level of care at discharge than at admission.The mean IADL functional scores increased slightly after hospitalizationfor patients with RSV infection (4.1±4.1 to 4.9±4.0),and a similar trend was observed among patients with influenza.Overall, according to the diagnosis at discharge, RSV infectionaccounted for 10.6 percent of hospitalizations for pneumonia,11.4 percent for chronic obstructive pulmonary disease, 5.4percent for congestive heart failure, and 7.2 percent for asthma.
This four-year prospective, diagnosis-specific study firmlydocuments that RSV is an important pathogen in elderly and high-riskadults. Although pediatricians are keenly aware that RSV maycause serious illness in their patients, most internists areless aware of RSV. Given the difficulty with diagnosis in clinicalpractice and the lack of treatment, this lack of awareness isunderstandable. However, from a public health perspective, ourstudy shows the substantive disease burden associated with thisvirus and validates the results of earlier, mathematically derivedestimates.
Diagnosis by nested RT-PCR allowed a precise determination ofthe rates of RSV infection that had not previously been possible.In addition, the use of RT-PCR in this study strengthens thecausal link between RSV infection and hospitalization, whichcan be questioned in serologically based studies. In our study,61 percent of patients who had an increase in antibodies toRSV also had a positive RT-PCR assay, a finding suggesting thatinfection occurred shortly before admission. Conversely, since83 percent of patients with a positive PCR assay for RSV whoseserum was tested during convalescence had an immune response,it is unlikely that detectable viral RNA reflects transientcolonization.
The annual incidence of RSV infection in the prospective cohortsaveraged 5.5 percent and was relatively constant during thefour years and nearly twice that of influenza A. The rate ofRSV infection in this study was higher than the 3 percent observedby Nicholson and colleagues in elderly adults in the UnitedKingdom and probably reflects our use of RT-PCR and a more sensitiveserologic test.31 It must be recognized that the rate of influenzawas probably reduced by the high rate of vaccination in ourpopulation. Since immunization is estimated to have an efficacyof approximately 50 percent for the prevention of respiratoryillness in elderly persons, influenza cases might have beenexpected to double without vaccination.32
Almost all RSV infections were symptomatic, and they frequentlyled to acute functional impairment and to the use of healthcare services. One quarter of all healthy elderly patients hadcontact with a health care provider during their illness; nearlyhalf of all high-risk patients sought medical attention, and16 percent were hospitalized. Although influenza resulted ingreater use of health care services by healthy elderly patientsthan did RSV infection, differences between RSV infection andinfluenza were less distinct in the high-risk group, with asimilar number of hospitalizations for each type of infectionduring the four years. However, the effect of the circulatinginfluenza strain was clearly seen. During years 2 and 4, whenthe dominant strain was H1N1 (one not associated with substantialmorbidity and mortality in the elderly), hospitalizations forRSV infection outnumbered those for influenza.14,33 In contrast,when H3N2 influenza was prevalent, in years 1 and 3, admissionsfor influenza were two to three times as common as those forRSV infection. This finding is consistent with other data indicatingthat infection with influenza H3N2 but not H1N1 results in amore severe illness than does RSV infection.14 In addition,the high rate of vaccination for influenza in our communityprobably affected the rate of hospitalization. The efficacyof vaccination in reducing the rate of hospitalization frominfluenza is estimated to be 40 to 50 percent.34,35 Sixty-eightpercent of patients who were hospitalized with influenza reportedhaving been vaccinated, as compared with 75 percent of thosewith RSV infection, a finding that suggests a more modest vaccineeffect. However, even if the number of influenza cases weredoubled, rates of hospitalization for RSV and influenza wouldnot be dramatically different.
Overall, during the study period, RSV infection accounted for11 percent of hospitalizations for pneumonia, 11 percent forchronic obstructive pulmonary disease, 5 percent for congestiveheart failure, and 7 percent for asthma. According to the NationalCenter for Health Statistics of the Centers for Disease Controland Prevention, in 1999 the numbers of discharges from U.S.hospitals of adults 65 years of age or older for the diagnosesof pneumonia, chronic obstructive pulmonary disease, congestiveheart failure, and asthma were 1.3 million, 0.76 million, 2.5million, and 0.35 million, respectively.36 By applying our ratesand adjusting by 50 percent for surveillance during the wintermonths, RSV infection would account for approximately 177,525admissions each year. On the basis of our study, which showedthat the death rate for hospitalized patients with RSV infectionwas 8 percent, 14,000 annual deaths would be predicted, a numbersimilar to that estimated by Thompson et al.14 Hospitalizationcosts alone would exceed $1 billion, an estimate not dissimilarto that made by Han et al.37 Outpatient costs would also probablybe substantial given our findings and those of Zambon et al.,who reported that up to 18 percent of office visits made byelderly adults for respiratory illnesses during winter wereRSV-related.38
In addition to bringing RSV to the attention of internists,our study underscores the continuing importance of yearly influenzaepidemics in the expanding elderly and high-risk populations.Programs to improve the efficacy of influenza vaccination andto ensure adequate and timely supplies of vaccine should remaina high priority. However, in order to optimize the reductionin the total burden of viral respiratory disease, we must recognizethat other pathogens also contribute to the swell of patientsin offices and hospitals during the winter months. The resultsof this study document the importance of RSV infection in adultsand confirm the need for the development of an RSV vaccine forhigh-risk and elderly adults.
Supported by a grant (R01-AI-45969) from the National Institutesof Health.
Dr. Falsey reports having received consulting fees from Sanofi–Aventisand GlaxoSmithKline and a grant from Sanofi–Aventis. Dr.Walsh reports having received consulting fees from Sanofi–Aventis,Arrow Therapeutics, and Alnylam Pharmaceuticals.
We are indebted to Mary Criddle, R.N., and Anita Gellert, R.N.,for evaluations of patients; to Barbara Sikora and Gloria Andolinafor technical assistance; to Christine Brower for data management;to the staff and patients at Lifetime Health and Lori Callahanat the Rochester General Hospital Pulmonary Rehabilitation Programfor their help in conducting the study; and to Drs. John Treanorand Robert Betts for their thoughtful review of the manuscript.
Source Information
From the Department of Medicine, Rochester General Hospital (A.R.F., P.A.H., M.A.F., E.E.W.) and the Department of Medicine, University of Rochester School of Medicine and Dentistry (A.R.F., E.E.W.) — both in Rochester, N.Y.; and the Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md. (C.C.).
Address reprint requests to Dr. Falsey at the Infectious Diseases Unit, Rochester General Hospital, 1425 Portland Ave., Rochester, NY 14621, or at ann.falsey{at}viahealth.org.
References
Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med 2001;344:1917-1928. [Free Full Text]
Hall CB, Geiman JM, Biggar R, Kotok DI, Hogan PM, Douglas RG Jr. Respiratory syncytial virus infections within families. N Engl J Med 1976;294:414-419. [Abstract]
Johnson KM, Bloom HH, Mufson MA, Chanock RM. Natural infection of adults by respiratory syncytial virus: possible relation to mild upper respiratory disease. N Engl J Med 1962;267:68-72. [Medline]
Hart RJC. An outbreak of respiratory syncytial virus infection in an old people's home. J Infect 1984;8:259-261. [CrossRef][Web of Science][Medline]
Sorvillo FJ, Huie SF, Strassburg MA, Butsumyo A, Shandera WX, Fannin SL. An outbreak of respiratory syncytial virus pneumonia in a nursing home for the elderly. J Infect 1984;9:252-256. [CrossRef][Web of Science][Medline]
Respiratory syncytial virus infection in the elderly 1976-1982. Br Med J (Clin Res Ed) 1983;287:1618-1619.
Vikerfors T, Grandien M, Olcen P. Respiratory syncytial virus infections in adults. Am Rev Respir Dis 1987;136:561-564. [Web of Science][Medline]
Falsey AR, Cunningham CK, Barker WH, et al. Respiratory syncytial virus and influenza A infections in the hospitalized elderly. J Infect Dis 1995;172:389-394. [Web of Science][Medline]
Dowell SF, Anderson LJ, Gary HE Jr, et al. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis 1996;174:456-462. [Web of Science][Medline]
Griffin MR, Coffey CS, Neuzil KM, Mitchel EF Jr, Wright PF, Edwards KM. Winter viruses: influenza- and respiratory syncytial virus-related morbidity in chronic lung disease. Arch Intern Med 2002;162:1229-1236. [Free Full Text]
Nicholson KG. Impact of influenza and respiratory syncytial virus on mortality in England and Wales from January 1975 to December 1990. Epidemiol Infect 1996;116:51-63. [Medline]
Neuzil KM, Maynard C, Griffin MR, Heagerty P. Winter respiratory viruses and health care use: a population-based study in the northwest United States. Clin Infect Dis 2003;37:201-207. [Medline]
Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-186. [Free Full Text]
Morens DM. Influenza-related mortality: considerations for practice and public health. JAMA 2003;289:227-229. [Free Full Text]
McIntosh K, Kapikian AZ, Turner HC, Hartley JW, Parrott RH, Chanock RM. Seroepidemiologic studies of coronavirus infection in adults and children. Am J Epidemiol 1970;91:585-592. [Free Full Text]
Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350:443-450. [Free Full Text]
La Montagne JR. RSV pneumonia, a community-acquired infection in adults. Lancet 1997;349:149-150. [Medline]
Simoes EA. Overlap between respiratory syncytial virus infection and influenza. Lancet 2001;358:1382-1383. [Medline]
Management of chronic heart failure. In: Braunwald E, Zipes DP, Libby P, eds. Heart disease: a textbook of cardiovascular medicine. Philadelphia: W.B. Saunders, 2001:640-1.
Lawton MP. The functional assessment of elderly people. J Am Geriatr Soc 1971;19:465-481. [Web of Science][Medline]
Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged: the index of ADL: a standardized measure of biological and psychological function. JAMA 1963;185:914-919. [Free Full Text]
Walsh EE, Falsey AR, Swinburne IA, Formica MA. Reverse transcription polymerase chain reaction (RT-PCR) for diagnosis of respiratory syncytial virus infection in adults: use of a single-tube "hanging droplet" nested PCR. J Med Virol 2001;63:259-263. [CrossRef][Web of Science][Medline]
Walsh EE, Cox C, Falsey AR. Clinical features of influenza A virus infection in older hospitalized persons. J Am Geriatr Soc 2002;50:1498-1503. [CrossRef][Web of Science][Medline]
Falsey AR, Formica MA, Walsh EE. Diagnosis of respiratory syncytial virus infection: comparison of reverse transcription-PCR to viral culture and serology in adults with respiratory illness. J Clin Microbiol 2002;40:817-820. [Free Full Text]
Falsey AR, Formica MA, Treanor JJ, Walsh EE. Comparison of quantitative reverse transcription-PCR to viral culture for assessment of respiratory syncytial virus shedding. J Clin Microbiol 2003;41:4160-4165. [Free Full Text]
Falsey AR, Treanor JJ, Betts RF, Walsh EE. Viral respiratory infections in the institutionalized elderly: clinical and epidemiologic findings. J Am Geriatr Soc 1992;40:115-119. [Web of Science][Medline]
Harmon MW, Kendal AP. Influenza viruses. In: Schmidt NJ, Emmons RW, eds. Diagnostic procedures for viral, rickettsial, and chlamydial infections. 6th ed. Washington, D.C.: American Public Health Association, 1989:631-68.
Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley, 1981:113-6.
Nicholson KG, Kent J, Hammersley V, Cancio E. Acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden. BMJ 1997;315:1060-1064. [Free Full Text]
Govaert TME, Thijs CTMCN, Masurel N, Sprenger MJW, Dinant GJ, Knottnerus JA. The efficacy of influenza vaccination in elderly individuals: a randomized double-blind placebo-controlled trial. JAMA 1994;272:1661-1665. [Free Full Text]
Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 1994;331:778-784. [Free Full Text]
Foster DA, Talsma A, Furumoto-Dawson A, et al. Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly. Am J Epidemiol 1992;136:296-307. [Free Full Text]
National Center for Health Statistics, Popovic JR. National Hospital Discharge Survey: annual summary with detailed diagnosis and procedure data. Hyattsville, Md.: National Center for Health Statistics, 2001. (DHHS publication no. (PHS) 2001-1722.)
Han LL, Alexander JP, Anderson LJ. Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden. J Infect Dis 1999;179:25-30. [CrossRef][Web of Science][Medline]
Zambon MC, Stockton JD, Clewley JP, Fleming DM. Contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study. Lancet 2001;358:1410-1416. [CrossRef][Web of Science][Medline]
Kohlmann, R., Schwannecke, S., Tippler, B., Ternette, N., Temchura, V. V., Tenbusch, M., Uberla, K., Grunwald, T.
(2009). Protective Efficacy and Immunogenicity of an Adenoviral Vector Vaccine Encoding the Codon-Optimized F Protein of Respiratory Syncytial Virus. J. Virol.
83: 12601-12610
[Abstract][Full Text]
Dodd, J. S., Lum, E., Goulding, J., Muir, R., Van Snick, J., Openshaw, P. J. M.
(2009). IL-9 Regulates Pathology during Primary and Memory Responses to Respiratory Syncytial Virus Infection. J. Immunol.
183: 7006-7013
[Abstract][Full Text]
Collarini, E. J., Lee, F. E.-H., Foord, O., Park, M., Sperinde, G., Wu, H., Harriman, W. D., Carroll, S. F., Ellsworth, S. L., Anderson, L. J., Tripp, R. A., Walsh, E. E., Keyt, B. A., Kauvar, L. M.
(2009). Potent High-Affinity Antibodies for Treatment and Prophylaxis of Respiratory Syncytial Virus Derived from B Cells of Infected Patients. J. Immunol.
183: 6338-6345
[Abstract][Full Text]
Musiyenko, A., Correa, L., Stock, N., Hutchinson, J. H., Lorrain, D. S., Bain, G., Evans, J. F., Barik, S.
(2009). A Novel 5-Lipoxygenase-Activating Protein Inhibitor, AM679, Reduces Inflammation in the Respiratory Syncytial Virus-Infected Mouse Eye. CVI
16: 1654-1659
[Abstract][Full Text]
Alvarez, R., Elbashir, S., Borland, T., Toudjarska, I., Hadwiger, P., John, M., Roehl, I., Morskaya, S. S., Martinello, R., Kahn, J., Van Ranst, M., Tripp, R. A., DeVincenzo, J. P., Pandey, R., Maier, M., Nechev, L., Manoharan, M., Kotelianski, V., Meyers, R.
(2009). RNA Interference-Mediated Silencing of the Respiratory Syncytial Virus Nucleocapsid Defines a Potent Antiviral Strategy. Antimicrob. Agents Chemother.
53: 3952-3962
[Abstract][Full Text]
Groskreutz, D. J., Monick, M. M., Babor, E. C., Nyunoya, T., Varga, S. M., Look, D. C., Hunninghake, G. W.
(2009). Cigarette Smoke Alters Respiratory Syncytial Virus-Induced Apoptosis and Replication. Am. J. Respir. Cell Mol. Bio.
41: 189-198
[Abstract][Full Text]
Lukens, M. V., Kruijsen, D., Coenjaerts, F. E. J., Kimpen, J. L. L., van Bleek, G. M.
(2009). Respiratory Syncytial Virus-Induced Activation and Migration of Respiratory Dendritic Cells and Subsequent Antigen Presentation in the Lung-Draining Lymph Node. J. Virol.
83: 7235-7243
[Abstract][Full Text]
Chen, L., Song, W., Davis, I. C., Shrestha, K., Schwiebert, E., Sullender, W. M., Matalon, S.
(2009). Inhibition of Na+ Transport in Lung Epithelial Cells by Respiratory Syncytial Virus Infection. Am. J. Respir. Cell Mol. Bio.
40: 588-600
[Abstract][Full Text]
Walsh, E. E., Peterson, D. R., Falsey, A. R.
(2008). Human Metapneumovirus Infections in Adults: Another Piece of the Puzzle. Arch Intern Med
168: 2489-2496
[Abstract][Full Text]
Castro, S. M., Kolli, D., Guerrero-Plata, A., Garofalo, R. P., Casola, A.
(2008). Cigarette Smoke Condensate Enhances Respiratory Syncytial Virus-Induced Chemokine Release by Modulating NF-kappa B and Interferon Regulatory Factor Activation. Toxicol Sci
106: 509-518
[Abstract][Full Text]
Olson, M. R., Hartwig, S. M., Varga, S. M.
(2008). The Number of Respiratory Syncytial Virus (RSV)-Specific Memory CD8 T Cells in the Lung Is Critical for Their Ability to Inhibit RSV Vaccine-Enhanced Pulmonary Eosinophilia. J. Immunol.
181: 7958-7968
[Abstract][Full Text]
Sethi, S., Murphy, T. F.
(2008). Infection in the Pathogenesis and Course of Chronic Obstructive Pulmonary Disease. NEJM
359: 2355-2365
[Full Text]
Seemungal, T., Sykes, A., and the ICEAD Contributors,
(2008). Recent advances in exacerbations of COPD. Thorax
63: 850-852
[Full Text]
Munir, S., Le Nouen, C., Luongo, C., Buchholz, U. J., Collins, P. L., Bukreyev, A.
(2008). Nonstructural Proteins 1 and 2 of Respiratory Syncytial Virus Suppress Maturation of Human Dendritic Cells. J. Virol.
82: 8780-8796
[Abstract][Full Text]
Li, D., Jans, D. A., Bardin, P. G., Meanger, J., Mills, J., Ghildyal, R.
(2008). Association of Respiratory Syncytial Virus M Protein with Viral Nucleocapsids Is Mediated by the M2-1 Protein. J. Virol.
82: 8863-8870
[Abstract][Full Text]
Kota, S., Sabbah, A., Chang, T. H., Harnack, R., Xiang, Y., Meng, X., Bose, S.
(2008). Role of Human {beta}-Defensin-2 during Tumor Necrosis Factor-{alpha}/NF-{kappa}B-mediated Innate Antiviral Response against Human Respiratory Syncytial Virus. J. Biol. Chem.
283: 22417-22429
[Abstract][Full Text]
Hui, D S, Woo, J, Hui, E, Foo, A, Ip, M, To, K-W, Cheuk, E S C, Lam, W-Y, Sham, A, Chan, P K S
(2008). Influenza-like illness in residential care homes: a study of the incidence, aetiological agents, natural history and health resource utilisation. Thorax
63: 690-697
[Abstract][Full Text]
Mohapatra, S. S., Boyapalle, S.
(2008). Epidemiologic, Experimental, and Clinical Links between Respiratory Syncytial Virus Infection and Asthma. Clin. Microbiol. Rev.
21: 495-504
[Abstract][Full Text]
Sandrock, C., Stollenwerk, N.
(2008). Acute Febrile Respiratory Illness in the ICU: Reducing Disease Transmission. Chest
133: 1221-1231
[Abstract][Full Text]
Tregoning, J. S., Yamaguchi, Y., Harker, J., Wang, B., Openshaw, P. J. M.
(2008). The Role of T Cells in the Enhancement of Respiratory Syncytial Virus Infection Severity during Adult Reinfection of Neonatally Sensitized Mice. J. Virol.
82: 4115-4124
[Abstract][Full Text]
Nichols, W. G., Peck Campbell, A. J., Boeckh, M.
(2008). Respiratory Viruses Other than Influenza Virus: Impact and Therapeutic Advances. Clin. Microbiol. Rev.
21: 274-290
[Abstract][Full Text]
Ward, T. M., Traina-Dorge, V., Davis, K. A., Gray, W. L.
(2008). Recombinant simian varicella viruses expressing respiratory syncytial virus antigens are immunogenic. J. Gen. Virol.
89: 741-750
[Abstract][Full Text]
Elliot, A. J., Cross, K. W., Fleming, D. M.
(2008). Acute respiratory infections and winter pressures on hospital admissions in England and Wales 1990-2005. J Public Health (Oxf)
30: 91-98
[Abstract][Full Text]
Collins, P. L., Graham, B. S.
(2008). Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis. J. Virol.
82: 2040-2055
[Full Text]
Castilow, E. M., Olson, M. R., Meyerholz, D. K., Varga, S. M.
(2008). Differential Role of Gamma Interferon in Inhibiting Pulmonary Eosinophilia and Exacerbating Systemic Disease in Fusion Protein-Immunized Mice Undergoing Challenge Infection with Respiratory Syncytial Virus. J. Virol.
82: 2196-2207
[Abstract][Full Text]
Castilow, E. M., Meyerholz, D. K., Varga, S. M.
(2008). IL-13 Is Required for Eosinophil Entry into the Lung during Respiratory Syncytial Virus Vaccine-Enhanced Disease. J. Immunol.
180: 2376-2384
[Abstract][Full Text]
Pletneva, L. M., Haller, O., Porter, D. D., Prince, G. A., Blanco, J. C. G.
(2008). Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats. J. Gen. Virol.
89: 261-270
[Abstract][Full Text]
Jansen, A. G. S. C., Sanders, E. A. M., Hoes, A. W., van Loon, A. M., Hak, E.
(2007). Influenza- and respiratory syncytial virus-associated mortality and hospitalisations. Eur Respir J
30: 1158-1166
[Abstract][Full Text]
Treanor, J. D.
(2007). Influenza -- The Goal of Control. NEJM
357: 1439-1441
[Full Text]
Peebles, R. S. Jr., Moore, M. L.
(2007). A Mechanistic Advance in Understanding RSV Pathogenesis, but Still a Long Way from Therapy. Am. J. Respir. Cell Mol. Bio.
37: 375-377
[Full Text]
Anzueto, A., Sethi, S., Martinez, F. J.
(2007). Exacerbations of Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc
4: 554-564
[Abstract][Full Text]
Davis, I. C., Lazarowski, E. R., Chen, F.-P., Hickman-Davis, J. M., Sullender, W. M., Matalon, S.
(2007). Post-Infection A77-1726 Blocks Pathophysiologic Sequelae of Respiratory Syncytial Virus Infection. Am. J. Respir. Cell Mol. Bio.
37: 379-386
[Abstract][Full Text]
Liu, B., Kimura, Y.
(2007). Local immune response to respiratory syncytial virus infection is diminished in senescence-accelerated mice. J. Gen. Virol.
88: 2552-2558
[Abstract][Full Text]
Chapman, J., Abbott, E., Alber, D. G., Baxter, R. C., Bithell, S. K., Henderson, E. A., Carter, M. C., Chambers, P., Chubb, A., Cockerill, G. S., Collins, P. L., Dowdell, V. C. L., Keegan, S. J., Kelsey, R. D., Lockyer, M. J., Luongo, C., Najarro, P., Pickles, R. J., Simmonds, M., Taylor, D., Tyms, S., Wilson, L. J., Powell, K. L.
(2007). RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication. Antimicrob. Agents Chemother.
51: 3346-3353
[Abstract][Full Text]
Davis, I. C., Xu, A., Gao, Z., Hickman-Davis, J. M., Factor, P., Sullender, W. M., Matalon, S.
(2007). Respiratory syncytial virus induces insensitivity to beta-adrenergic agonists in mouse lung epithelium in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol.
293: L281-L289
[Abstract][Full Text]
Hall, C. B.
(2007). Therapy for Bronchiolitis: When Some Become None. NEJM
357: 402-404
[Full Text]
Min, D., Panoskaltsis-Mortari, A., Kuro-o, M., Hollander, G. A., Blazar, B. R., Weinberg, K. I.
(2007). Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood
109: 2529-2537
[Abstract][Full Text]
Martinez, I., Lombardia, L., Garcia-Barreno, B., Dominguez, O., Melero, J. A.
(2007). Distinct gene subsets are induced at different time points after human respiratory syncytial virus infection of A549 cells. J. Gen. Virol.
88: 570-581
[Abstract][Full Text]
Wedzicha, J A, Hurst, J R
(2007). Chronic obstructive pulmonary disease exacerbation and risk of pulmonary embolism. Thorax
62: 103-104
[Full Text]
Wang, H., Peters, N., Schwarze, J.
(2006). Plasmacytoid Dendritic Cells Limit Viral Replication, Pulmonary Inflammation, and Airway Hyperresponsiveness in Respiratory Syncytial Virus Infection. J. Immunol.
177: 6263-6270
[Abstract][Full Text]
Lorber, B.
(2006). Update in infectious diseases.. ANN INTERN MED
145: 354-360
[Full Text]
Wang, H., Peters, N., Laza-Stanca, V., Nawroly, N., Johnston, S. L., Schwarze, J.
(2006). Local CD11c+ MHC Class II- Precursors Generate Lung Dendritic Cells during Respiratory Viral Infection, but Are Depleted in the Process. J. Immunol.
177: 2536-2542
[Abstract][Full Text]
Martin, D., Calder, L. J., Garcia-Barreno, B., Skehel, J. J., Melero, J. A.
(2006). Sequence elements of the fusion peptide of human respiratory syncytial virus fusion protein required for activity. J. Gen. Virol.
87: 1649-1658
[Abstract][Full Text]
Smit, J. J., Rudd, B. D., Lukacs, N. W.
(2006). Plasmacytoid dendritic cells inhibit pulmonary immunopathology and promote clearance of respiratory syncytial virus. JEM
203: 1153-1159
[Abstract][Full Text]
Douville, R. N., Bastien, N., Li, Y., Pochard, P., Simons, F. E. R., HayGlass, K. T.
(2006). Human Metapneumovirus Elicits Weak IFN-{gamma} Memory Responses Compared with Respiratory Syncytial Virus. J. Immunol.
176: 5848-5855
[Abstract][Full Text]
Chi, B., Dickensheets, H. L., Spann, K. M., Alston, M. A., Luongo, C., Dumoutier, L., Huang, J., Renauld, J.-C., Kotenko, S. V., Roederer, M., Beeler, J. A., Donnelly, R. P., Collins, P. L., Rabin, R. L.
(2006). Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus.. J. Virol.
80: 5032-5040
[Abstract][Full Text]
Williams, O. W., Sharafkhaneh, A., Kim, V., Dickey, B. F., Evans, C. M.
(2006). Airway Mucus: From Production to Secretion. Am. J. Respir. Cell Mol. Bio.
34: 527-536
[Abstract][Full Text]
Wilkinson, T. M. A., Donaldson, G. C., Johnston, S. L., Openshaw, P. J. M., Wedzicha, J. A.
(2006). Respiratory Syncytial Virus, Airway Inflammation, and FEV1 Decline in Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med.
173: 871-876
[Abstract][Full Text]
Glezen, W P., Simonsen, L.
(2006). Commentary: Benefits of influenza vaccine in US elderly--new studies raise questions. Int J Epidemiol
35: 352-353
[Full Text]
Borek, A. P., Clemens, S. H., Gaskins, V. K., Aird, D. Z., Valsamakis, A.
(2006). Respiratory Syncytial Virus Detection by Remel Xpect, Binax Now RSV, Direct Immunofluorescent Staining, and Tissue Culture.. J. Clin. Microbiol.
44: 1105-1107
[Abstract][Full Text]
Sapey, E, Stockley, R A
(2006). COPD exacerbations {middle dot} 2: Aetiology.. Thorax
61: 250-258
[Abstract][Full Text]
Harcourt, J., Alvarez, R., Jones, L. P., Henderson, C., Anderson, L. J., Tripp, R. A.
(2006). Respiratory Syncytial Virus G Protein and G Protein CX3C Motif Adversely Affect CX3CR1+ T Cell Responses. J. Immunol.
176: 1600-1608
[Abstract][Full Text]
Rudd, B. D., Smit, J. J., Flavell, R. A., Alexopoulou, L., Schaller, M. A., Gruber, A., Berlin, A. A., Lukacs, N. W.
(2006). Deletion of TLR3 Alters the Pulmonary Immune Environment and Mucus Production during Respiratory Syncytial Virus Infection. J. Immunol.
176: 1937-1942
[Abstract][Full Text]
Trento, A., Viegas, M., Galiano, M., Videla, C., Carballal, G., Mistchenko, A. S., Melero, J. A.
(2006). Natural History of Human Respiratory Syncytial Virus Inferred from Phylogenetic Analysis of the Attachment (G) Glycoprotein with a 60-Nucleotide Duplication. J. Virol.
80: 975-984
[Abstract][Full Text]
Fry, A. M., Shay, D. K., Holman, R. C., Curns, A. T., Anderson, L. J.
(2005). Trends in Hospitalizations for Pneumonia Among Persons Aged 65 Years or Older in the United States, 1988-2002. JAMA
294: 2712-2719
[Abstract][Full Text]
de Bree, G. J., van Leeuwen, E. M.M., Out, T. A., Jansen, H. M., Jonkers, R. E., van Lier, R. A.W.
(2005). Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung. JEM
202: 1433-1442
[Abstract][Full Text]
Gorelick, K. J., Simonsen, L., Viboud, C., Falsey, A. R., Walsh, E. E.
(2005). Respiratory Syncytial Virus Infection in Elderly Adults. NEJM
353: 422-423
[Full Text]
(2005). RSV: An Important Pathogen in Elderly and High-Risk Adults. JWatch Infect. Diseases
2005: 1-1
[Full Text]
(2005). RSV Infection Is Common in Older Adults. JWatch General
2005: 5-5
[Full Text]
Sethi, S., Murphy, T. F.
(2005). RSV Infection -- Not for Kids Only. NEJM
352: 1810-1812
[Full Text]
65 years of age) and high-risk adults (those with chronic heart or lung disease) and in patients hospitalized with acute cardiopulmonary conditions. RSV infection and influenza A were diagnosed on the basis of culture, reverse-transcriptase polymerase chain reaction, and serologic studies. 
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