An update on respiratory syncytial virus epidemiology: a developed country perspective

Transcription

1 Vol. 96 (2002) (SUPPLEMENT B), S1^S7 An update on respiratory syncytial virus epidemiology: a developed country perspective B. J. LAW, 1 X.CARBONELL-ESTRANY 2 AND E.A.F.SIMOES 3 1 Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada; 2 Hospital Clinic, Institute Clinic de Ginecologia, Obstetricia Neonatologia, Barcelona, Spain; 3 Department of Pediatrics, Section of Infectious Diseases, The University of Colorado School of Medicine and The Children s Hospital, Denver, CO, U.S.A. Abstract Respiratory syncytialvirus (RSV) is a leading cause of lower respiratory tractinfectionsin infants and young children worldwide, and animportantcause of morbidity, hospitalization, and mortality.theinfections caused by RSVare seasonal, peaking predictably in the winter months in temperate climates, and in the hottest months and the rainy season intropicalclimates.theinvolvementofthelower respiratory tract, manifestclinically as bronchiolitis or pneumonia, is the hallmark of severe RSVdisease.Other indicators of severe disease include requirement for, and duration of, hospitalization, supplemental oxygen, managementin anintensive care setting, and mechanicalventilation.host-related risk factors for severe RSVdiseaseinclude pretermbirth, infection before 6 months of age, chroniclung disease, and congenitalheart disease. Environmental risk factors for severe RSV infection include poverty, crowding, exposure to tobacco smoke, and malnutrition.factors thatincrease frequency oftheinfectioninclude youngage, multiple gestation, familyhistoryof atopy, lack of parental education, household crowding, older school-age siblings, lack of breast feeding, day-care attendance, passive smoke exposure, and discharge from a neonatal intensive care unit between September and December.Recent studies in Europe, North America and Japan have evaluated the number of children affected as well as the medical resources necessary to care for these children.continuing surveillance is the key to tracking the seasonality, risk factors, morbidity and mortality associated with RSV infection. Epidemiological studies are also the basis for development of appropriate local prevention strategies. r 2002 Elsevier Science Ltd doi: /rmed , available online at on Keywords lower respiratory tract infection; prematurity; palivizumab; prophylaxis; respiratory syncytial virus; epidemiology. INTRODUCTION Nearly all children become infected with respiratory syncytial virus (RSV) and over half experience their primary infection before their rst birthday (1).This virus is a leading cause of both morbidity and mortality in infants and young children, with disease severity dependent on the presence of associated medical and social risk factors. It is implicated in many cases of lower respiratory tract infection (LRTI) in young children, and may manifest as bronchiolitis, pneumonia, or both. Premature infants and infants with underlying cardiopulmonary or immune de ciency disease are at a higher risk of LRTI, hospitalization, risk of respiratory failure and mechanical ventilation. Correspondence should be addressed to: X.Carbonell-Estrany Sabino Arana No Barcelona, Spain. Fax: xcarbone@medicina.ub.es The infection caused by RSV is a seasonal disease. The onset, peak, duration, and severity of the RSV season vary somewhat from country to country and from year to year. In temperate climates, RSV activity typically peaks during the winter months, although the actual peak of the season may vary by region (2,3). In tropical climates, RSV tends to peak during the rainy season and in the hottest months (4). Regional surveillance studies are thus an important source of information, both for discerning the patterns of infection and for identifying the patient populations who are at greatest risk of severe RSVdisease. One of the ultimate goals in RSV epidemiology research is to facilitate the creation of guidelines for appropriate use of prophylaxis during seasonal epidemics. Epidemiological studies are the key to understanding regional patterns of RSV infection.these studies also serve to identify the host and environmental risk factors for RSVdisease, allowing physicians to determine which subgroups may require prophylaxis or medical attention for

2 S2 RESPIRATORY MEDICINE severe RSVdisease.This review will focus on the risk factors for severe RSV infection and identify the paediatric populations most at risk. The most recent global epidemiological studies will be reviewed in order to evaluate patterns of infection worldwide. INDICATORS OF SEVERE RSV DISEASE Throughout life, RSV infections recur frequently with clinical symptoms and signs ranging from mild to severe. The level of involvement in the respiratory tractffrom upper to lowerfis a key indicator of severe RSVdisease. Mild to moderate infection, presenting with symptoms such as runny nose and sore throat with or without fever, remains localized in the upper respiratory tract. However, involvement of the lower respiratory tract, characterized clinically as bronchiolitis, bronchopneumonia or pneumonia, is evidence of severe RSV disease. Other measures of severe disease include the need for and duration of hospitalization, supplemental oxygen, management in an intensive care setting and mechanical ventilation. Mortality is the ultimate measure of severe disease. RISK FACTORS FOR SEVERE RSV DISEASE Premature infants have been proven to be at an increased risk of severe RSVdisease by all indicators noted above. In a study by Cunningham et al., infants born at o32 weeks gestation were hospitalized for respiratory illness14 times more often than full-term infants (36% vs. 2.5%, Po0?001)(5). Infants born at o37 weeks gestation had a higher incidence of intensive care unit (ICU) admission (25?0% vs. 7?3%), mechanical ventilation (18?2% vs. 3?2%) and death (3?4% vs. 0%) than those with no known risk factors (6). Several anatomic factors predispose preterm infants to lower respiratory tract disease.these include smaller airway diameter and lack of maternal neutralizing antibodies, which are transferred in the nal stages of pregnancy. Respiratory tract infections are the major cause of rehospitalization of preterm infants after discharge home from their birth hospital and RSV is the major cause of LRTI in infants and children (5). Although the incidence of preterm birth ranges from 5 to15% in developed and developing countries worldwide, such infants account for a quarter to a third of all hospital admissions for RSVdisease (7^9).The reported incidence of RSV-associated hospitalization in preterm infants ranges from 10 to 20% with the highest rates occurring in those with underlying lung disease (10,11). In a study by Stevens et al., 16?8% of infants requiring respiratory support beyond 36 weeks of post-conceptual age were hospitalized for RSV LRTI compared with 6?2% of infants on respiratory support up to 36 weeks post-conceptual age, a 2?5-fold increase (Po0?001) (12). They also found that prematurity contributed to the need for hospitalization in RSV illness. Studies have found that these infants require ICU admission, supplemental oxygen, and mechanical ventilation much more frequently than full-term infants (Po0?001) (8,9,13,14). In addition to prematurity, very young age, congenital heart disease and congenital lung abnormalities are risk factors for severe RSV disease (15). Underlying causes of congenital lung abnormalities such as cystic brosis, recurrent aspiration pneumonia, pulmonary malformations, neurogenic disorders and tracheo-oesophageal stula all predispose children to severe RSVdisease (16). Environmental factors such as poverty, crowding, exposure to tobacco smoke, and malnutrition increase the risk of both developing RSV disease and the risk for severe disease. Discharge from the neonatal ICU between September and December can increase the likelihood of infection and rehospitalization. Other associated factors, such as day-care center attendance, multiple birth, older school-age siblings, and crowding in the home may also increase the risk of RSV illness. WORLDWIDE RSV EPIDEMIOLOGY UPDATE Europe Belgium and The Netherlands A retrospective analysis of data from the weekly epidemiologic surveillance of acute respiratory infections (ARI) and in uenza was conducted in Belgium from 1998 though 2000 (2). The incidence of ARI tracked closely with the RSV season, with the majority of infections occurring from late autumn through early spring. During the 2000 ^2001 season, RSV was responsible for the majority of acute respiratory infections, accounting for 62% of all illnesses reported in children o5 years of age, and 78% of all illnesses in infants. At the peak of the season, RSV was responsible for about 90% of the acute ARIs in infants, and 80% throughout the season. Although such surveillance programmes provide valuable information regarding pathogen epidemiology, the observed predominance of RSV may be subject to selection bias, in that the surveillance is passive. The Sentinel System of the Dutch Working Group for Clinical Virology has collected virological data from 17 virology laboratories for more than 10 years. Hospitals submit 94% of the RSVdata, while the remaining 6% originate from general practitioners o ces and clinics; 96% of the diagnoses of RSV infection occur in children under 5 years of age, and 57% are male. These data are posted on the internet every 4 weeks, enabling physicians to track RSV and other viral and bacterial infection activity in The Netherlands (17). Over the last few seasons, the

3 UPDATE ON RSV EPIDEMIOLOGY S3 RSV epidemic has occurred progressively later into the winter. However, this may be a gradual return to the usual pattern, as the 1998 ^1999 epidemic occurred earlier than the mean for the10-year period (Figure1).These data are important in determining when to initiate prophylaxis to ensure children are protected when RSV activity is high in the community. In a retrospective study, data were collected to estimate the incidence of RSV-related hospitalization in 29 hospitals located in the southwest region of The Netherlands between 1996 and 1999 (18). Data on RSV-positive tests were collected from virological laboratories and patient characteristics were documented. Nosocomial infections were excluded, and there was no correction for children who were not tested for RSV. The incidence of RSV-related hospitalization during the respiratory season for children with a gestational age o32 weeks was 7?2%, 3?6% in children with a gestational age of 32^ 36 weeks, and 1.5% in children with gestational age of 37 weeks or more. Retrospective analyses such as this underestimate the actual hospitalization rate for RSV because data are often incomplete. Nevertheless, it does permit comparison of the relative rates between the groups studied. United Kingdom Hospital admissions for high-risk infants and the e ect prophylaxis might have had on these infants were studied during the 1998^1999 and 1999^2000 RSV seasons in northern England (19). High-risk infants were de ned as those under o6 months of age, born prior to 36 weeks gestation, not requiring oxygen at home (group1, n=519); or those infants and children o24 months of age who required oxygen at home (group 2, n=137).there were10?4 hospital admissions per 100 at-risk infants over the 2 years studied. More group 2 infants required hospital admission; the odds ratio for readmissions was 9?2 for group 2 (38%) compared with group 1 (6%). It was estimated that if all of the high-risk infants had been given prophylaxis, a potential cost savings of ƒ to ƒ could have been realized over 2 years. In another study, the morbidity and mortality from RSV, as well as the cost-e ectiveness of prophylaxis, was investigated over three RSV seasons in 82 preterm infants discharged from a regional neonatal unit (20). Information on hospital admissions for respiratory illness during the rst 2 years of life was obtained from hospital records, referring hospitals and general practitioners. There were no deaths from RSV disease in this study. In the rst season, the hospitalization rate for RSV LRTI was 4%, all occurring in infants with chronic lung disease (CLD). No children were hospitalized for RSV in the second or third season, con rming earlier reports that frequency of RSV LRTI and RSV hospitalization decreases with increasing age (21). They compared the actual cost of the LRTI hospitalizations with the potential cost of prophylaxis for these infants with palivizumab and concluded that prophylaxis would have only been cost-e ective for infants o2 years of age given oxygen at home. However, treatment expenses were not included in the hospitalization cost estimates, and prophylaxis costs were based on six injections per patient, contrary to labelling recommendations. These factors may have contributed to their ndings. Although usage guidelines have been published for palivizumab, the National Health Service felt there were insu cient data available to support its use. A study was conducted in the U.K. to evaluate the use of healthcare resources and associated costs of treatment of RSV infection in infants born at o32 weeks gestational age with CLD (22). Incidence of admission for RSV disease FIGURE 1. RSV epidemic activity inthe Netherlands. Data collected by and presented with permission from the Sentinel System of the Dutch Working Group for Clinical Virology. Cases were recorded in the week in which test results became available, which may be delayed up to 2 weeks from actual case presentation.

4 S4 RESPIRATORY MEDICINE was collected in children o2 years of age between1july 1994 and 30 June Of all neonates born at o32 weeks gestation who were screened, 22% had CLD, and 19% of these were hospitalized at least once for proven RSV disease during the rst 2 years of life; 45 children were admitted 242 times. Children with proven RSV disease had longer stays in wards and paediatric ICUs than those without RSV disease. The primary care and hospital costs associated with RSV morbidity were ve times higher in infants admitted at least once for RSV infection than for infants with other or no admissions. The low rates of hospital admission in the second study are in contrast to those reported in the rst and third studies. The small size of the population evaluated in this study may have contributed to this discrepancy. Spain The Infeccio n Respiratoria Infantil por Virus Respiratorio Sincitial (IRIS) Study Group prospectively followed premature infants born at r 32 weeks gestational age in Spain over two consecutive seasons, 1998 ^1999 and 1999^2000 (3).The availability of prophylaxis was limited during the time of these studies, minimizing any bias that might be introduced if certain infants had received protection. Hospitalization for RSV disease occurred throughout the season, peaking in January (Figure 2). Admissions to ICUs paralleled hospital admissions.the incidence of hospitalization in RSV-positive children was 13?4% in the 1998^1999 season, and13?1% in the 1999^ 2000 season. Infants born at 29^32 week s gestation without CLD composed a major portion of the study population both seasons (78% [456/584] and 83% [827/ 999], respectively). Hospitalization rates in this subgroup were10?1% and12?9% in the two seasons, illustrating that infants born at between 29 and 32 weeks gestation are at substantial risk for severe RSVdisease. Hospitalization for more than one episode of RSV illness in the same Hospitalizations % % Oct NovDecJanFebMarApr ICU Admissions Oct NovDecJanFebMarApr FIGURE 2. Seasonal frequency of RSV infection.rsvactivity is seasonal, with year to year variations in activity. Hospital admissions for RSV infection peaked in January in Spain in both 1999 and2000(3).however,the2000seasonwasbroaderand atter than the previous year. child occurred frequently in both seasons (11% and 8%, respectively), suggesting the need for prophylaxis throughout the RSV season. In a multivariate logistic regression analysis, signi cant independent prognostic variables for risk of hospitalization for RSV illness included low gestational age, CLD, age o3 months at the start of the RSV season, co-habitation with school-age siblings, and exposure to tobacco smoke. The importance of targeting high-risk populations for RSV prophylaxis was underscored, particularly in areas where nancial resources are limited. Italy Two epidemiology studies were recently reported from Italy.The RADAR Study group, made up from 32 centres throughout Italy, collected data on all children o2 years of age hospitalized for LRTI between November1999 and April 2000 (23). Of the 1232 children enrolled, 14% had birth weights less than 2500 g, while in the general population, the incidence is only 6%. Likewise, 8?5% of the children studied were born prematurely (o36 weeks gestational age), compared with 4?0% in the general population. A total of 42% of the infants and children with LRTI were RSV-positive. The highest prevalence occurred in February, when 52% of the admissions were RSV-positive. Children with RSV LRTI su ered more severe respiratory impairment, with higher respiratory rates, lower SpO 2,andmoredaysonoxygentherapy than children with non-rsv LRTI. Risk factors identi ed for RSVadmission included smoke exposure and birth order, where a signi cantly higher proportion of infants were RSV-positive if they were the sixth or later child born into a family, compared with those born rst, second or third (83?3% vs.48.3%,po0?05). The Osservatorio RSV study collected epidemiology data on RSV infections in children o4 years of age seen for respiratory infections at eight paediatric centres distributed throughout Italy and posted it weekly on a website, (24). The characteristics of the 272 subjects enrolled were as follows: 9% had gestational age o36 weeks, 11?3% had birth weight o2500g, 17?3% had bronchopulmonary dysplasia (BPD), 24?3% had a history of prior RSV infection, 50?7% had been exposed to smoke, 48?2% hadreceived steroids and/or b 2 -agonistsin the previous 3 months, and 40?2% had been hospitalized. Subjects were enrolled between October 2000 and April 2001, of whom 30?5% (83/272) had at least one sample (nasal and/or pharyngeal) test positive for RSV. RSV-positive patients accounted for 42?6% of hospitalizations and only 23?4% of non-hospitalized cases. Only 9% of the study population were born prematurely (o36 weeks gestation), but accounted for 71?4% of RSV-positive hospitalizations. RSV disease and prematurity were identi ed as risk factors for hospitalization.

5 UPDATE ON RSV EPIDEMIOLOGY S5 North America Canada The Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) has conducted numerous studies examining the risk factors and outcomes of children with RSV-associated LRTI. A secondary analysis of 159 children with underlying lung disease and enrolled as part of a prospective cohort study of children hospitalized with RSV LRTI during the 1993^1994 and 1994^ 1995 RSV seasons was recently published (16). Morbidity was evaluated by comparing measures such as duration of hospital or ICU stay and need for ventilation among children with BPD, CLD of prematurity, cystic brosis, recurrent aspiration pneumonia, pulmonary malformations, neurogenic disorders, tracheo-oesophageal stula and other diseases. The median length of hospital stay was not signi cantly di erent between children with these various disorders and was comparable with that observed in preterm infants with CLD. No di erences were notedin the number of ICU admissions or the number of patients requiring ventilation. Infants and children with underlying lung conditions, particularly recurrent aspiration pneumonia and malformations, experienced as much morbidity as those with CLD of prematurity. Children requiring supplemental oxygen at home developed more severe disease. United States of America A 19-year retrospective analysis of multiple cause-ofdeath data reported that 1806 bronchiolitis-associated deaths between 1979 and 1997 occurred among children under 5 years of age in the U.S.A. (mean 95 annually, range 66 ^127) (25). Signi cantly more deaths occurred among children who were under1 year of age, compared with those who were 1^ 4 years of age (P=0?02). These deaths occurred from November through April, peaking in January of each year, with no overall trend towards an increase or decrease in deaths from 1979 to The authors projected that there were between 171 and 510 RSV-associated deaths annually during the study period, fewer than previously estimated. This may be an underestimate, since in a U.S. study of RSV pneumonia, estimates varied from 100 to 180 deaths per year from pneumonia alone (26). Another retrospective study of U.S. National Hospital discharge survey data found that hospitalization rates increased signi cantly for infants with bronchiolitis, from 5?4% in 1980 to 16?4% in 1996 (Po0?001) (27).The most dramatic increases occurred among infants less than 6 months of age. The hospitalizations were seasonal, occurring between November and April, peaking in January or February of each year. It was estimated that between and infant hospitalizations were attributable to RSV. A retrospective cohort study of children under 3 years of age enrolled in the Tennessee Medicaid programme included both high-risk and normal healthy children (28). The study used records from 1 July 1989 to 30 June Children were grouped according to whether they had BPD, congenital heart disease, prematurity, or other complicating conditions; if they had none of these conditions, they were placed in a low-risk group. Children in the rst year of life and those with BPD, congenital heart disease, or prematurity were at the highest risk of the RSV-associated hospitalization. The incidence of the RSV-associated hospitalization in each risk group decreased with increasing age. The strongest independent risk factor for RSV-associated hospitalization was BPD. Being born in close proximity to the RSV season and having one or more siblings were additional important risk factors for infants under1year of age. Approximately half of all hospitalizations occurred in healthy, full-term children. The use of RSV prophylaxis with palivizumab was projected to be most bene cial during the rst year of life. Using discharge records from the U.S. National Inpatient Sample from the Healthcare Cost and Utilization Project, hospital stay, mortality, and associated costs were calculated for children 4 years of age and younger who had RSV-pneumonia (ICD-9CM code 480.1)(26). Cases of RSV pneumonia increased from in1993 to in1995.over 70% of these were in children o1year of age.there were approximately100, 180, and 100 RSV pneumonia-associated deaths in 1993, 1994, and 1995, respectively. Inpatient charges for RSV disease were estimated to be between $300 and $400 million per year in the U.S.A., emphasizing the high burden RSV disease places on both morbidity and economic costs. A study of 1029 consecutive infants born at up to 32 weeks gestational age was performed in a 12-county neonatal network in Rochester, New York (12). Patients were recruited over the ve RSV seasons between 1992 and1996.the average length of stay was 5?9 days,and the average hospital charge was $9431. This study found that lower gestational age and requirement for respiratory support in infants over 36 weeks postconceptual age were correlated with higher hospitalization rates, longer hospital stays, and higher hospital charges. In children with chronic lung disease, the hospitalization rates were 2?5 times higher than those without chronic lung disease. Childrenwithchroniclungdiseasehadlongeroverall lengths of stay and increased overall hospital charges. Although this study did not nd that global prophylaxis was less costly than hospital charges, it did conclude that the most premature infants and those infants who required prolonged respiratory support would be the best candidates for RSV prophylaxis.

6 S6 RESPIRATORY MEDICINE Japan A recent study examined the records of 535 children in Japan who were under 3 years of age and hospitalized at Shizuoka Red Cross Hospital between 1 July 1997 and 30 June 2000 with LRTI (29). Data were collected on patient age, gender, and risk factors for RSV illness such as congenital heart disease, BPD, or prematurity. They reported that 31?4% (168 of 535) of children had RSV infection. Over the 3-year period, the incidence of LRTI increased dramatically in the winter months, peaking in December. The number of LRTIs was strongly associated with the RSV epidemic (Po0?0001). The majority of these children (94%) were previously healthy, although the subpopulation of infants who were less than 6 months of age were signi cantly more likely to be RSV positive (Po0?0001). The authors concluded that RSV prophylaxis was needed, particularly for young infants. IMPLICATIONS OF EPIDEMIOLOGIC DATA FOR PREVENTINGRSV RSVdisease is prevalent among the worldwide paediatric population. Risk factors for severe RSVdisease have been clearlyidenti edinmanystudies.therelativecontribution of these risk factors to morbidity, requirement for hospitalization, and mortality varies by country, however. It will thus continue to be important to conduct surveillance studies in order to identify which paediatric subgroups are most in need of prophylaxis, so that severe disease can be avoided, and its impact on healthcare utilization can be decreased. REFERENCES 1. Glezen WP,Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am JDis Child1986; 140: 543^ Duco re G, Cauchi P, Hendrickx E. Respiratory syncytial virus epidemiologyin Belgium in1998,1999 and Abstract presented at the 5th World Congress of Perinatal Medicine, 23^27 September, 2001, Barcelona, Spain. 3. Carbonell-Estrany X, Quero J, and the IRIS Study Group. RSV hospitalization rates in premature infants born over two consecutive seasons. Pediatr Infect Dis J 2001; 20: 874 ^ CherianT, Simoes EA, Steinho MC, et al. Bronchiolitis in tropical south India. Am J Dis Child1990; 144: 1026^ Cunningham CK, McMillan JA, Gross SJ. Rehospitalization for respiratory illness in infants of less than 32 weeks gestation. Pediatrics 1991; 88: 527^ Wang EEL, Law BJ, Stephens D, and other members of PICNIC. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection.jpediatr1995; 126: 212^ WHO Bulletin OMS:1995; Chapters 2 and 3 (Supplement): Brandenburg AH, Jeannet PY, Steensel-Moll HA, et al. Local variability in respiratory syncytial virus disease severity. Arch Dis Child 1997; 77: 410^ Behrendt CE, Decker MD, Burch DJ, Watson PH. International variation in the management of infants hospitalized with respiratory syncytial virus. International RSV Study Group. Eur J Pediatr 1998; 157: 215^ The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531^ Groothuis, JR, Simoes EAF, Levin MJ, et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993; 329: 1524 ^ StevensTP, Sinkin RA, Hall CB, Maniscalco WM, McConnochie KM. Respiratory syncytial virus and premature infants born at 32 weeks gestation or earlier. Arch Pediatr Adolesc Med 2000; 154: 55^ Navas L, Wang E, de Carvalho V, Robinson J. Improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children.jpediatr1992; 121: 348^ Meert K, Heidermann S, Abella B, Saeniak A. Does prematurity alter the course of respiratory syncytial virus infection? Crit Care Med1990; 18: 1357^ Simoes EAF, Rieger CHL.RSVinfection in developed and developing countries. Infect Med 1999; 16: S11^S Arnold SR, Wang EE, Law BJ, et al.variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease: A review of the PICNIC RSV database. Pediatr Infect Dis J 1999; 18: 866^ Rijksinstituut voor Volksgezondheid en Milieu (National Institute of Public Health and the Environment) Infectieziekten Surveillance Informatie Systeem. Available at: Accessed December 5, Rietveld E, Huysman WA, Steyerberg EW, Polder J, de Groot R, Moll HA. Variability of the incidence of hospitalization caused by infection with Respiratory Syncytial Virus (RSV). Abstract presented at European Society for Paediatric Infectious Diseases, Istanbul,Turkey, March 26^28, Clark SJ, Beresford MW, Subhedar, NV, Shaw, NJ.Respiratory syncytial virus infection in high risk infants and the potential impact of prophylaxis in a United Kingdom cohort. Arch Dis Child 2000; 83: 313 ^ Thomas M, Bedford-Russell A, Sharland M. Hospitalization for RSV infection in ex-preterm infants^implications for use of RSV immune globulin. Arch Dis Child 2000; 83: 122^ Wang EEL, Law BJ, Robinson JL, et al. PICNIC (Pediatric Investigators Collaborative Network on Infections in Canada) study of the role of age and respiratory syncytial virus neutralizing antibody on respiratory syncytial virus illness in patients with underlying heart or lung disease. Pediatrics 1997; 99: e Greenough A, Cox S, Alexander J, et al.healthcareutilisationof infants with chronic lung disease, related to hospitalisation for RSV infection. Arch Dis Child 2001; 85:463^ Lanari M, Giovannini M, Giu re L, et al. Epidemiological survey on Italian infants hospitalized with lower respiratory tract infections: role of respiratory syncytial virus. Abstract presented at the 5th World Congress of Perinatal Medicine, 23^27 September 2001, Barcelona, Spain. 24. Chezzi C and the Investigators study group. Epidemiologic multicenter study on the incidence of RSVrespiratory infections in early childhood in Italy^relationship with hospitalization. Abstract presented at the 5th World Congress of Perinatal Medicine, 23^27 September 2001, Barcelona, Spain. 25.ShayDK,HolmanRC,RooseveltGE,ClarkeMJ,AndersonLJ. Bronchiolitis-associated mortality and estimates of respiratory

7 UPDATE ON RSV EPIDEMIOLOGY S7 syncytial virus-associated deaths among US children, 1979^1997. J Infect Dis 2001; 183: 16 ^ Howard TS, Ho man LH, Stang PE, Simoes EA. Respiratory syncytial virus pneumonia in the hospital setting: length of stay, charges, and mortality.jpediatr2000; 137: 227^ Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980 ^1996.JAMA1999; 282:1440 ^ BoyceTG, Mellen BG, Mitchel EF, et al. Rates of hospitalization for respiratory syncytial virus infection among children in Medicaid. J Pediatr 2000; 137: 865^ Kaneko M, Watanabe J, Kuwahara M, et al. Impact of RSV infection as a cause of lower respiratory tract infection in children younger than 3 years of age in Japan. Abstract presented at the 5th World Congress of Perinatal Medicine, 23^27 September 2001, Barcelona, Spain.