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Respiratory Syncytial Virus Infections in Children and Adults
Journal of Infection (2002) 45: 10±17 doi:10.1053/jinf.2001.1016, available online at http://www.idealibrary.com on
SCIENCE AND CLINICAL PRACTICE
Respiratory Syncytial Virus Infections in Children and Adults C. L. Collins and A. J. Pollard* Department of Paediatrics, University of Oxford, Level 4, John Radcliffe Hospital, Oxford OX3 9DU, U.K. Respiratory syncytial virus is the leading cause of hospital admission for lower respiratory tract infection in young children and appears to be responsible for a significant burden of disease in adults, particularly the elderly and the immunocompromised. In this review, we describe the epidemiology, diagnosis and clinical manifestations of infection attributed to this virus. We also consider current therapeutic and prophylactic options and appraise strategies for # 2002 The British Infection Society vaccination that are in clinical trials.
Introduction Chimpanzee coryza agent was first isolated from an ape suffering from an upper respiratory tract infection in 1956 [1] and was soon renamed respiratory syncytial virus (RSV) on account of its propensity to induce syncytia formation in tissue culture. RSV is an enveloped RNA virus of the family Paramyxoviridae, which also includes measles and mumps virus. The two main groups of RSV, A and B, have several subgroups, which are defined by genetic and antigenic differences. RSV is a hugely successful human pathogen, which is highly transmissible, replicating in the respiratory epithelium, and infecting every human on the planet. The burden of morbidity caused by this virus in the first year of life is well-known and enormous but it is only in the past decade that the impact of RSV infection in later life has been widely appreciated.
Transmission and Immunity As noted above, RSV is highly transmissible and spread via person±person contact or through exposure to contaminated environmental surfaces, with significant implications for infection control within care facilities. Transmission via aerosolised droplets is probably limited as the virus is inactivated in aerosols. Incubation is from a few days to a week. *Please address all correspondence to: Dr A. J. Pollard, Oxford Vaccine Group, Department Paediatrics, Level 4, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU. Tel./Fax: 44 01856 221068; E-mail address: [email protected] (A. J. Pollard). 0163-4453/02/$35.00
Viral replication is greatest and most prolonged in infants and the immunocompromised and viral shedding has been detected in hospitalised infants for up to 21 days. By contrast, adults usually shed virus for as little as 4±5 days and probably not longer than 12 days [2±4]. Although immune responses directed at the virus, or virally infected cells, are known to include humoral and cell mediated mechanisms, natural immunity to RSV is incomplete and reinfection occurs throughout life as demonstrated in a number of epidemiological studies involving infants, families and adults [5,6]. Reinfection is the rule and in one prospective study, which explored acquisition within families, 44% of families with infants became infected with RSV when it was prevalent within the community, and 46% of exposed family members became infected [7]. It appears that both secretory and serum antibodies protect against infection of the respiratory tract and cell mediated responses directed against internal viral proteins appear to terminate infection. In support of the latter individuals with defects in cell mediated immunity have more prolonged viral shedding [8]. However, the high reinfection rates noted above serve to emphasise the failure of this immunity to prevent reinfection, which can be induced within weeks of a primary infection in adults [2]. Ageing may be associated with a defect in the T cell response to RSV, and explain the increased morbidity experienced in this population [9].
Epidemiology RSV causes a significant burden of disease in infants and adults; it is a seasonal virus with peak rates of infection # 2002 The British Infection Society
RSV Infections in Children and Adults in the cold season in temperate climates and the rainy season in tropical areas. Both group A and B RSV circulate concurrently, although group A viruses tend to predominate. There is a seasonal shift in the dominant subgroup of virus, which may explain the propensity for reinfection. The majority of severe RSV infections are in young infants and it is the main respiratory pathogen isolated from those admitted to hospital with pneumonia or bronchiolitis. A geographical variation in clinical presentation of disease has been described in children. The ratio of those presenting with bronchiolitis versus pneumonia in the USA and Europe is 3 : 1 compared with 1 : 3 in the Gambia [10±12]. This may be due to viral factors or nutritional, socio-economic and environmental differences. Half of the infants will be infected with RSV during their first winter. By 2 years of age almost every child will have been infected, with 95% of children seropositive for RSV by 24 months [13]. At this age 50% of infants will have been infected twice. Up to 2% of infants with RSV will require hospital admission, and, of these, one fifth may require respiratory support and 1.5% will die [14]. Risk factors for severe infection in children aged less than 6 months include, prematurity [15], bronchopulmonary dysplasia [16], immunodeficiency [17] and those with underlying cardio-pulmonary disease [18]. Low socio-economic status is associated with a higher attack rate: children from middle income families in North Carolina had a hospitalisation rate of 1/1000 compared with 5±10/1000 in lower-income populations [19]. Some studies have inconclusively associated more severe disease with some strains [20]. Although reinfection is probably common at all ages, significant morbidity is probably very uncommon in young adults. Conversely, it has become increasingly recognised that RSV can be a significant pathogen in elderly adults, particularly those living in residential care, or with underlying cardio-pulmonary disease. Rates of infection in long-term care facilities for the eldely have been estimated at 5±10% per season with mortality as high as 5% of infections [21]. The immunocompromised are also at particular risk of serious infection with the most severe disease observed in bone marrow transplant recipients, for whom mortality rates attributed to RSV pneumonia exceed 70% [21].
Diagnosis Although RSV infection is predominately a self limiting condition, laboratory diagnosis is helpful for hospitalised patient management to reduce unnecessary alternative
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interventions, for infection control and epidemiological monitoring. The principle laboratory methods of RSV diagnosis rely on the detection of virus in respiratory secretions. All of these tests are more sensitive in infants as they shed virus in a higher concentration and for longer duration than adults.
Culture Although culture is highly sensitive and specific in infants and remains the gold standard to which other diagnostic methods are compared, its use is limited by practical problems. RSV is an extremely labile virus and often does not survive transport and culture. RSV grows slowly, often taking over 5 days, further limiting the utility of culture as a diagnostic tool.
Antigen detection Antigen detection in respiratory secretions by immunofluorescence assay (IFA) or enzyme immunoassay (EIA) are most commonly used in infants where the sensitivity varies with methods between 75% and 94% [22]. The rapid turnaround time of these tests allows their use as a clinical diagnostic tool in the acute setting. In adults, viral titres are much lower in nasopharyngeal washings and the sensitivity of this test is likely to be much lower.
Serology Serology is not currently widely used in infants because of the sensitivity of the alternative tests, IFA and EIA. Since these methods are much less sensitive for the diagnosis of lower titre adults disease, serology has been studied more closely, and demonstration of RSV-specific IgM at the time of acute infection or a significant rise in RSV-specific IgG antibodies between acute and convalescent sera appears to be a reasonably sensitive diagnostic method for adult practice, though not widely available or used.
Reverse Transcription-Polymerase Chain Reaction (RT-PCR) RT-PCR allows detection of viral RNA in nasopharyngeal secretion with a 97.5% sensitivity in one study of culture positive infants [23]. It seems likely that such a method would be of particular use in diagnosis of infection in adults.
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Clinical Manifestations RSV most commonly causes upper respiratory tract infection in children, characterised by rhinitis, cough and fever. The virus may also cause croup and otitis media but bronchiolitis and pneumonia associated with RSV are the most common manifestations requiring hospital admission. In hospitalised patients with severe disease there is commonly a history of premature birth, bronchopulmonary dysplasia or congenital heart disease. Lung function tests suggest presence of obstructive small airways disease in two thirds of children, characteristic of bronchiolitis, with the remaining third having a restrictive pattern more suggestive of pneumonia [24]. The presence of tachypnoea, chest wall recession, audible wheeze and difficulty feeding are predictable features of lower respiratory tract infection with RSV, which typically develop several days after onset of rhinitis and cough. Chest radiograph in RSV bronchiolitis reveals hyperinflation with diffuse interstitial markings and peribronchial thickening, and segmental atelectasis may be seen which usually resolves spontaneously. Secondary bacterial infection is probably uncommon in the developed world but may partly explain the increased mortality rate from this infection in resource poor countries (2% vs. 7%) [25]. Respiratory failure and apnoea are the most common life-threatening complications of RSV bronchiolitis in early childhood. Apnoea is usually observed only in infants less than 2 months of age who were born prematurely. Suggested mechanisms include RSV associated hypersensitivity of the laryngeal chemoreceptors and immaturity of the respiratory centres in the brainstem. A number of studies have looked at the association between RSV infection in infancy and the development of asthma in later life and have found an increased risk which is independent from a family history of atopy [26,27]. Although RSV infections in adults have been recognised for decades, it is only recently that the importance of this virus as a cause of significant lower respiratory tract infection has been recognised outside of infancy. RSV is one of the three most commonly identified pathogens in adults with community acquired pneumonia [28] and is especially associated with exacerbations of chronic pulmonary and cardiac disease. The impact of RSV infections on adults in the community has not been fully quantified, Nicholson used statistical modelling and estimated that the impact of RSV may be even greater than that of influenza [29]. Elder adults living in residential care homes appear at particular risk
of RSV infection. In prospective studies, the rates of infection varied between 2% and 12% and the complication rates also varied widely, with the incidence of pneumonia ranging from 0% to 55% and mortality of 0±53% [30,31]. The majority of subjects in the residential care setting had other underlying chronic medical conditions. As noted above, reinfection with RSV is common throughout life and is usually manifest as upper respiratory tract infection. The clinical manifestations are difficult to distinguish from influenzaÐnasal congestion, cough, fever and wheeze were more common in RSV than influenza and myalgia and malaise more common in influenza [28]. RSV infection in the immunocompromised is associated with significant morbidity and mortality in adults and children and is related to the degree of immunosuppression. Those at the highest risk are recipients of bone marrow transplants (BMT) with those infected preengraftment at the highest risk, Harrington et al. [32] reported that 79% of subjects developed pneumonia when infected pre-engraftment vs. 41% when infected post-engraftment. In patients who are severely immunosuppressed through chemotherapy or following BMT mortality is over 50% in those who develop RSV pneumonia.
Treatment RSV infection of the respiratory tract in immunocompetent hosts is usually a self limiting condition and there is no unequivocal evidence that demonstrates that any therapy alone or in combination can reduce duration of hospitalisation in these individuals and there is consequent variation in clinical practice. In infants, hospital admission is advised if there is a supplemental oxygen requirement, recurrent apnoea, impending respiratory failure or an inability to feed. Supportive therapy is required for respiratory failure and the presence of secondary bacterial infection should be considered. Similar supportive measures seem appropriate for adult practice. Ribavirin Ribavarin is a synthetic guanosine nucleoside analogue with antiviral properties, which is administered as an aerosol over several hours a day. A Cochrane review which considered the use of ribavirin for treatment infants with RSV bronchiolitis reported that there was no reduction in mortality or duration of hospitalisation in
RSV Infections in Children and Adults infants who received this therapy [33]. There are no placebo-controlled trials of use of this agent in adults and use of this agent in the immunocompromised patients does not seem to be associated with lower mortality than historical controls [32,34]. Furthermore, there are practical difficulties with administration of the agent and concerns about teratogenic effects for attending hospital personnel, which have led to restriction of use of ribavirin to high risk infants requiring mechanical ventilation. RSV immunoglobulin In a study of 105 children with RSV infection who were randomised to receive RSV immunoglobulin (RSVIG) or placebo there was no significant difference in duration of hospitalisation, duration of intensive care stay, number requiring mechanical ventilation, supplemental oxygen requirement or number of adverse events [35]. As discussed below, RSVIG appears to have some benefit as a prophylactic agent and it seems somewhat counterintuitive that RSVIG has no therapeutic efficacy when given at the time of acute infection. By the time respiratory symptoms are present the virus has already penetrated the respiratory epithelium and RSVIG would probably have little effect, whilst prophylactic administration may prevent cellular penetration and thus development of symptoms [36]. Administration of RSVIG directly to the respiratory mucosa by aerosol in infants with RSV infection appears to be safe but had no benefit in a randomised controlled trial of 65 patients [37,38]. Combination therapy with intravenous ribavirin and RSVIG has been reported in bone marrow transplant recipients, where the mortality was 22% in those treated before the development of respiratory failure and 100% in the untreated group or those only treated within the first 24 h of the development of respiratory failure [39]. Further studies of RSVIG and ribavirin therapy in immunocompromised patients are underway. Other adjunctive therapies A number of studies have addressed the use of adjunctive therapies in RSV infection. A randomised controlled trial of the routine use of antibiotics in infants with bronchiolitis showed no benefit [40] and several studies have investigated the administration of steroids but none demonstrated any improvement in acute symptoms or for reduction in long term wheeze [41,42]. Bronchodilators may improve acute symptoms and
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facilitate feeding but there is no reduction in hospitalisation [43±45]. Serum levels of Vitamin A have been noted to be low in children admitted with RSV infection but a clinical trial evaluating the use of Vitamin A as a therapy not only failed to demonstrate any benefit but recipients had a significantly longer hospital stays [46]. Interferon alpha has been investigated as therapy in acute RSV infection in infants and experimental infection in adult volunteers without any demonstrable benefit [47]. There are a number of new therapies under evaluation. Polysaccharide compounds extracted from marine algae have been shown to have anti-RSV activity in vitro as have a number of organic compounds, but these have proven too cytotoxic for clinical use. A number of synthetic peptides and proteins have been evaluated for their ability to impair RSV replication and there has been much interest in the development of RNAses to cleave RSV RNA at antisense oligonucleotide-binding sites, and this has been shown to inhibit RSV replication [48].
Prophylaxis RSV immunoglobulin The use of passive immunisation with pooled immunoglobulin containing high titres of anti-RSV antibody given as monthly infusions during the RSV season has been shown to decrease the number and duration of hospital admissions in infants [49,50]. There was however an increased number of deaths in infants with congenital cyanotic heart disease who received RSVIG which was thought to be due to the volume of infusion (15 ml/kg) and its effect on plasma viscosity [35]. RSVIG, as with all blood products, carries the risk of blood borne infection, fever and systemic reactions which when combined with the need for line placement and its expense means it is not an ideal prophylactic agent. Monoclonal antibody Palivizumab is a chimeric mouse-human IgG monoclonal antibody preparation licensed for RSV prophylaxis. It is administered by intramuscular injection monthly during the RSV season to high risk infants. In a multicentre randomised placebo controlled trial the Impact-RSV study group reported a decrease in hospitalisation in the treatment group, there was no decrease however in those requiring mechanical ventilation [51]. In this analysis, the number needed to treat to prevent one hospitalisation was 17. Although there are clear
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benefits of Palivizumab, the combination of the limited efficacy and the high cost of the treatment have led to wide variation in clinical use. In view of the data available from the RSVIG trials noted above, Palivizumab is not currently recommended for children with congenital heart disease with the exception of those with patent ductus arteriosus or a septal defect with no haemodynamic compromise. Trials are currently ongoing, which will evaluate the safety and efficacy of Palivizumab in other congenital heart disorders. Palivizumab may be of use in control of outbreaks of RSV infection amongst high risk groups. Its use is reported in controlling a neonatal unit outbreak in the UK, but the authors conclude that further investigation is merited [52]. As a result of the difficulties that arise over costbenefit analysis, use of Palivizumab in many institutions is restricted. Guidelines for the use of Palivizumab have been published by the American Academy of Pediatrics (AAP) who recommend use in: Infants under the age of 2 years with chronic lung disease (CLD) who are receiving oxygen. Infants under the age of 2 years with CLD who have required oxygen or other medical therapy for their CLD within 6 months of the start of the RSV season. Infants born at less than 29 weeks gestation who do not meet the first two criteria up to 12 months of age. Infants born at 29±32 weeks gestation who do not meet the first two criteria up to the age of 6 months. Where there are constraints on health budgets, local decisions should be made balancing the cost of this agent against other therapeutic options.
Vaccines The global distribution, universality of infection and the morbidity and mortality of RSV make disease prevention through vaccination a worthwhile goal but no vaccine is yet in routine use despite over 30 years of development [53]. There are some particular problems for development of a successful RSV vaccine. Such a vaccine needs to provide protection against multiple antigenic strains within the two distinct groups, A and B. Even natural infection dose not induce complete immunity and it seems likely that an RSV vaccine would have to be judged by its ability to reduce lower respiratory tract disease rather than infection. Newborns and young infants are most at risk from disease, yet they may not mount an effective immune response due either to
relative immaturity of their immune system or persistence of maternally derived antibody. Furthermore, vaccine development has been hampered by the limitations of available animal models. Early experience with an RSV vaccine has also hampered development. In the original trials of a formalin inactivated vaccine in the 1960s, hospitalisation rates for vaccinees approached 80% compared with 5% of controls and two infants who received the vaccine died [54]. The mechanism for this exaggerated clinical response to wild type infection that resulted in enhanced disease in the recipients of this vaccine are still not fully understood. One hypothesis suggests that vaccinees remained susceptible to wild type infection because vaccination produced inadequate levels of neutralizing antibody in the serum and did not induce local immunity [55]. In contrast to natural infection, it appears that the use of this vaccine induces heightened production of Th2 cytokines, less activity of cytotoxic T lymphocytes and an eosinophilic pulmonary infiltrate [56,57]. Despite these early experiences, a wide variety of approaches to production of an RSV vaccine are being considered including both live and subunit vaccines.
Live vaccines The greatest attraction of live attenuated virus vaccines is that viral replication allows generation of immunity that might mimic natural infection without causing significant morbidity. Measles, mumps rubella, and oral polio vaccines have demonstrated the effectiveness of this approach. However, there are problems involved in the administration of such vaccines to groups of individuals at greatest risk from disease: in early infancy maternal antibody may interfere with the immune response, and there are concerns about the use of live vaccines in the immunocompromised. Attenuation of live RSV vaccines has been achieved by the creation of either cold-passaged (cp) or temperature sensitive (ts) mutants [58,59]. Unfortunately, these vaccines proved either over or under attenuated with reversion to wild type virus observed in some and transmission from vaccinees to placebo recipients documented [60]. Cold-passaged temperature sensitive vaccines (cpts) have now been developed that seem to be more stable and results of efficacy trials are currently awaited [61]. A new generation of live vaccines have been developed from cDNA copies of the RSV genome. Genetic engineering of these viral vaccines provides the potential to produce attenuated, stable viral vaccines that
RSV Infections in Children and Adults express proteins from multiple subgroups of RSV and other paramyxoviruses and even immunomodulatory molecules [62]. Further development of such vaccines is in progress. Live viral vectors, including vaccinia virus, modified vaccinia virus Ankara and adenovirus, that express the immunogenic F and G gene products of RSV have also been considered in pre-clinical trials, but have had various safety and immunogenicity problems associated with their development [63,64]. Subunit vaccines RSV F and G are the viral glycoproteins that induce neutralising and protective antibodies and as such are potential vaccine candidates. Vaccines that comprise purified F and G proteins do not appear to be very immunogenic in young children and, in rodents, induce T cell responses that are similar to those found with the formalin inactivated RSV vaccines used in the 1960s. However, these RSV subunit vaccines appear to be safe and immunogenic in older children and adults, who are not RSV naõÈve, and to reduce the severity of respiratory problems [65,66] and may be particularly suitable for those at high risk of severe disease following reinfection including children with cystic fibrosis, bronchopulmonary dysplasia, asthma and the elderly [67,68]. Other subunit vaccines are currently in early human trials [69] and different adjuvants are being considered in an attempt to avoid generation of enhanced disease after immunisation [70].
Conclusion RSV remains a major cause of morbidity in early childhood, individuals with cardiopulmonary diseases, the immunocompromised and the elderly. Upper respiratory tract infections are troublesome and recurrent for much of the rest of the population. Hospital admission is remarkably common in the high risk groups but specific therapies are disappointing. Antiviral therapy with ribavirin remains controversial in most patients but some data suggest that there may be a role for its use, perhaps in combination with anti-RSV antibody preparations in the immunocompromised. Both immunisation of those at high risk of severe RSV disease and universal immunisation of infants and the elderly are worthwhile goals. Continuing development of new vaccines using molecular manipulation of live viruses or subunit vaccines continues to hold out promise that such a goal can be obtained.
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RSV Infections in Children and Adults 60 Kim HW, Arrobio JO, Pyles G, Brandt CD, Camargo E, Chanock RM et al. Clinical and immunological response of infants and children to administration of low-temperature adapted respiratory syncytial virus. Pediatrics 1971; 48(5): 745±755. 61 Murphy BR, Collins PL. Current status of respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) vaccine development: memorandum from a joint WHO/NIAID meeting. Bull World Health Organ 1997; 75(4): 307±313. 62 Crowe JE Jr. Respiratory syncytial virus vaccine development. Vaccine 2001; 20(Suppl 1): S32±S37. 63 Crowe JE Jr, Collins PL, London WT, Chanock RM, Murphy BR. A comparison in chimpanzees of the immunogenicity and efficacy of live attenuated respiratory syncytial virus (RSV) temperaturesensitive mutant vaccines and vaccinia virus recombinants that express the surface glycoproteins of RSV. Vaccine 1993; 11(14): 1395±1404. 64 Immugenicity of recombinant adenovirus-respiratory syncytial virus vaccines with adenovirus types 4, 5 and 7 vectors in dogs and a chimpanzee. J Infect Dis 1992; 166(4): 769±775. 65 Piedra PA, Grace S, Jewell A, Spinelli S, Bunting D, Hogeost lower respiratory tract illness during respiratory syncytial virus season
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in children with cystic fibrosis. Pediatr Infect Dis J 1996; 15(1): 23±31. Falsey AR, Walsh EE. Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in the institutionalized elderly. Vaccine 1997; 15(10): 1130±1132. Falsey AR, Walsh EE. Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in ambulatory adults over age 60. Vaccine 1996; 14(13): 1214±1218. Tristram DA, Welliver RC, Mohar CK, Hogerman DA, Hildreth SW, Paradiso P. Immunogenicity and safety of respiratory syncytial virus subunit vaccine in seropositive children 18±36 months old. J Infect Dis 1993; 167(1): 191±195. Siegrist CA, Plotnicky-Gilquin H, Cordova M, Berney M, Bonnefoy JY, Nguyen TN et al. Protective efficacy against respiratory syncytial virus following murine neonatal immunization with BBG2Na vaccine: influence of adjuvants and maternal antibodies. J Infect Dis 1999; 179(6): 1326±1333. Neuzil KM JJTYPJSMGNGBS. Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine. Vaccine 1997; 15(5): 525±532.
SCIENCE AND CLINICAL PRACTICE
Respiratory Syncytial Virus Infections in Children and Adults C. L. Collins and A. J. Pollard* Department of Paediatrics, University of Oxford, Level 4, John Radcliffe Hospital, Oxford OX3 9DU, U.K. Respiratory syncytial virus is the leading cause of hospital admission for lower respiratory tract infection in young children and appears to be responsible for a significant burden of disease in adults, particularly the elderly and the immunocompromised. In this review, we describe the epidemiology, diagnosis and clinical manifestations of infection attributed to this virus. We also consider current therapeutic and prophylactic options and appraise strategies for # 2002 The British Infection Society vaccination that are in clinical trials.
Introduction Chimpanzee coryza agent was first isolated from an ape suffering from an upper respiratory tract infection in 1956 [1] and was soon renamed respiratory syncytial virus (RSV) on account of its propensity to induce syncytia formation in tissue culture. RSV is an enveloped RNA virus of the family Paramyxoviridae, which also includes measles and mumps virus. The two main groups of RSV, A and B, have several subgroups, which are defined by genetic and antigenic differences. RSV is a hugely successful human pathogen, which is highly transmissible, replicating in the respiratory epithelium, and infecting every human on the planet. The burden of morbidity caused by this virus in the first year of life is well-known and enormous but it is only in the past decade that the impact of RSV infection in later life has been widely appreciated.
Transmission and Immunity As noted above, RSV is highly transmissible and spread via person±person contact or through exposure to contaminated environmental surfaces, with significant implications for infection control within care facilities. Transmission via aerosolised droplets is probably limited as the virus is inactivated in aerosols. Incubation is from a few days to a week. *Please address all correspondence to: Dr A. J. Pollard, Oxford Vaccine Group, Department Paediatrics, Level 4, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU. Tel./Fax: 44 01856 221068; E-mail address: [email protected] (A. J. Pollard). 0163-4453/02/$35.00
Viral replication is greatest and most prolonged in infants and the immunocompromised and viral shedding has been detected in hospitalised infants for up to 21 days. By contrast, adults usually shed virus for as little as 4±5 days and probably not longer than 12 days [2±4]. Although immune responses directed at the virus, or virally infected cells, are known to include humoral and cell mediated mechanisms, natural immunity to RSV is incomplete and reinfection occurs throughout life as demonstrated in a number of epidemiological studies involving infants, families and adults [5,6]. Reinfection is the rule and in one prospective study, which explored acquisition within families, 44% of families with infants became infected with RSV when it was prevalent within the community, and 46% of exposed family members became infected [7]. It appears that both secretory and serum antibodies protect against infection of the respiratory tract and cell mediated responses directed against internal viral proteins appear to terminate infection. In support of the latter individuals with defects in cell mediated immunity have more prolonged viral shedding [8]. However, the high reinfection rates noted above serve to emphasise the failure of this immunity to prevent reinfection, which can be induced within weeks of a primary infection in adults [2]. Ageing may be associated with a defect in the T cell response to RSV, and explain the increased morbidity experienced in this population [9].
Epidemiology RSV causes a significant burden of disease in infants and adults; it is a seasonal virus with peak rates of infection # 2002 The British Infection Society
RSV Infections in Children and Adults in the cold season in temperate climates and the rainy season in tropical areas. Both group A and B RSV circulate concurrently, although group A viruses tend to predominate. There is a seasonal shift in the dominant subgroup of virus, which may explain the propensity for reinfection. The majority of severe RSV infections are in young infants and it is the main respiratory pathogen isolated from those admitted to hospital with pneumonia or bronchiolitis. A geographical variation in clinical presentation of disease has been described in children. The ratio of those presenting with bronchiolitis versus pneumonia in the USA and Europe is 3 : 1 compared with 1 : 3 in the Gambia [10±12]. This may be due to viral factors or nutritional, socio-economic and environmental differences. Half of the infants will be infected with RSV during their first winter. By 2 years of age almost every child will have been infected, with 95% of children seropositive for RSV by 24 months [13]. At this age 50% of infants will have been infected twice. Up to 2% of infants with RSV will require hospital admission, and, of these, one fifth may require respiratory support and 1.5% will die [14]. Risk factors for severe infection in children aged less than 6 months include, prematurity [15], bronchopulmonary dysplasia [16], immunodeficiency [17] and those with underlying cardio-pulmonary disease [18]. Low socio-economic status is associated with a higher attack rate: children from middle income families in North Carolina had a hospitalisation rate of 1/1000 compared with 5±10/1000 in lower-income populations [19]. Some studies have inconclusively associated more severe disease with some strains [20]. Although reinfection is probably common at all ages, significant morbidity is probably very uncommon in young adults. Conversely, it has become increasingly recognised that RSV can be a significant pathogen in elderly adults, particularly those living in residential care, or with underlying cardio-pulmonary disease. Rates of infection in long-term care facilities for the eldely have been estimated at 5±10% per season with mortality as high as 5% of infections [21]. The immunocompromised are also at particular risk of serious infection with the most severe disease observed in bone marrow transplant recipients, for whom mortality rates attributed to RSV pneumonia exceed 70% [21].
Diagnosis Although RSV infection is predominately a self limiting condition, laboratory diagnosis is helpful for hospitalised patient management to reduce unnecessary alternative
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interventions, for infection control and epidemiological monitoring. The principle laboratory methods of RSV diagnosis rely on the detection of virus in respiratory secretions. All of these tests are more sensitive in infants as they shed virus in a higher concentration and for longer duration than adults.
Culture Although culture is highly sensitive and specific in infants and remains the gold standard to which other diagnostic methods are compared, its use is limited by practical problems. RSV is an extremely labile virus and often does not survive transport and culture. RSV grows slowly, often taking over 5 days, further limiting the utility of culture as a diagnostic tool.
Antigen detection Antigen detection in respiratory secretions by immunofluorescence assay (IFA) or enzyme immunoassay (EIA) are most commonly used in infants where the sensitivity varies with methods between 75% and 94% [22]. The rapid turnaround time of these tests allows their use as a clinical diagnostic tool in the acute setting. In adults, viral titres are much lower in nasopharyngeal washings and the sensitivity of this test is likely to be much lower.
Serology Serology is not currently widely used in infants because of the sensitivity of the alternative tests, IFA and EIA. Since these methods are much less sensitive for the diagnosis of lower titre adults disease, serology has been studied more closely, and demonstration of RSV-specific IgM at the time of acute infection or a significant rise in RSV-specific IgG antibodies between acute and convalescent sera appears to be a reasonably sensitive diagnostic method for adult practice, though not widely available or used.
Reverse Transcription-Polymerase Chain Reaction (RT-PCR) RT-PCR allows detection of viral RNA in nasopharyngeal secretion with a 97.5% sensitivity in one study of culture positive infants [23]. It seems likely that such a method would be of particular use in diagnosis of infection in adults.
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Clinical Manifestations RSV most commonly causes upper respiratory tract infection in children, characterised by rhinitis, cough and fever. The virus may also cause croup and otitis media but bronchiolitis and pneumonia associated with RSV are the most common manifestations requiring hospital admission. In hospitalised patients with severe disease there is commonly a history of premature birth, bronchopulmonary dysplasia or congenital heart disease. Lung function tests suggest presence of obstructive small airways disease in two thirds of children, characteristic of bronchiolitis, with the remaining third having a restrictive pattern more suggestive of pneumonia [24]. The presence of tachypnoea, chest wall recession, audible wheeze and difficulty feeding are predictable features of lower respiratory tract infection with RSV, which typically develop several days after onset of rhinitis and cough. Chest radiograph in RSV bronchiolitis reveals hyperinflation with diffuse interstitial markings and peribronchial thickening, and segmental atelectasis may be seen which usually resolves spontaneously. Secondary bacterial infection is probably uncommon in the developed world but may partly explain the increased mortality rate from this infection in resource poor countries (2% vs. 7%) [25]. Respiratory failure and apnoea are the most common life-threatening complications of RSV bronchiolitis in early childhood. Apnoea is usually observed only in infants less than 2 months of age who were born prematurely. Suggested mechanisms include RSV associated hypersensitivity of the laryngeal chemoreceptors and immaturity of the respiratory centres in the brainstem. A number of studies have looked at the association between RSV infection in infancy and the development of asthma in later life and have found an increased risk which is independent from a family history of atopy [26,27]. Although RSV infections in adults have been recognised for decades, it is only recently that the importance of this virus as a cause of significant lower respiratory tract infection has been recognised outside of infancy. RSV is one of the three most commonly identified pathogens in adults with community acquired pneumonia [28] and is especially associated with exacerbations of chronic pulmonary and cardiac disease. The impact of RSV infections on adults in the community has not been fully quantified, Nicholson used statistical modelling and estimated that the impact of RSV may be even greater than that of influenza [29]. Elder adults living in residential care homes appear at particular risk
of RSV infection. In prospective studies, the rates of infection varied between 2% and 12% and the complication rates also varied widely, with the incidence of pneumonia ranging from 0% to 55% and mortality of 0±53% [30,31]. The majority of subjects in the residential care setting had other underlying chronic medical conditions. As noted above, reinfection with RSV is common throughout life and is usually manifest as upper respiratory tract infection. The clinical manifestations are difficult to distinguish from influenzaÐnasal congestion, cough, fever and wheeze were more common in RSV than influenza and myalgia and malaise more common in influenza [28]. RSV infection in the immunocompromised is associated with significant morbidity and mortality in adults and children and is related to the degree of immunosuppression. Those at the highest risk are recipients of bone marrow transplants (BMT) with those infected preengraftment at the highest risk, Harrington et al. [32] reported that 79% of subjects developed pneumonia when infected pre-engraftment vs. 41% when infected post-engraftment. In patients who are severely immunosuppressed through chemotherapy or following BMT mortality is over 50% in those who develop RSV pneumonia.
Treatment RSV infection of the respiratory tract in immunocompetent hosts is usually a self limiting condition and there is no unequivocal evidence that demonstrates that any therapy alone or in combination can reduce duration of hospitalisation in these individuals and there is consequent variation in clinical practice. In infants, hospital admission is advised if there is a supplemental oxygen requirement, recurrent apnoea, impending respiratory failure or an inability to feed. Supportive therapy is required for respiratory failure and the presence of secondary bacterial infection should be considered. Similar supportive measures seem appropriate for adult practice. Ribavirin Ribavarin is a synthetic guanosine nucleoside analogue with antiviral properties, which is administered as an aerosol over several hours a day. A Cochrane review which considered the use of ribavirin for treatment infants with RSV bronchiolitis reported that there was no reduction in mortality or duration of hospitalisation in
RSV Infections in Children and Adults infants who received this therapy [33]. There are no placebo-controlled trials of use of this agent in adults and use of this agent in the immunocompromised patients does not seem to be associated with lower mortality than historical controls [32,34]. Furthermore, there are practical difficulties with administration of the agent and concerns about teratogenic effects for attending hospital personnel, which have led to restriction of use of ribavirin to high risk infants requiring mechanical ventilation. RSV immunoglobulin In a study of 105 children with RSV infection who were randomised to receive RSV immunoglobulin (RSVIG) or placebo there was no significant difference in duration of hospitalisation, duration of intensive care stay, number requiring mechanical ventilation, supplemental oxygen requirement or number of adverse events [35]. As discussed below, RSVIG appears to have some benefit as a prophylactic agent and it seems somewhat counterintuitive that RSVIG has no therapeutic efficacy when given at the time of acute infection. By the time respiratory symptoms are present the virus has already penetrated the respiratory epithelium and RSVIG would probably have little effect, whilst prophylactic administration may prevent cellular penetration and thus development of symptoms [36]. Administration of RSVIG directly to the respiratory mucosa by aerosol in infants with RSV infection appears to be safe but had no benefit in a randomised controlled trial of 65 patients [37,38]. Combination therapy with intravenous ribavirin and RSVIG has been reported in bone marrow transplant recipients, where the mortality was 22% in those treated before the development of respiratory failure and 100% in the untreated group or those only treated within the first 24 h of the development of respiratory failure [39]. Further studies of RSVIG and ribavirin therapy in immunocompromised patients are underway. Other adjunctive therapies A number of studies have addressed the use of adjunctive therapies in RSV infection. A randomised controlled trial of the routine use of antibiotics in infants with bronchiolitis showed no benefit [40] and several studies have investigated the administration of steroids but none demonstrated any improvement in acute symptoms or for reduction in long term wheeze [41,42]. Bronchodilators may improve acute symptoms and
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facilitate feeding but there is no reduction in hospitalisation [43±45]. Serum levels of Vitamin A have been noted to be low in children admitted with RSV infection but a clinical trial evaluating the use of Vitamin A as a therapy not only failed to demonstrate any benefit but recipients had a significantly longer hospital stays [46]. Interferon alpha has been investigated as therapy in acute RSV infection in infants and experimental infection in adult volunteers without any demonstrable benefit [47]. There are a number of new therapies under evaluation. Polysaccharide compounds extracted from marine algae have been shown to have anti-RSV activity in vitro as have a number of organic compounds, but these have proven too cytotoxic for clinical use. A number of synthetic peptides and proteins have been evaluated for their ability to impair RSV replication and there has been much interest in the development of RNAses to cleave RSV RNA at antisense oligonucleotide-binding sites, and this has been shown to inhibit RSV replication [48].
Prophylaxis RSV immunoglobulin The use of passive immunisation with pooled immunoglobulin containing high titres of anti-RSV antibody given as monthly infusions during the RSV season has been shown to decrease the number and duration of hospital admissions in infants [49,50]. There was however an increased number of deaths in infants with congenital cyanotic heart disease who received RSVIG which was thought to be due to the volume of infusion (15 ml/kg) and its effect on plasma viscosity [35]. RSVIG, as with all blood products, carries the risk of blood borne infection, fever and systemic reactions which when combined with the need for line placement and its expense means it is not an ideal prophylactic agent. Monoclonal antibody Palivizumab is a chimeric mouse-human IgG monoclonal antibody preparation licensed for RSV prophylaxis. It is administered by intramuscular injection monthly during the RSV season to high risk infants. In a multicentre randomised placebo controlled trial the Impact-RSV study group reported a decrease in hospitalisation in the treatment group, there was no decrease however in those requiring mechanical ventilation [51]. In this analysis, the number needed to treat to prevent one hospitalisation was 17. Although there are clear
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benefits of Palivizumab, the combination of the limited efficacy and the high cost of the treatment have led to wide variation in clinical use. In view of the data available from the RSVIG trials noted above, Palivizumab is not currently recommended for children with congenital heart disease with the exception of those with patent ductus arteriosus or a septal defect with no haemodynamic compromise. Trials are currently ongoing, which will evaluate the safety and efficacy of Palivizumab in other congenital heart disorders. Palivizumab may be of use in control of outbreaks of RSV infection amongst high risk groups. Its use is reported in controlling a neonatal unit outbreak in the UK, but the authors conclude that further investigation is merited [52]. As a result of the difficulties that arise over costbenefit analysis, use of Palivizumab in many institutions is restricted. Guidelines for the use of Palivizumab have been published by the American Academy of Pediatrics (AAP) who recommend use in: Infants under the age of 2 years with chronic lung disease (CLD) who are receiving oxygen. Infants under the age of 2 years with CLD who have required oxygen or other medical therapy for their CLD within 6 months of the start of the RSV season. Infants born at less than 29 weeks gestation who do not meet the first two criteria up to 12 months of age. Infants born at 29±32 weeks gestation who do not meet the first two criteria up to the age of 6 months. Where there are constraints on health budgets, local decisions should be made balancing the cost of this agent against other therapeutic options.
Vaccines The global distribution, universality of infection and the morbidity and mortality of RSV make disease prevention through vaccination a worthwhile goal but no vaccine is yet in routine use despite over 30 years of development [53]. There are some particular problems for development of a successful RSV vaccine. Such a vaccine needs to provide protection against multiple antigenic strains within the two distinct groups, A and B. Even natural infection dose not induce complete immunity and it seems likely that an RSV vaccine would have to be judged by its ability to reduce lower respiratory tract disease rather than infection. Newborns and young infants are most at risk from disease, yet they may not mount an effective immune response due either to
relative immaturity of their immune system or persistence of maternally derived antibody. Furthermore, vaccine development has been hampered by the limitations of available animal models. Early experience with an RSV vaccine has also hampered development. In the original trials of a formalin inactivated vaccine in the 1960s, hospitalisation rates for vaccinees approached 80% compared with 5% of controls and two infants who received the vaccine died [54]. The mechanism for this exaggerated clinical response to wild type infection that resulted in enhanced disease in the recipients of this vaccine are still not fully understood. One hypothesis suggests that vaccinees remained susceptible to wild type infection because vaccination produced inadequate levels of neutralizing antibody in the serum and did not induce local immunity [55]. In contrast to natural infection, it appears that the use of this vaccine induces heightened production of Th2 cytokines, less activity of cytotoxic T lymphocytes and an eosinophilic pulmonary infiltrate [56,57]. Despite these early experiences, a wide variety of approaches to production of an RSV vaccine are being considered including both live and subunit vaccines.
Live vaccines The greatest attraction of live attenuated virus vaccines is that viral replication allows generation of immunity that might mimic natural infection without causing significant morbidity. Measles, mumps rubella, and oral polio vaccines have demonstrated the effectiveness of this approach. However, there are problems involved in the administration of such vaccines to groups of individuals at greatest risk from disease: in early infancy maternal antibody may interfere with the immune response, and there are concerns about the use of live vaccines in the immunocompromised. Attenuation of live RSV vaccines has been achieved by the creation of either cold-passaged (cp) or temperature sensitive (ts) mutants [58,59]. Unfortunately, these vaccines proved either over or under attenuated with reversion to wild type virus observed in some and transmission from vaccinees to placebo recipients documented [60]. Cold-passaged temperature sensitive vaccines (cpts) have now been developed that seem to be more stable and results of efficacy trials are currently awaited [61]. A new generation of live vaccines have been developed from cDNA copies of the RSV genome. Genetic engineering of these viral vaccines provides the potential to produce attenuated, stable viral vaccines that
RSV Infections in Children and Adults express proteins from multiple subgroups of RSV and other paramyxoviruses and even immunomodulatory molecules [62]. Further development of such vaccines is in progress. Live viral vectors, including vaccinia virus, modified vaccinia virus Ankara and adenovirus, that express the immunogenic F and G gene products of RSV have also been considered in pre-clinical trials, but have had various safety and immunogenicity problems associated with their development [63,64]. Subunit vaccines RSV F and G are the viral glycoproteins that induce neutralising and protective antibodies and as such are potential vaccine candidates. Vaccines that comprise purified F and G proteins do not appear to be very immunogenic in young children and, in rodents, induce T cell responses that are similar to those found with the formalin inactivated RSV vaccines used in the 1960s. However, these RSV subunit vaccines appear to be safe and immunogenic in older children and adults, who are not RSV naõÈve, and to reduce the severity of respiratory problems [65,66] and may be particularly suitable for those at high risk of severe disease following reinfection including children with cystic fibrosis, bronchopulmonary dysplasia, asthma and the elderly [67,68]. Other subunit vaccines are currently in early human trials [69] and different adjuvants are being considered in an attempt to avoid generation of enhanced disease after immunisation [70].
Conclusion RSV remains a major cause of morbidity in early childhood, individuals with cardiopulmonary diseases, the immunocompromised and the elderly. Upper respiratory tract infections are troublesome and recurrent for much of the rest of the population. Hospital admission is remarkably common in the high risk groups but specific therapies are disappointing. Antiviral therapy with ribavirin remains controversial in most patients but some data suggest that there may be a role for its use, perhaps in combination with anti-RSV antibody preparations in the immunocompromised. Both immunisation of those at high risk of severe RSV disease and universal immunisation of infants and the elderly are worthwhile goals. Continuing development of new vaccines using molecular manipulation of live viruses or subunit vaccines continues to hold out promise that such a goal can be obtained.
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