Respiratory Syncytial Virus Infections in Children and Adults

Journal of Infection (2002) 45: 10±17doi: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 youngchildren and appears to be responsible for a significant burden of disease in adults, particularly the elderly and theimmunocompromised. In this review, we describe the epidemiology, diagnosis and clinical manifestations of infectionattributed to this virus. We also consider current therapeutic and prophylactic options and appraise strategies forvaccination that are in clinical trials. # 2002 The British Infection Society

Introduction

Chimpanzee coryza agent was first isolated from an apesuffering from an upper respiratory tract infection in1956 [1] and was soon renamed respiratory syncytialvirus (RSV) on account of its propensity to induce syn-cytia formation in tissue culture. RSV is an envelopedRNA virus of the family Paramyxoviridae, which alsoincludes measles and mumps virus. The two maingroups of RSV, A and B, have several subgroups, whichare defined by genetic and antigenic differences.

RSV is a hugely successful human pathogen, which ishighly transmissible, replicating in the respiratory epi-thelium, and infecting every human on the planet. Theburden of morbidity caused by this virus in the first yearof life is well-known and enormous but it is only in thepast decade that the impact of RSV infection in later lifehas been widely appreciated.

Transmission and Immunity

As noted above, RSV is highly transmissible and spreadvia person±person contact or through exposure to con-taminated environmental surfaces, with significantimplications for infection control within care facilities.Transmission via aerosolised droplets is probably limitedas the virus is inactivated in aerosols. Incubation is froma few days to a week.

*Please address all correspondence to: Dr A. J. Pollard, Oxford Vaccine

Group, Department Paediatrics, Level 4, University of Oxford, JohnRadcliffe 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 ininfants and the immunocompromised and viral sheddinghas been detected in hospitalised infants for up to 21days. By contrast, adults usually shed virus for as little as4±5 days and probably not longer than 12 days [2±4].Although immune responses directed at the virus, orvirally infected cells, are known to include humoral andcell mediated mechanisms, natural immunity to RSV isincomplete and reinfection occurs throughout life asdemonstrated in a number of epidemiological studiesinvolving infants, families and adults [5,6]. Reinfection isthe rule and in one prospective study, which exploredacquisition within families, 44% of families with infantsbecame infected with RSV when it was prevalent withinthe community, and 46% of exposed family membersbecame infected [7].

It appears that both secretory and serum antibodiesprotect against infection of the respiratory tract and cellmediated responses directed against internal viral pro-teins appear to terminate infection. In support of thelatter individuals with defects in cell mediated immunityhave more prolonged viral shedding [8]. However, thehigh reinfection rates noted above serve to emphasise thefailure of this immunity to prevent reinfection, whichcan be induced within weeks of a primary infection inadults [2]. Ageing may be associated with a defect in theT cell response to RSV, and explain the increased mor-bidity experienced in this population [9].

Epidemiology

RSV causes a significant burden of disease in infants andadults; it is a seasonal virus with peak rates of infection

# 2002 The British Infection Society

RSV Infections in Children and Adults 11

in the cold season in temperate climates and the rainyseason in tropical areas. Both group A and B RSV cir-culate concurrently, although group A viruses tend topredominate. There is a seasonal shift in the dominantsubgroup of virus, which may explain the propensity forreinfection. The majority of severe RSV infections are inyoung infants and it is the main respiratory pathogenisolated from those admitted to hospital with pneumoniaor bronchiolitis.

A geographical variation in clinical presentation ofdisease has been described in children. The ratio of thosepresenting with bronchiolitis versus pneumonia in theUSA and Europe is 3 : 1 compared with 1 : 3 in theGambia [10±12]. This may be due to viral factors or nutri-tional, socio-economic and environmental differences.

Half of the infants will be infected with RSV duringtheir first winter. By 2 years of age almost every childwill have been infected, with 95% of children sero-positive for RSV by 24 months [13]. At this age 50% ofinfants will have been infected twice. Up to 2% of infantswith 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 lessthan 6 months include, prematurity [15], broncho-pulmonary dysplasia [16], immunodeficiency [17] andthose with underlying cardio-pulmonary disease [18].Low socio-economic status is associated with a higherattack rate: children from middle income families inNorth Carolina had a hospitalisation rate of 1/1000compared with 5±10/1000 in lower-income populations[19]. Some studies have inconclusively associated moresevere disease with some strains [20].

Although reinfection is probably common at all ages,significant morbidity is probably very uncommon inyoung adults. Conversely, it has become increasinglyrecognised that RSV can be a significant pathogen inelderly adults, particularly those living in residentialcare, or with underlying cardio-pulmonary disease.Rates of infection in long-term care facilities for theeldely have been estimated at 5±10% per season withmortality as high as 5% of infections [21]. The immuno-compromised are also at particular risk of serious infec-tion with the most severe disease observed in bonemarrow transplant recipients, for whom mortality ratesattributed to RSV pneumonia exceed 70% [21].

Diagnosis

Although RSV infection is predominately a self limitingcondition, laboratory diagnosis is helpful for hospitalisedpatient management to reduce unnecessary alternative

interventions, for infection control and epidemiologicalmonitoring. The principle laboratory methods of RSVdiagnosis rely on the detection of virus in respiratorysecretions. All of these tests are more sensitive in infantsas they shed virus in a higher concentration and forlonger duration than adults.

Culture

Although culture is highly sensitive and specific ininfants and remains the gold standard to which otherdiagnostic methods are compared, its use is limited bypractical problems. RSV is an extremely labile virus andoften does not survive transport and culture. RSV growsslowly, often taking over 5 days, further limiting theutility of culture as a diagnostic tool.

Antigen detection

Antigen detection in respiratory secretions by immuno-fluorescence assay (IFA) or enzyme immunoassay (EIA)are most commonly used in infants where the sensitivityvaries with methods between 75% and 94% [22]. Therapid turnaround time of these tests allows their use asa clinical diagnostic tool in the acute setting. In adults,viral titres are much lower in nasopharyngeal washingsand the sensitivity of this test is likely to be much lower.

Serology

Serology is not currently widely used in infants becauseof the sensitivity of the alternative tests, IFA and EIA.Since these methods are much less sensitive for thediagnosis of lower titre adults disease, serology has beenstudied more closely, and demonstration of RSV-specificIgM at the time of acute infection or a significant rise inRSV-specific IgG antibodies between acute and con-valescent sera appears to be a reasonably sensitivediagnostic method for adult practice, though not widelyavailable or used.

Reverse Transcription-Polymerase

Chain Reaction (RT-PCR)

RT-PCR allows detection of viral RNA in nasopharyngealsecretion with a 97.5% sensitivity in one study of culturepositive infants [23]. It seems likely that such a methodwould be of particular use in diagnosis of infection inadults.

12 C. L. Collins and A. J. Pollard

Clinical Manifestations

RSV most commonly causes upper respiratory tractinfection in children, characterised by rhinitis, coughand fever. The virus may also cause croup and otitismedia but bronchiolitis and pneumonia associated withRSV are the most common manifestations requiringhospital admission. In hospitalised patients with severedisease there is commonly a history of premature birth,bronchopulmonary dysplasia or congenital heartdisease. Lung function tests suggest presence of ob-structive small airways disease in two thirds of children,characteristic of bronchiolitis, with the remaining thirdhaving a restrictive pattern more suggestive ofpneumonia [24].

The presence of tachypnoea, chest wall recession,audible wheeze and difficulty feeding are predictablefeatures of lower respiratory tract infection with RSV,which typically develop several days after onset of rhi-nitis and cough. Chest radiograph in RSV bronchiolitisreveals hyperinflation with diffuse interstitial markingsand peribronchial thickening, and segmental atelectasismay be seen which usually resolves spontaneously.Secondary bacterial infection is probably uncommon inthe developed world but may partly explain theincreased mortality rate from this infection in resourcepoor countries (2% vs. 7%) [25].

Respiratory failure and apnoea are the most commonlife-threatening complications of RSV bronchiolitis inearly childhood. Apnoea is usually observed only ininfants less than 2 months of age who were born pre-maturely. Suggested mechanisms include RSV associatedhypersensitivity of the laryngeal chemoreceptors andimmaturity of the respiratory centres in the brainstem.

A number of studies have looked at the associationbetween RSV infection in infancy and the development ofasthma in later life and have found an increased riskwhich is independent from a family history of atopy[26,27].

Although RSV infections in adults have been recog-nised for decades, it is only recently that the importanceof this virus as a cause of significant lower respiratorytract infection has been recognised outside of infancy.RSV is one of the three most commonly identifiedpathogens in adults with community acquired pneu-monia [28] and is especially associated with exacerba-tions of chronic pulmonary and cardiac disease. Theimpact of RSV infections on adults in the community hasnot been fully quantified, Nicholson used statisticalmodelling and estimated that the impact of RSV may beeven greater than that of influenza [29]. Elder adultsliving in residential care homes appear at particular risk

of RSV infection. In prospective studies, the rates ofinfection varied between 2% and 12% and the compli-cation rates also varied widely, with the incidence ofpneumonia ranging from 0% to 55% and mortality of0±53% [30,31]. The majority of subjects in the resi-dential care setting had other underlying chronicmedical conditions.

As noted above, reinfection with RSV is commonthroughout life and is usually manifest as upperrespiratory tract infection. The clinical manifestationsare difficult to distinguish from influenzaÐnasal con-gestion, cough, fever and wheeze were more commonin RSV than influenza and myalgia and malaise morecommon in influenza [28].

RSV infection in the immunocompromised is asso-ciated with significant morbidity and mortality in adultsand children and is related to the degree of immuno-suppression. Those at the highest risk are recipients ofbone marrow transplants (BMT) with those infected pre-engraftment at the highest risk, Harrington et al. [32]reported that 79% of subjects developed pneumoniawhen infected pre-engraftment vs. 41% when infectedpost-engraftment. In patients who are severely immuno-suppressed through chemotherapy or followingBMT mortality is over 50% in those who develop RSVpneumonia.

Treatment

RSV infection of the respiratory tract in immuno-competent hosts is usually a self limiting condition andthere is no unequivocal evidence that demonstrates thatany therapy alone or in combination can reduce dura-tion of hospitalisation in these individuals and there isconsequent variation in clinical practice. In infants,hospital admission is advised if there is a supplementaloxygen requirement, recurrent apnoea, impendingrespiratory failure or an inability to feed. Supportivetherapy is required for respiratory failure and the pre-sence of secondary bacterial infection should be con-sidered. Similar supportive measures seem appropriatefor adult practice.

Ribavirin

Ribavarin is a synthetic guanosine nucleoside analoguewith antiviral properties, which is administered as anaerosol over several hours a day. A Cochrane reviewwhich considered the use of ribavirin for treatmentinfants with RSV bronchiolitis reported that there was noreduction in mortality or duration of hospitalisation in


infants who received this therapy [33]. There are noplacebo-controlled trials of use of this agent in adults anduse of this agent in the immunocompromised patientsdoes not seem to be associated with lower mortality thanhistorical controls [32,34].

Furthermore, there are practical difficulties withadministration of the agent and concerns about terato-genic effects for attending hospital personnel, whichhave led to restriction of use of ribavirin to high riskinfants requiring mechanical ventilation.

RSV immunoglobulin

In a study of 105 children with RSV infection who wererandomised to receive RSV immunoglobulin (RSVIG) orplacebo there was no significant difference in duration ofhospitalisation, duration of intensive care stay, numberrequiring mechanical ventilation, supplemental oxygenrequirement or number of adverse events [35].

As discussed below, RSVIG appears to have somebenefit as a prophylactic agent and it seems somewhatcounterintuitive that RSVIG has no therapeutic efficacywhen given at the time of acute infection. By the timerespiratory symptoms are present the virus has alreadypenetrated the respiratory epithelium and RSVIG wouldprobably have little effect, whilst prophylactic adminis-tration may prevent cellular penetration and thusdevelopment of symptoms [36].

Administration of RSVIG directly to the respiratorymucosa by aerosol in infants with RSV infection appearsto be safe but had no benefit in a randomised controlledtrial of 65 patients [37,38].

Combination therapy with intravenous ribavirin andRSVIG has been reported in bone marrow transplantrecipients, where the mortality was 22% in those treatedbefore the development of respiratory failure and 100%in the untreated group or those only treated within thefirst 24 h of the development of respiratory failure [39].Further studies of RSVIG and ribavirin therapy inimmunocompromised patients are underway.

Other adjunctive therapies

A number of studies have addressed the use of adjunctivetherapies in RSV infection. A randomised controlledtrial of the routine use of antibiotics in infants withbronchiolitis showed no benefit [40] and several studieshave investigated the administration of steroids butnone demonstrated any improvement in acute symp-toms or for reduction in long term wheeze [41,42].Bronchodilators may improve acute symptoms and

facilitate feeding but there is no reduction in hospitali-sation [43±45].

Serum levels of Vitamin A have been noted to be lowin children admitted with RSV infection but a clinicaltrial evaluating the use of Vitamin A as a therapy notonly failed to demonstrate any benefit but recipients hada significantly longer hospital stays [46]. Interferonalpha has been investigated as therapy in acute RSVinfection in infants and experimental infection in adultvolunteers without any demonstrable benefit [47].

There are a number of new therapies under evalua-tion. Polysaccharide compounds extracted from marinealgae have been shown to have anti-RSV activity in vitroas have a number of organic compounds, but these haveproven too cytotoxic for clinical use. A number of syn-thetic peptides and proteins have been evaluated for theirability to impair RSV replication and there has beenmuch interest in the development of RNAses to cleaveRSV RNA at antisense oligonucleotide-binding sites, andthis has been shown to inhibit RSV replication [48].

Prophylaxis

RSV immunoglobulin

The use of passive immunisation with pooled immu-noglobulin containing high titres of anti-RSV antibodygiven as monthly infusions during the RSV season hasbeen shown to decrease the number and duration ofhospital admissions in infants [49,50]. There was how-ever an increased number of deaths in infants withcongenital cyanotic heart disease who received RSVIGwhich 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 bloodborne infection, fever and systemic reactions whichwhen combined with the need for line placement and itsexpense means it is not an ideal prophylactic agent.

Monoclonal antibody

Palivizumab is a chimeric mouse-human IgG mono-clonal antibody preparation licensed for RSV prophyl-axis. It is administered by intramuscular injectionmonthly during the RSV season to high risk infants. Ina multicentre randomised placebo controlled trial theImpact-RSV study group reported a decrease in hospita-lisation in the treatment group, there was no decreasehowever in those requiring mechanical ventilation [51].In this analysis, the number needed to treat to preventone hospitalisation was 17. Although there are clear


benefits of Palivizumab, the combination of the limitedefficacy and the high cost of the treatment have led towide variation in clinical use.

In view of the data available from the RSVIG trialsnoted above, Palivizumab is not currently recommendedfor children with congenital heart disease with theexception of those with patent ductus arteriosus or aseptal defect with no haemodynamic compromise. Trialsare currently ongoing, which will evaluate the safetyand efficacy of Palivizumab in other congenital heartdisorders. Palivizumab may be of use in control of out-breaks of RSV infection amongst high risk groups. Its useis reported in controlling a neonatal unit outbreak in theUK, but the authors conclude that further investigationis merited [52].

As a result of the difficulties that arise over cost-benefit analysis, use of Palivizumab in many institutionsis restricted. Guidelines for the use of Palivizumab havebeen published by the American Academy of Pediatrics(AAP) who recommend use in:

� Infants under the age of 2 years with chronic lungdisease (CLD) who are receiving oxygen.

� Infants under the age of 2 years with CLD who haverequired oxygen or other medical therapy for theirCLD within 6 months of the start of the RSV season.

� Infants born at less than 29 weeks gestation who donot meet the first two criteria up to 12 months of age.

� Infants born at 29±32 weeks gestation who do notmeet the first two criteria up to the age of 6 months.

Where there are constraints on health budgets, localdecisions should be made balancing the cost of this agentagainst other therapeutic options.

Vaccines

The global distribution, universality of infection andthe morbidity and mortality of RSV make disease pre-vention through vaccination a worthwhile goal but novaccine is yet in routine use despite over 30 years ofdevelopment [53].

There are some particular problems for developmentof a successful RSV vaccine. Such a vaccine needs toprovide protection against multiple antigenic strainswithin the two distinct groups, A and B. Even naturalinfection dose not induce complete immunity and itseems likely that an RSV vaccine would have to bejudged by its ability to reduce lower respiratory tractdisease rather than infection. Newborns and younginfants are most at risk from disease, yet they maynot mount an effective immune response due either to

relative immaturity of their immune system or persis-tence of maternally derived antibody. Furthermore,vaccine development has been hampered by the limita-tions of available animal models.

Early experience with an RSV vaccine has also ham-pered development. In the original trials of a formalininactivated vaccine in the 1960s, hospitalisation ratesfor vaccinees approached 80% compared with 5% ofcontrols and two infants who received the vaccinedied [54]. The mechanism for this exaggerated clinicalresponse to wild type infection that resulted in enhanceddisease in the recipients of this vaccine are still not fullyunderstood. One hypothesis suggests that vaccineesremained susceptible to wild type infection becausevaccination produced inadequate levels of neutralizingantibody in the serum and did not induce local immunity[55]. In contrast to natural infection, it appears that theuse of this vaccine induces heightened production of Th2cytokines, less activity of cytotoxic T lymphocytes and aneosinophilic pulmonary infiltrate [56,57]. Despite theseearly experiences, a wide variety of approaches toproduction of an RSV vaccine are being consideredincluding both live and subunit vaccines.

Live vaccines

The greatest attraction of live attenuated virus vaccinesis that viral replication allows generation of immunitythat might mimic natural infection without causingsignificant morbidity. Measles, mumps rubella, and oralpolio vaccines have demonstrated the effectiveness ofthis approach. However, there are problems involved inthe administration of such vaccines to groups of indivi-duals at greatest risk from disease: in early infancymaternal antibody may interfere with the immuneresponse, and there are concerns about the use of livevaccines in the immunocompromised.

Attenuation of live RSV vaccines has been achievedby the creation of either cold-passaged (cp) or tempera-ture sensitive (ts) mutants [58,59]. Unfortunately, thesevaccines proved either over or under attenuated withreversion to wild type virus observed in some andtransmission from vaccinees to placebo recipientsdocumented [60]. Cold-passaged temperature sensitivevaccines (cpts) have now been developed that seem to bemore stable and results of efficacy trials are currentlyawaited [61].

A new generation of live vaccines have been devel-oped from cDNA copies of the RSV genome. Geneticengineering of these viral vaccines provides the poten-tial to produce attenuated, stable viral vaccines that


express proteins from multiple subgroups of RSV andother paramyxoviruses and even immunomodulatorymolecules [62]. Further development of such vaccines isin progress.

Live viral vectors, including vaccinia virus, modifiedvaccinia virus Ankara and adenovirus, that express theimmunogenic F and G gene products of RSV have alsobeen considered in pre-clinical trials, but have had var-ious safety and immunogenicity problems associatedwith their development [63,64].

Subunit vaccines

RSV F and G are the viral glycoproteins that induceneutralising and protective antibodies and as such arepotential vaccine candidates. Vaccines that comprisepurified F and G proteins do not appear to be veryimmunogenic in young children and, in rodents, induceT cell responses that are similar to those found with theformalin inactivated RSV vaccines used in the 1960s.However, these RSV subunit vaccines appear to be safeand immunogenic in older children and adults, who arenot RSV naõÈve, and to reduce the severity of respiratoryproblems [65,66] and may be particularly suitable forthose at high risk of severe disease following reinfectionincluding children with cystic fibrosis, broncho-pulmonary dysplasia, asthma and the elderly [67,68].Other subunit vaccines are currently in early humantrials [69] and different adjuvants are being consideredin an attempt to avoid generation of enhanced diseaseafter immunisation [70].

Conclusion

RSV remains a major cause of morbidity in early child-hood, individuals with cardiopulmonary diseases, theimmunocompromised and the elderly. Upper respiratorytract infections are troublesome and recurrent for muchof the rest of the population.

Hospital admission is remarkably common in the highrisk groups but specific therapies are disappointing. Anti-viral therapy with ribavirin remains controversial inmost patients but some data suggest that there may be arole for its use, perhaps in combination with anti-RSVantibody preparations in the immunocompromised.

Both immunisation of those at high risk of severe RSVdisease and universal immunisation of infants and theelderly are worthwhile goals. Continuing development ofnew vaccines using molecular manipulation of liveviruses or subunit vaccines continues to hold out pro-mise that such a goal can be obtained.

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Respiratory Syncytial Virus Infections in Children and Adults