Respiratory Syncytial Virus

Authors: Edward E. Walsh M.D. , Ann R. Falsey M.D.

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History

Virology

Respiratory Syncytial Virus (RSV) is an enveloped negative-sense single stranded RNA virus of the Paramyxoviridae family, genus Pneumovirus (20). The 10 genes encode 11 unique products, including 8 structural and 2 non-structural (NS1, NS2) proteins. The lipid envelope, with its associated matrix protein (M), encompasses the replicative complex (N,P,L, two M2 proteins, virion RNA) and has three glycoproteins (F,G,SH) protruding from its surface (32). The G (attachment) protein initiates infection by binding to receptors, a heparin-like glycosaminoglycan and the fractalkine chemokine receptor (64,134). The F (fusion) protein then mediates fusion of the virus and cellular membranes allowing entry of the replicative complex into the cytoplasm (170). NS1 and NS2 competitively inhibit the antiviral activity of type I interferons (145). The F and G proteins carry neutralizing epitopes while N, M and F are principal targets for cytotoxic T-cells (CTL) (27, 169). RSV also activates the innate immune response by interaction with toll-like receptor 4 (TLR4) expressed on mononuclear cells (164). RSV can be classified into two major groups, A and B, each with multiple subgroups, primarily distinguishable by genetic and antigenic variability in the G protein (157). This antigenic variability may be the result of immune pressure in the population, although its contribution to reinfection is unclear (20). Some studies in infants suggest that group A infections are more severe than group B infections (168).

Epidemiology

RSV causes annual winter outbreaks of respiratory tract illness in temperate climates, and during the rainy season in the tropics (125). In the United States, virus activity generally lasts 3-5 months with peaks in early winter in the South and late winter in the North (69, 162). Both group A and B viruses circulate concurrently, and genetic analysis of strains indicates outbreaks are primarily local, rather than national or global, in nature (94, 95). RSV accounts for 85-144,000 hospitalizations and approximately 100-500 deaths among children annually in the U.S. and is estimated to cause 600,000 annual deaths world wide (146,147,161). The virus is often introduced into the home by school age children, and subsequently infects 43% of adult family members, as well as newborn infants (79). Approximately 70% of infants are infected in their first year of life, with the remainder the following winter (71). Transmission is by large particle fomites, requiring close physical contact, although inanimate objects may sustain infectious virus for several hours (78). Reinfection is common throughout life, and is generally less severe than primary infection. However, children with cardiopulmonary disorders and certain adult populations are susceptible to severe disease with reinfection (57). Severely immunocompromised adults, such as pre-engrafted bone marrow transplant recipients or those undergoing chemotherapy for leukemia, may have mortality rates of 60-90% when infected (36, 102, 176) In addition, the frail elderly, and adults with underlying cardiopulmonary disease, are also at greater risk of severe disease with reinfection (58,62,167). Han and colleagues have estimated that RSV accounts for 2-9% of all hospitalizations for pneumonia in elderly populations (89). In long term care facilities, nosocomial attack rates of 2-18% are frequently reported, and are commonly misidentified as influenza outbreaks (57).

Clinical Manifestations

After an incubation period of 3-5 days, most infants develop nasal congestion, rhinnitis, coryza, and fever. Otitis media, often with bacterial superinfection, is a common sequelae of RSV upper respiratory tract infection (7). Development of lower respiratory tract symptoms is age dependent, occurring in 45% of infants less than 6 months of age and 20% of those 2-5 years old (84). Approximately 0.5-1% of infected infants require hospitalization, with stays of 3-4 days. The risk of hospitalization is greatest in infants less than 3 months of age, those with underlying cardiac or pulmonary disease, certain neuromuscular diseases and premature infants (121). Although hospitalization rates are greatest in high risk children, approximately 70% of all infants hospitalized are previously healthy term infants (86). Case fatality rates among hospitalized children range from 2-37% in those with heart and lung disease and <1% for healthy children (172).

The principal clinical syndromes are bronchiolitis and pneumonia, both resulting in significant hypoxia. Clinical findings of wheezing, rales and rhonchi and signs of air trapping with flaring of nasal passages and intercostal muscle retractions are the hallmark of bronchiolitis. Thick respiratory secretions and mucous plugging can result in atelectasis on chest radiograph, and can be indistinguishable from infiltrates due to pneumonia. Apnea may be seen with RSV infection, most commonly in premature infants or those less than 6 weeks of age (28).

Normal adults have typical common cold symptoms; nasal stuffiness, rhinorrhea, sore throat, cough and low grade fever (81). Lower respiratory tract infection (LRTI) with symptoms such as cough and wheezing occur in 26%, and persistence of reactive airway disease for several weeks has been documented (85, 87). Adults with underlying cardiopulmonary disease may have more severe manifestations with hypoxia and prolonged wheezing, and up to 16% may require hospitalization (57, 62). RSV infection in immunocompromised adults can very severe (26, 90, 102). In pre-engraftment hematopoetic stem cell (HSCT) or bone marrow transplant recipients progression from upper respiratory symptoms to pneumonia occurs in half, with mortality rates approaching 90%. Chest radiographs reveal diffuse interstitial pneumonia, and pleural effusions in up to 25% of patients (90). Among recipients of lung transplants, RSV infection has been linked to the development of bronchiolitis obliterans syndrome (115). A useful clue to the presence of RSV is the almost universal finding of radiographically demonstrable sinusitis (56).

Laboratory Diagnosis

Diagnostic methods include cell culture, antigen detection using enzyme immunoassay (EIA) or immunoflouresence, detection of viral RNA using reverse transcription-polymerase chain reaction (RT-PCR), and serology (59, 95). Although culture remains the gold standard, it requires 2-10 days for diagnosis, and may be less sensitive than rapid antigen detection methods in children if optimal culture techniques are not available. Antigen detection in nasal secretions using EIA has a sensitivity of 70-94% compared to culture in hospitalized infants. In adults, culture is considerably less sensitive, while antigen detection identifies only 10% of culture positive patients (23, 60). Serology provides sensitivity of ~90% in elderly adults, but is less useful in infants because of poor antibody responses. RT-PCR to detect viral RNA in respiratory secretions is the optimal method of diagnosis, having a sensitivity of 98% in infants compared to culture, and the ability to identify culture negative infections (66). In adults RT-PCR has a sensitivity of ~70% and specificity of 99% when compared to a combination of culture and serology, although this test is not currently widely available (59). Rapid accurate diagnosis of RSV is particularly important in immunocompromised persons where early therapy may be life saving (53). When compared with RT-PCR, culture and antigen detection are only 57% and 43% sensitive, respectively (102).

Pathogenesis

Respiratory epithelial cell necrosis and occasionally characteristic syncytial formation, along with extensive neutrophilic inflammatory changes can be found in autopsy specimens of infants succumbing to RSV infection (77, 127). Based upon animal studies, it has been postulated that the pathological changes and clinical manifestations of RSV are principally caused by complex host immune responses to the virus rather than direct virus cytopathology (73,122). However, more recent studies in children and adults using quantitative RT-PCR indicate that high viral load may also be an important determinant of disease severity (45, 49, 98). RSV stimulates IL-8 production, a neutrophil chemokine, in respiratory epithelial cells and alveolar macrophages in vitro (9,10). RSV induces both Th1 and Th2 lymphocyte responses, each with distinct inflammatory characteristics. In animals the response to the RSV G protein is predominantly Th2 with IL-4, IL-5, IL-10 and IL-13 secretion and is associated with production of IgG and IgE immunoglobulins, and PMN and eosinophil infiltration. In contrast the response to the F protein is predominantly Th1 directed with IL-2 and IFN-γ secretion and CD8+CTL production (131). Although able to sterilize infected lungs, CTL also produce substantial pathology when present in high numbers (21). In addition, RSV has been shown to induce inflammation by direct stimulation of the tachykine neuropeptide, substance P (163). Correlation of animal data to the cellular immune response in humans is variable, although Welliver correlated RSV specific IgE and eosinophilic cationic protein (ECP) in nasal secretions to wheezing in RSV infection (171). Recent data from the Netherlands suggests that the neutrophilic infiltration into lower respiratory secretions, as measured in bronchoalveolar lavage fluid from intubated RSV infected infants, and not delayed T cell responses, are temporally associated with disease severity (116).

ANTIVIRAL THERAPY

Drug of Choice

At the present time, aerosolized ribavirin is the only antiviral agent approved by the FDA for the treatment of infants and young children hospitalized with severe lower respiratory tract disease caused by RSV (33). Ribavirin is a synthetic nucleoside analog that appears to act by interfering with the function of mRNA and has broad antiviral activity against RNA, DNA and retroviruses (22). Ribavirin inhibits RSV viral replication in cell culture at a concentration of 2-8 µg/ml and, when given by small particle aerosol, the drug reaches high concentration (mean level 197 µg/ml) in respiratory secretions (22,39). Ribavirin was licensed in 1986 for treatment of RSV in non-intubated, hospitalized infants, based on the results of three randomized placebo-controlled trials (81, 82, 156). These studies, which included both normal infants and those with underlying cardiopulmonary disorders, demonstrated modest clinical benefits and diminished viral shedding. Effects included improvement in illness scores, cough, rales, heart rate and oxygenation. These studies have been criticized for their small number of subjects, vague enrollment criteria, and lack of stratification, but primarily for failure to demonstrate benefit in objective treatment outcomes such as length of hospital stay, need for supportive care or survival (22, 141). Subsequent post-marketing, large, non-randomized studies have failed to show a reduction in length of stay for children treated with Ribavirin (129).

Ribavirin was licensed in 1986 for treatment of RSV in non-intubated, hospitalized infants, based on the results of three randomized placebo-controlled trials (58, 59, 120). These studies, which included both normal infants and those with underlying cardiopulmonary disorders, demonstrated modest clinical benefits and diminished viral shedding. Effects included improvement in illness scores, cough, rales, heart rate and oxygenation. These studies have been criticized for their small number of subjects, vague enrollment criteria, and lack of stratification, but primarily for failure to demonstrate benefit in objective treatment outcomes such as length of hospital stay, need for supportive care or survival (13, 105). Subsequent post-marketing, large, non-randomized studies have failed to show a reduction in length of stay for children treated with Ribavirin (94).

Ribavirin was not initially approved for use with ventilators because of concern about crystal precipitation causing occlusion in respirator tubing and exhalation valves (97). However, in 1993, aerosolized ribavirin was approved for the treatment of infants requiring mechanical ventilation after further study demonstrated that it could be safely administered via respirators (97, 141). A randomized, double-blind, placebo-controlled study of ribavirin in 28 infants requiring ventilatory support demonstrated a significant benefit in the ribavirin group compared to a water placebo with decreased days ventilated, oxygen use and length of hospital stay (152). However, these conclusions were questioned because the water placebo might have caused airway hyperreactivity, biasing the study in favor of ribavirin (124). Two subsequent studies of infants with respiratory failure using a saline placebo have failed to demonstrate significant benefit of treatment (76, 122). Although there was a trend towards better outcomes (length of ventilation, intensive care days, oxygen use, hospitalization) in the ribavirin group, none was statistically significant. Another non-randomized study of 439 previously healthy infants with ventilatory failure used a multivariate model to control for age, gender and prematurity status, paradoxically found that ribavirin was associated with prolonged mechanical ventilation (124).

Several studies have addressed the issue of long-term safety of ribavirin in children treated as infants, and no significant differences in episodes of reactive airway disease, bronchitis or pulmonary function over periods of 8 to 12 years (109, 114, 142). In contrast, in a one-year retrospective study, Edell reported a significant reduction in reactive airway disease among 22 ribavirin-treated children compared to 19 conservatively treated children (50). Ribavirin treatment has been associated with a diminished IgE antibody response in treated children, and it has also been suggested that ribavirin has a direct immunomodulatory effect, favoring a Th-2 type immune response (34,42). The clinical relevance of these effects are unknown.

All of the randomized trials of ribavirin either show a benefit or a trend towards benefit favoring the ribavirin groups. Several meta-analyses have been performed and show modest benefits but lack statistical power to provide reliable estimates of effects (136,166). Whether these benefits are clinically relevant and cost effective remains a subject of continued controversy. To add to the decision-making difficulty regarding ribavirin treatment are potential health risks among exposed health care workers. Although no human data exists, teratogenicity or embryo lethality has been demonstrated in virtually all animal species treated with ribavirin. Although aerosolization exposes health care workers to the drug, absorption from the lung is minimal. In two studies involving 19 nurses caring for infants receiving the drug, ribavirin was detected in the erythrocytes of only one nurse at a concentration of 0.44 µg/mL (22). No plasma or urine samples were positive and the Academy of Pediatrics concluded that extreme precautions were not justified.

Because of the issues of efficacy and cost and ribavirin is not recommended for routine use but may be considered for use in select patients with documented, potentially life-threatening RSV infection. The most recent recommendations from the Academy of Pediatrics suggests that practitioners decide whether ribavirin therapy is appropriate by taking into account the particular clinical situation and their own preferences (33). They suggest that ribavirin be considered the situations outlined in Table 1. At the current time, the majority of hospitalized infants are not treated with ribavirin.

Ribavirin can be administered by either of two treatment schedules. Standard therapy consists of 20 mg drug/mL of diluent administered continuously with a small particle aerosol generator for 12 to 18 hours daily, for 3 to 7 days. Particles of 1 to 2 µm in diameter are generated and are small enough to reach the lower airways (141). Alternatively, short duration high-dose regimen using 60 mg drug/mL for 2 hours, 3 times a day can be used (54). This schedule was found to be equally effective, reduced environmental contamination, and allowed more patient-care time.

Alternative Therapy

High titers of serum neutralizing antibody to RSV appear to have a beneficial role in the prevention of serious RSV disease based on epidemiological data and animal models of infection (70, 92). Thus, products containing high concentrations of polyclonal RSV antibodies as well as monoclonal antibodies targeting the F protein have been developed. Studies of high-titered RSV intravenous immunoglobulin (RSV-IGIV) in cotton rats and owl monkeys have demonstrated efficacy for both prophylaxis and treatment (91, 92, 134). Standard IVIG, RSV-IGIV (RespiGam® ), which is a polyclonal human immunoglobulin enriched for RSV neutralizing antibody is no longer commercially available but a new candidate for hyperimmune RSV IVIG is under development by ADMA biologicals (51). Palivizumab (Synagis® ), a humanized monoclonal antibody to the RSV F protein, is FDA approved for the prevention of RSV disease in children . These products are principally for immunoprophylaxis in high-risk children (See prophylaxis below, Section II E) but have also been evaluated for the treatment of RSV disease, particularly immunocompromised patients.

The therapeutic use of standard IVIG containing high titers of antibody to RSV was initially studied by Hemming and colleagues in 35 young children hospitalized with RSV pneumonia or bronchiolitis (93). Significant reductions in nasal RSV shedding and increases in oxygenation at 24 hours were demonstrated but there was no difference in length of hospitalization compared to placebo. Subsequent randomized, placebo-controlled studies of IVIG treatment of children hospitalized with RSV infection have not shown significant clinical benefits (139,140). Aerosolized standard IVIG has also been evaluated as a treatment for RSV in a placebo-controlled trial of 68 infants requiring mechanical ventilation and was associated with serious adverse events (137).

Palivizumab is 50-100 times more active in-vitro than RSV-IGIV (99). Combined treatment with palivizumab and systemic glucocorticosteroids accelerated viral clearance and reversal of histopathologic changes in the lungs of RSV infected cotton rats (135). Furthermore, palivizumab inhibited neurogenic inflammation of the lower airways in RSV infected rats when given 72 hours after virus inoculation (132,133). In therapeutic trials of intubated infants with RSV infection, viral titers in tracheal aspirates were reduced after receiving 15mg/kg palivizumab but overall outcome was not improved compared to placebo. Palivizumab is not licensed for the treatment of RSV infection (117).

Special Situations

Elderly Patients with Co-morbid Conditions

Reinfection with RSV occurs throughout adult life and is usually manifest by a self-limited upper respiratory tract illness. Antiviral therapy is not warranted at this time for upper respiratory tract symptoms in healthy adults, and symptomatic treatment should be used. Depending upon the circumstances, specific antiviral therapy may be considered in the management of RSV infection in the high-risk adult. Serious RSV illness has been observed in several groups of adults including frail elderly, nursing home residents and adults with chronic cardiopulmonary diseases such as COPD and CHF (58,61, 162). The pathophysiology of severe RSV disease in these groups is not well understood and it is not known whether unchecked viral replication and direct viral cytotoxicity occurs. Thus, it is difficult to predict whether antiviral therapy may ameliorate the disease. Anecdotal reports and personal experience in treating elderly persons with severe lower respiratory tract infection with RSV does not provide sufficient evidence to judge efficacy (63, 159). Elderly persons with confirmed RSV infection and interstitial pneumonia who show signs of deterioration in the absence of evidence of bacterial infection could be considered for ribavirin treatment on an individual basis. Liss and Bernstein evaluated the safety of ribavirin aerosol in eight uninfected elderly volunteers, most with COPD, and found that 8 to18 hours per day was well tolerated with minimal effect on lung function (114). However, it may be difficult to administer prolonged aerosolized ribavirin therapy by face mask (20 mg/ml for 18 hours per day) to elderly persons with cognitive impairment, and high dose short duration therapy (60 mg/ml for 2 hours three times per day) may be a better option (52).

Bone Marrow Transplant and Immunocompromised Patients

Immunocompromised patients with lower respiratory symptoms should be considered for antiviral therapy since mortality rates associated with RSV pneumonia are high, especially among hematopoietic stem cell transplant (HSCT) recipients who become infected prior to marrow engraftment. Uncontrolled studies of intravenous, oral or aerosolized ribavirin with or without IVIG or palivizumab infusions have been reported (12,13,25,46,55,65,96,102,112,118,154,155, 173-176). Because these are primarily anecdotal reports using a variety of different treatment regimens compared to historical control data, no conclusions can be made regarding the efficacy of specific products and their treatment effects. However, mortality rates have dropped from 50-80% to 0 to 30% within single centers over the past 20 years for a variety of reasons making the role of treatment difficult (kanna). Use of aerosolized ribavirin alone to treat RSV pneumonia in HSCT recipients has been associated with a 70% mortality, which is not significantly different than historical controls (90,96). The most common treatment regimen has been the combination of inhaled ribavirin in combination with IVIG (102). Combination therapy with high titer RSV immunoglobulin plus aerosolized ribavirin (20 mg/ml for 18 hours per day) may offer a more favorable prognosis and was used in 16 HSCT patients with RSV pneumonia with a mortality rate of 50% (173). DeVincenzo and colleagues treated 11 RSV infected children undergoing HSCT with a single dose of RSV-IGIV (1500 mg/kg) together with aerosolized ribavirin, and observed a 9.1% mortality rate (41). Intravenous ribavirin therapy does not appear to be effective and was associated with 80% mortality in one study and can lead to significant hemolytic anemia (112). Oral ribavirin at a dose of 1800 mg per day was given to 19 HSCT patients with a 26% reversible hemolysis rate and was otherwise relatively well tolerated (102). Although clinical endpoints are very difficult to judge investigators have shown a more rapid decrease in viral load among treated patients compared to those untreated (12,102).

It is likely that the timing and stage of disease at the time of treatment are critically important and influences outcomes to a much greater extent that the effects of variable treatment regimens. Initiation of therapy at least one day prior to respiratory failure is an important prognostic factor for success since mortality rates are 100% in patients treated after the onset of respiratory failure (173,174). Preemptive treatment of HSCT patients with upper respiratory infection (URI), especially if prior to engraftment, is reasonable given the high rate of progression to pneumonia. In one study Bowden treated 25 HSCT patients with RSV URI with ribavirin for 2 hours per day for 7 days in an attempt to prevent spread to the lower respiratory tract (17). Despite failing to reduce virus shedding, only 32% developed pneumonia compared to historical rates of 50 to 60%, and of those who developed pneumonia the mortality was 29% compared to 80% historically. In another study, 14 HSCT patients with RSV URI were treated with ribavirin and RSV-IGIV (500 mg/kg every other day), 3 of whom developed pneumonia with 2 deaths (68). Preemptive use of aerosolized ribavirin was used successfully in one small study of immunocompromised children with asymptomatic RSV (3). Patients had weekly nasal washes for viral culture and were treated with ribavirin if positive for RSV. Seven asymptomatic subjects were treated and never developed symptoms of infection. The Collaborative Antiviral Study Group attempted to study the utility of preemptive inhaled ribavirin with IVIG compared to standard care in HSCT patients with RSV URI in a randomized trial however the trial was stopped due to low recruitment and the question of efficacy remains unclear (13).

Palivizumab has been found to be safe and well tolerated in HSCT patients in a study of 15 adult and pediatric HSCT patients with acute RSV URI, 12 of whom also had intersititial pneumonia. Patients received 15mg/kg of palivizumab as a single IV infusion and aerosolized Ribavirin, and treatment was well tolerated (12). The 3 patients with URI did not progress to pneumonia, and 10 of 12 patients with pneumonia survived for the 28 days of the study. In a subsequent study of 18 immunocompromised children with RSV infection who a single dose of palivizumab, 89% survived (25).

Lastly, there is one report of a HSCT patient who received donor lymphocyte transfusions for relapsed plasma cell leukemia during active RSV pneumonia (106). The patient’s respiratory condition improved and RSV antigen cleared from the nasal swabs and lavage fluid after transfusion.

ADJUNCTIVE THERAPY

Standard supportive care during antiviral therapy includes fluid replacement and use of supplemental oxygen. The results of inhaled bronchodilators, such as salbuterol, for RSV associated wheezing have been mixed (4, 88, 107). However, most authorities believe that a trial of these agents is warranted as some infants, even those on ventilator support, appear to show improvement in respiratory function. A recent trial of nebulized normal saline (0.9%) compared to hypertonic saline (5%) in infants with bronchiolitis indicated improved symptom scores at 48 hours suggesting this mode of therapy may offer benefit (5). Glucocorticosteroids have not been proven to be of benefit (18, 143). The macrolide antibiotics exhibit anti-inflammatory effects apart from the antimicrobial activity and have been studied as adjunctive therapy in RSV LRTI, however, no benefit has been demonstrated (108).

ENDPOINTS FOR MONITORING THERAPY

Both clinical and virological endpoints to monitor therapy of RSV infection have been used (83). Reductions in virus titer in respiratory secretions have been the primary virological endpoint, although direct correlation to clinical improvement may be difficult. Clinical endpoints useful in evaluating the benefit of therapy include the rate of improvement in hypoxia, wheezing, requirement for and duration of hospitalization, need for intensive care or ventilator support.

VACCINES

There are no licensed vaccines for RSV. However, subunit vaccines using the F and G surface glycoproteins of RSV, and live attenuated viruses produced by reverse genetics, are currently undergoing evaluation in pediatric and adult populations (48). The disastrous results following the use of a formalin-inactivated killed whole virus vaccine in infants in the late 1960’s has inhibited evaluation of subunit or peptide vaccines in infants (104).

INFECTION CONTROL MEASURES

Since RSV is principally transmitted by large particle fomites from infected persons, infection control measures are directed at limiting spread by direct contact. Gloves, gowns, and eye shields have been shown to reduce transmission and reduce nosocomial spread of RSV (78, 80). Hand washing with virucidal agents is also important in reducing spread of virus. Although not a controlled study, one report describes interruption of a nosocomial outbreak of RSV in a neonatal special care nursery among premature infants by administration of palivizumab to uninfected high-risk infants (37).

PREVENTION

Prophylaxis

Although serum-neutralizing antibody appears to prevent lower respiratory tract disease, attempts to develop a safe and effective RSV vaccine have thus far been unsuccessful (see Vaccines, section IV). An alternative to active immunization is passive immunization with immunoglobulin preparations. Several strategies for immunoprophylaxis have been studied. Initially standard IVIG was evaluated in a randomized placebo–controlled trial in 49 children with congenital heart disease (CHD) or bronchopulmonary dysplasia (BPD) (123). No difference in overall infection rates were noted although illnesses were milder in the treatment group. The lack of efficacy of standard IVIG was attributed to the relatively low quantity of RSV neutralizing antibody. RSV-IVIG (RespiGam® ) was licensed by the FDA in 1996 for use in premature infants and children with BPD. This polyclonal human antibody preparation is a pool of serum from multiple donors selected for high RSV neutralizing activity by micro-neutralization assay and was shown to reduce hospitalizations in high risk children (74, 75, 144, 149, 150). RSV-IVIG has been discontinued since the development of effect monoclonal antibodies which target single neutralize viral epitopes.

Palivizumab (Synagis) is a humanized IgG-1 monoclonal antibody that binds the F protein of both RSV group A and B viruses and is FDA approved for the purpose of immunoprophylaxis against RSV (99). The antibody was created by recombinant methods by which the F protein-specific neutralizing regions of the murine monoclonal antibody were inserted into the human IgG1 frame work. The preparation is administered by intramuscular injection at a dose of 15 mg/kg. A double-blind, placebo-controlled trial (IMpact-RSV) at 139 centers in the US, UK and Canada randomized 1502 children with BPD or prematurity to treatment or placebo during the 1996-1997 RSV season. Palivizumab resulted in a 55% reduction in RSV hospitalization (children with prematurity had a 78% reduction and those with BPD had a 39% reduction). Fewer hospital days, oxygen use and ICU admissions due to RSV were also observed in the treatment group. No significant adverse events were observed, and anti-palivizumab antibodies did not develop as a result of treatment. Unlike RSV-IGIV no differences in non-RSV illnesses were observed. In 1998 the FDA approved the use of palivizumab for infants who are premature or have chronic lung disease. Post-licensure analysis of 1839 children who received at least one dose of palivizumab found a 2.3% RSV hospitalization rate for treatment that compared favorably to the infection rates in the treatment group in the IMpact trial (153). Palivizumab is now also recommended for children with congenital heart disease and infants neuromuscular diseases and congenital airway abnormalities (1). The emergence of antibody resistant RSV among palivizumab recipients is extremely rare with only one report to date. Current recommendations by the Academy of Pediatrics for palivizumab are listed in Table 2 (2).

Although Palivizumab is not routinely recommended for immunocompromised children, it has been used successfully in the control of nosocomial outbreaks of RSV infection on HSCT wards (101). A recent decision model analysis of palivizumab as a prophylaxis agent after HSCT concluded that 12 children would need to be treated to save one from RSV related death. Further study of immunocompromised populations is needed.

Motavizumab (MEDI-524;Medimmune) is a second generation IgG1 monoclonal antibody with approximately 70 fold higher affinity for the RSV F protein and 20 fold greater neutralizing capacity. (1,174) In the rat model, motavizumab had 50-100 times greater activity in the lower airways compared to palivizumab. Unlike palivizumab, motavizumab also reduced viral load in the upper airways (177). In a large phase 3 trial comparing motavizumab to palivizumab for prevention of RSV in high risk children, motivizumab demonstrated a statistically non-significant 26% reduction in hospitalization (the primary outcome endpoint) and a 50% reduction in medically attended infections (32). During a recent FDA advisory panel review motivizumab was not recommended for licensure for prophylaxis, in a part due to an increased rate of rash in the motavizumab treated children. In children hospitalized with RSV, treatment with motavizumab significantly reduced viral load after one day of treatment raising the possibility it could be useful as a therapeutic agent (111).

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Table 1. American Academy of Pediatrics Recommendations on Ribavirin Use (18)

Ribavirin may be considered for the following infants hospitalized with RSV infection:

Children with complicated congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis and other chronic lung disease
Previously well premature infants (< 37 weeks gestation)
Infants < 6 weeks of age
Children with immunosuppressive conditions
Severely ill children with or without mechanical ventilation
Infants at increased risk of progressive to severe disease such as multiple congenital anomalies or certain neurologic or metabolic diseases.

Table 2. American Academy of Pediatrics Recommendations on the Use of Palivizumab and RSV-IGIV (1)

Infants Eligible for a maximum of 5 Doses Infants Eligible for a maximum of 3 Doses

Infants with CLD, <24 mo of age and require medical therapy	Premature infants with a gestational afe of 32 wk 0 days to 34 wk 6 days with at least 1 risk factor and born 3 months before or during RSV season
Infants with CHD, <24 mo age and require medical therapy
Premature infants born at ≤31 wk 6 days
Certain infants with neuromuscular disease of congenital abnormalities of the airways