Respiratory Syncytial Virus

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


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) (27169). 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).


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 (69162). 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 (9495). 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 (36102176) 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).

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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 (8587). Adults with underlying cardiopulmonary disease may have more severe manifestations with hypoxia and prolonged wheezing, and up to 16% may require hospitalization (5762). RSV infection in immunocompromised adults can very severe (2690102).  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 (5995). 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 (2360). 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).

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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 (77127). 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 (454998). 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).


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 (8182156). 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 (22141). 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 (5859120).  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 (13105). 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 (97141). 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 (76122). 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 (109114142).  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.

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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 (7092). 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 (9192134). 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 (58,61162). 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 (63159). 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 (12,13,25,46,55,65,96,102,112,118,154,155173-176). 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.

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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 (488107). 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 (18143). 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).


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.


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).

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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 (7880). 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).



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 (7475144149150).  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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1. Abarca K, Jung E, Fernández P, Zhao L, Harris B, Connor EM, Losonsky GA; Motavizumab Study Group. Safety, tolerability, pharmacokinetics, and immunogenicity of motavizumab, a humanized, enhanced-potency monoclonal antibody for the prevention of respiratory syncytial virus infection in at-risk children. Pediatr Infect Dis J2009; 28:267–272. [PubMed]

2. Academy of Pediatrics Committee on Infectious Diseases Policy Statement –Modified Recommendations for use of palivizumab for the Prevention of Respiratory Syncytial Virus Infections. Pediatrics 2009;124:1694-1701. [PubMed]

3. Adams R, Christenson J, Petersen F, Beatty P. Pre-emptive use of aerosolized ribavirin in the treatment of asymptomatic pediatric marrow transplant patients testing positive for RSV. Bone Marrow Transplant 1999;24:661-664. [PubMed]

4. Alario AJ, Lewander WJ, Dennehy P, Seifer R, Mansel AL. The efficacy of nebulized metaproterenol in wheezing infants and young children. Am J Dis Child 1992;146:412-418. [PubMed]

5. Al-Ansari K. Sakran M. Davidson BL. El Sayyed R. Mahjoub H. Ibrahim K. Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants. Journal of Pediatrics.2010;157(4): 630-4.  [PubMed]

6Alvarez RElbashir SBorland TToudjarska IHadwiger PJohn MRoehl IMorskaya SSMartinello RKahn JVan Ranst M,Tripp RADeVincenzo JPPandey RMaier MNechev LManoharan MKotelianski VMeyers R. RNAi-mediated silencing of the respiratory syncytial virus nucleocapsid defines a potent anti-viral strategy. Antimicrob Agents Chemother 2009; 53(9):3952–5862.[PubMed] 

7. Anderson LJ. Respiratory syncytial virus vaccines for otitis media. Vaccine 2001;19:S59-S65. [PubMed]

8. Andries K, Moeremans M, Gevers T, et al. Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus. Antiviral Res 2003; 60:209–219.

9. Becker H, Koren, Henke D. Interleukin-8 expression in normal nasal epithelium and its modulation by infection with respiratory syncytial virus and cytokines tumor necrosis factor, interleukin-1, and interleukin-6. Am J Respir Cell Mol Biol 1993;8:20-27.[PubMed]

10. Becker S, Quay and Soukup J.Cytokine (tumor necrosis factor, IL-6 and IL-8) production by respiratory syncytial virus-infected human alveolar macrophages. J Immunol 1991;147:4307-4312. [PubMed]

11. Bitko V, Musiyenko A, Shulyayeva O, Barik S. Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 2005; 11:50–55.  [PubMed]

12. Boeckh M, Berrey MM, Bowden RA, Crawford SW, Balsley J, Corey L. Phase 1 evaluation of the respiratory syncytial virus-specific monoclonal antibody Palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis 2001;184:350-354.[PubMed]

13. Boeckh M. Englund J. Li Y. Miller C. Cross A. Fernandez H. Kuypers J. Kim H. Gnann J. Whitley R. NIAID Collaborative Antiviral Study Group. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clinical Infectious Diseases. 2007;44(2):245-9.  [PubMed]

14. Bonfanti JF, Roymans D. Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection. Curr Opin Drug Discov Devel 2009; 12:479–487. [PubMed]

15. Bonfanti JF, Meyer C, Doublet FFortin JMuller PQueguiner LGevers TJanssens PSzel HWillebrords RTimmerman P,Wuyts Kvan Remoortere PJanssens FWigerinck PAndries K. Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, 2: discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121). J Med Chem 2008; 51:875–896.[PubMed]

16. Bonzel L, Kovacevic A, Mayatepek E, Hoehn T, Vogel M.  Palivizumab-resistant human respiratory syncytial Clinical Infectious Diseases.2010;51(2):185-8. [PubMed]

17. Bowden RA. Respiratory virus infections after marrow transplant: The Fred Hutchinson Cancer Research Center experience. Am J Med 1997;102:27-30. [PubMed]

18. Bulow SM, Nir M, Levin E, Friis B, Thomsen LL, Nielsen JE, Holm J, Moller T, Bonde-Hansen ME, Nielsen HE. Prednisolone treatment of respiratory syncytial virus infection: a randomized controlled trial of 147 infants. Pediatrics 1999;140:e77 [PubMed]

19. Campbell AP. Chien JW, Kuypers J, Englund JA, Wald A, Guthrie KA, Corey L, Boeckh M. Respiratory virus pneumonia after hematopoietic cell transplantation (HCT): associations between viral load in bronchoalveolar lavage samples, viral RNA detection in serum samples, and clinical outcomes of HCT. Journal of Infectious Diseases.2010; 201(9):1404-13.  [PubMed]

20. Cane PA, Pringle C. Evolution of subgroup A respiratory syncytial virus: evidence for progressive accumulation of amino acid changes in the attachment protein. J Virol 1995;69:2918-2925. [PubMed]

21. Cannon MJ, Openshaw P, Askonas BA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 1988;168:1163-1168. [PubMed]

22. Carmack MA, Prober CG. Respiratory syncytial virus and ribavirin: Quo vadis? Infect Agents Dis 1992;1:99-107. [PubMed]

23. Casiano-Colon AE, Hulbert BB, Mayer TK, Walsh EE, Falsey AR. Lack of sensitivity or rapid antigen tests for the diagnosis of respiratory syncytial virus infection in adults. J Clin Virol 2003; 28(2):169-174. [PubMed]

24. Chapman J, Abbott E, Alber DG, Baxter RCBithell SKHenderson EACarter MCChambers PChubb ACockerill GS,Collins PLDowdell VCKeegan SJKelsey RDLockyer MJLuongo CNajarro PPickles RJSimmonds MTaylor DTyms S,Wilson LJPowell KL. RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrob Agents Chemother 2007; 51:3346–3353.   [PubMed]

25. Chavez-Bueno S. Mejias A. Merryman RA. Ahmad N. Jafri HS. Ramilo O.  Intravenous palivizumab and ribavirin combination for respiratory syncytial virus disease in high-risk pediatric patients. Pediatric Infectious Disease Journal. 2007; 26(12):1089-93.[PubMed]

26. Chemaly RF, Ghosh S, Bodey GP, Rohatgi N, Safdar A, Keating MJ, Champlin RE, Aguilera EA, Tarrand JJ, Raad II. Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine. 2006;85(5):278-87. [PubMed]

27. Cherrie AH, Anderson K, Wertz GW, Openshaw PJ. Human cytotoxic T cells stimulated by antigen on dendritic cells recognize the N, SH, F, M, 22K, and 1b proteins of respiratory syncytial virus. J Virol 1992;66:2102-2110. [PubMed]

28. Church NR, Anas NG, Hall CB, Brooks JG. Respiratory syncytial virus-related apnea in infants. Am J Dis Child 1984;138:247-250. [PubMed]

29. Cianci C, Langley DR, Dischino DD, Sun YYu KLStanley ARoach JLi ZDalterio RColonno RMeanwell NAKrystal M.  Targeting a binding pocket within the trimer-of-hairpins: small-molecule inhibition of viral fusion. Proc Natl Acad Sci U S A 2004; 101:15046–15051.  [PubMed]

30Collarini EJLee FEFoord OPark MSperinde GWu HHarriman WDCarroll SFEllsworth SLAnderson LJTripp RA,Walsh EEKeyt BAKauvar LM.  Potent high-afinity antibodies for tretement oand prophylaxis of RSV derived from B cells of infected patients. J. Immunol. 2009; 183:6378-6345. [PubMed]

31. Collins P. The molecular biology of human respiratory syncytial viruses (RSV) of the genus Pneumovirus, p. 103-162. In D. W. Kingsbury (ed.), The Paramyxoviruses 1991. Plenum Publishing, [PubMed]

32. Collins PL, Hill MG, Cristina J, Grosfeld H. Transcription elongation factor of respiratory syncytial virus, a nonsegmented negative-strand RNA virus. Proc Natl Acad Sci USA 1996;93:81-85. [PubMed]

33. Committee on Infectious Diseases. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics 1996; 97:137-140. [PubMed]

34. Concise Communications. Effect of ribavirin therapy on respiratory syncytial virus-specific IgE and IgA responses after infection. J Infect Dis 1987;155:1043-1047. [PubMed]

35. Carbonell-Estrany X. Simoes EA. Dagan R. Hall CB. Harris B. Hultquist M. Connor EM. Losonsky GA. Motavizumab Study Group. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial. Pediatrics. 2010;125(1):e35-51.  [PubMed]

36. Couch RB, Englund JA, Whimbey E. Respiratory viral infections in immunocompetent and immunocomprised persons. Am J Med 1997;102:2-9. [PubMed]

37. Cox RA, Rao P, Brandon-Cox C. The use of palivizumab monoclonal antibody to control an outbreak of respiratory syncytial virus infection in a special care baby unit. J Hosp Infect 2001;48:186-192. [PubMed]

38. Cramer H. Antisense approaches for inhibiting respiratory syncytial virus. Expert Opin Biol Ther 2005; 5:207–220. [PubMed]

39. De Clercq E. Perspectives for the chemotherapy of respiratory syncytial virus (RSV) infections. Internatl J Antimicrob Agts 1996;7:193-202. [PubMed]

40. de Fougerolles A, Vornlocher HP, Maraganore J, Lieberman J. Interfering with disease: a progress report on siRNA-based therapeutics.Nat Rev Drug Discov 2007; 6:443–453. [PubMed]

41. DeVincenzo JP, Hirsch RL, Fuentes RJ, Top FH. Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation - a compassionate use experience. Bone Marrow Transplant 2000;25:161-165. [PubMed]

42. DeVincenzo JP. Therapy of respiratory syncytial virus infection. Pediatr Infect Dis J 2000;19:786-790. [PubMed]

43. DeVincenzo J, Cehelsky JE, Alvarez R, Elbashir SHarborth JToudjarska INechev LMurugaiah VVan Vliet AVaishnaw AKMeyers R. Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed againstrespiratory syncytial virus (RSV).Antiviral Res 2008; 77:225–231.   [PubMed]

44. DeVincenzo J, Lambkin-Williams R, Wilkinson T, Cehelsky J, Nochur S, Walsh E, Meyers R, Gollob J, Vaishnaw A. A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proceedings of the National Academy of Sciences of the United States of America.2010;107(19):8800-5.  [PubMed]

45. DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, Harrison L, Meeking P, Mann A, Moane E, Oxford J, Pareek R, Moore R, Walsh E, Studholme R, Dorsett P, Alvarez R, Lambkin-Williams R. Viral load drives disease in humans experimentally infected with respiratory syncytial virus. American Journal of Respiratory & Critical Care Medicine. 2010;182(10):1305-14.  [PubMed]

46. Doud JR, Hinkamp T, Garrity ER. Respiratory syncytial virus pneumonia in a lung transplant recipient: case report. J Heart Lung Transplant 1992;1:77-79. [PubMed]

47. Douglas JL, Panis ML, Ho E, Lin KY, Krawczyk SH, Grant DM, Cai R, Swaminathan S, Chen X, Cihlar T.  Small molecules VP-14637 and JNJ-2408068 inhibit respiratory syncytial virus fusion by similar mechanisms. Antimicrob Agents Chemother 2005; 49:2460–2466. [PubMed]

48. Dudas R, Karron R. Respiratory syncytial virus vaccines. Clin Micro Rev 1998; 11:430-439. [PubMed]

49. Duncan CB, Walsh EE, Peterson DR, F H Lee, Falsey AR, Risk Factors for Respiratory Failure Associated with RSV Infection in Adults. J Infect Dis 2009: 200; 1242-6. [PubMed]

50. Edell D, Bruce E, Hale K, Khoshoo V. Reduced long-term respiratory morbidity after treatment of respiratory syncytial virus bronchiolitis with ribavirin in previously healthy infants: a preliminary report. Pediatr Pulmonol 1998;25:154-158. [PubMed]

51. Empey KM, Peebles RS Jr, Kolls JK. Pharmacologic advances in the treatment and prevention of respiratory syncytial virus. Clinical Infectious Diseases.2010; 50(9):1258-67. [PubMed]

52. Englund JA, Piedra P, Jefferson LS, Wilson SZ, Taber LH, Gilbert BE. High-dose, short duration ribavirin aerosol therapy in children with suspected respiratory syncytial virus infection. J Pediatr 1990; 117:313-320. [PubMed]

53. Englund JA, Piedra P, Jewell A, Baxter BB, Whimbey E, Patel K. Rapid diagnosis of respiratory syncytial virus infections in immunocompromised adults. J Clin Microbiol 1996;34:1649-1653. [PubMed]

54. Englund JA, Piedra PA, Ahn Y, Gilbert BE, Hiatt PW. High-dose, short-duration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected respiratory syncytial virus infection. J Pediatr 1994;125:635-641. [PubMed]

55. Englund JA, Piedra PA, Whimbey E. Prevention and treatment of respiratory syncytial virus and parainfluenza viruses in immunocompromised patients. Am J Med 1997;102:61-70. [PubMed]

56. Englund JA, Sullivan CJ, Jordan MC, Dehner LP, Vercellotti GM, Balfour HH. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med 1988;109:203-208. [PubMed]

57. Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clinic Microbiol Rev 2000;13:371-384. [PubMed]

58. Falsey AR, Cunningham CK, Barker WH, Kouides RW, Yuen JB, Menegus M, Weiner LB, Bonville CB, Betts RF. Respiratory syncytial virus and Influenza A infections in the hospitalized elderly. J Infect Dis 1995;172:389-394. [PubMed]

59. Falsey AR, Formica MA, Walsh EE. Diagnosis of respiratory syncytial virus infection: comparison of reverse transcription-PCR to viral culture and serology in adults with respiratory illness. J Clin Microbiol 2002;40:817-820. [PubMed]

60. Falsey AR, McCann RM, Hall WJ, Criddle MM. Evaluation of four methods for the diagnosis of respiratory syncytial virus infection in older adults. J Am Geriatr Soc 1996;44:71-73.  [PubMed]

61. Falsey AR, Treanor JJ, Betts RF, Walsh EE. Viral respiratory infections in the institutionalized elderly: clinical and epidemiologic findings. J Am Geriatr Soc 1992; 40:115-119. [PubMed]

62. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory Syncytial Virus in Elderly and High-risk Adults. NEJM 2005; 352(17):1749-59  [PubMed]

63. Feldman, RJ, Fidalgo HC, John JF. Respiratory syncytial virus in a cardiac surgery intensive care unit. J Thor Cardiovascular Surg 1994;108:1152. [PubMed]

64. Feldman SA, Hendry RM, Beeler JA. Identification of a linear heparin binding domain for human respiratory syncytical virus attachment glycoprotein G. J Virol 1999;73:6610-6617. [PubMed]

65. Fouillard L, Mouthon L, LaPorte JP, Isnard LF, Strachowiak J, Aoudjhane M, Lucet JC, Wolf M, Bricort F, Douay L, Lopez M, Marche C, Najman A, Gorin NC. Severe respiratory syncytial virus pneumonia after autologous bone marrow transplantation: a report of three cases and review. Bone Marrow Transplant 1992;9:97-100. [PubMed]

66. Freymuth F, Eugene G, Vabret A, Petitjean J, Gennetay E, Brouard J, Duhamel JF, Guillois JB. Detection of respiratory syncytial virus by reverse transcription-PCR and hybridization with a DNA enzyme immunoassay. J Clin Microbiol 1995;33:3352-3355.[PubMed]

67. Gazumyan A, Mitsner B, Ellestad GA. Novel anti-RSV dianionic dendrimer-like compounds: design, synthesis and biological evaluation. Cur Pharmaceutical Design 2000;6:525-546. [PubMed]

68. Ghosh S, Champlin RE, Englund J, Giralt SA, Rolston K, Raad I, Jacobson K, Neumann J, Ippoliti C, Mallik S, Whimbey E. Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunogloblin. Bone Marrow Transplant 2000;25:751-755.  [PubMed]

69. Gilchrist S, Torok TJ, Gary HE, Alexander JP, Anderson LJ. National surveillance for respiratory syncytial virus, United States, 1985-1990. J Infect Dis 1994;170:986-990. [PubMed]

70. Glezen WP, Paredes A, Allison JE, Taber LH, Frank AL. Risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level. J Pediatr 1981;98:708-715. [PubMed]

71. Glezen WP, Taber LH, Frank A, Kasel J. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;40:543-546. [PubMed]

72. Gower TL, Graham BS. Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro. Antimicrob Agents Chemother 2001;45:1231-1237. [PubMed]

73. Graham BS. Immunologic determinants of RSV-induced disease. Trends in Microbiol 1996;4:290-293. [PubMed]

74. Groothuis JR, Simoes EA, Hemming VG. Respiratory syncytial virus immune gobulin study group. Respiratory syncytial virus (RSV) infection in preterm infants and the protective effects of RSV immune globulin (RSVIG). Pediatrics 1995;95:463-467. [PubMed]

75. Groothuis JR, Simoes EA, Levin MJ, Hall CB, Long CE, Rodriguez WJ, Arrobio JO, Meissner HC, Fulton DR, Welliver RC, Tristram DA, Siber GR, Prince GA, Van Radan M, Hemming VG. The Respiratory Syncytial Virus Immune Globulin Study Group. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. N Engl J Med 1993;329:1524-1530.  [PubMed]

76. Guerguerian A, Gauthier M, Lebel MH, Farrell CA, LaCroix J. Ribavirin in ventilated respiratory syncytial virus bronchiolitis: a randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160:829-834. [PubMed]

77. Hall CB. Respiratory syncytial virus and parainfluenza virus. NEJM 2001;344:1917-1928. [PubMed]

78. Hall CB, Douglas RG. Modes of transmission of respiratory syncytial virus. J Pediatr 1981;99:100-103.  [PubMed]

79. Hall CB, Geiman JM, Biggar R, Kotok DI, Hogan PM, Douglas RG. Respiratory syncytial virus infections within families. N Engl J Med 1976; 294:414-419. [PubMed]

80. Hall CB, Geiman JM, Douglas RG, Meagher MP. Control of nosocomial respiratory syncytial viral infections. Pediatrics 1978;62:728-732. [PubMed]

81. Hall CB, Long CE, Schnabel KC. Respiratory syncytial virus infections in previously healthy working adults. Clin Infect Dis 2001; 33:792-796. [PubMed]

82. Hall CB, McBride JT, Gala CL, Hildreth SW, Schnabel KC. Ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease. JAMA 1985; 254:3047-3051. [PubMed]

83. Hall CB, McBride JT, Walsh EE, Bell DM, Gala CL, Hildreth SW, Ten Eyck LG, Hall WJ. Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. N Engl J Med 1983;308:1443-1447.  [PubMed]

84. Hall CB, McCarthy CA. Respiratory Syncytial Virus 1986; 1501-1519. In Mandell G, Bennett J, Dolin, R (eds.), Mandell, Douglas and Bennett's Principles and Practice of Infectious Disease. Churchill Livingstone, New York NY. [PubMed]

85. Hall WJ, Hall CB, Speers DM. Respiratory syncytial virus infection in adults: clinical, virologic, and serial pulmonary function studies. Ann Intern Med 1978;88:203-205. [PubMed]

86. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, Auinger P, Griffin MR, Poehling KA, Erdman D, Grijalva CG, Zhu Y, Szilagyi P. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009; 360:588–598. [PubMed]

87. Hall WJ, Hall CB. Clinical significance of pulmonary function tests: alterations in pulmonary function following respiratory virus infection. Chest 1979;76:458-465. [PubMed]

88. Hammer J, Numa A, Newth CJ. Albuterol responsiveness in infants with respiratory failure caused by a respiratory syncytial virus infection. J Pediatr 1995;127:485-490. [PubMed]

89. Han LL, Alexander JP, Anderson LJ. Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden. J Infect Dis 1999;179:25-30.  [PubMed]

90. Harrington RD, Hooton TM, Hackman GA, Storch B, Osborne CA, Gleaves A, Meyers JD. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis 1992;165:987-993. [PubMed]

91. Hemming VG, Prince GA. Respiratory syncytial virus: babies and antibodies. Infect Agents Dis 1992;1:24-32. [PubMed]

92. Hemming VG, Prince GA, Horswood RL, London WT, Murphy BR, Walsh EE, Fischer G, Weisman L, Baron P, Chanock RM. Studies of passive immunotherapy for infections of respiratory syncytial virus in the respiratory tract of a primate model. J Infect Dis 1985;152:1083-1087. [PubMed]

93. Hemming VG, Rodriguez WJ, Kim HW, Brandt CD, Parrott RH, Burch B, Prince GA, Baron P, Fink RJ, Reaman G. Intravenous immunoglobulin treatment of resipratory syncytial virus infections in infants and young children. Antimicrob Agents Chemother 1987; 31:1882-1886. [PubMed]

94. Hendry RM, Fernie BF, Anderson LF, McIntosh K. Antigenic and epidemiologic analysis of distinct strains of respiratory syncytial virus from two successive community outbreaks (1983-85) 1985; 397-403. In B. Mahy and D. Kolakofsky (eds.), Biololgy of Negative Strand Viruses. Elsevier Science Publishers BV [PubMed]

95. Hendry RM, Talis AL, Godfrey E, Anderson LJ, Fernie BF, McIntosh K. Concurrent circulation of antigenically distinct strains of respiratory syncytial virus during community outbreaks. J Infect Dis 1986; 153:291-297. [PubMed]

96. Hertz MI, Englund JA, Snover D, Bitterman PB, McGlave P. Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine 1989; 68:269-281. [PubMed]

97. Hicks RA, Olson LC, Jackson MA, Burry VF, Hall CB, McBride JT, Nevil LE, Popplewell ED. Precipitation of ribavirin causing obstruction of a ventilation tube. Pediatr Infect Dis J 1986; 5:707-708. [PubMed]

98. Houben ML. Coenjaerts FE. Rossen JW. Belderbos ME. Hofland RW. Kimpen JL. Bont L. Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community. Journal of Medical Virology. 2010; 82(7):1266-71.  [PubMed]

99. Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1988; 102:531-537. [PubMed]

100. Kellogg JA. Culture vs direct antigen assays for detection of microbial pathogens from lower respiratory tract specimens suspected of containing the respiratory syncytial virus. Arch Pathol Lab Med 1991; 115:451-458. [PubMed]

101. Kassis C, Champlin RE, Hachem RY, Hosing C, Tarrand JJ, Perego CA, Neumann JL, Raad II, Chemaly RF. Detection and control of a nosocomial respiratory syncytial virus outbreak in a stem cell transplantation unit: the role of palivizumab. Biology of Blood & Marrow Transplantation.2010;16(9):1265-71. [PubMed]

102. Khanna N, Widmer AF, Decker M, Steffen I, Halter J, Heim D, Weisser M, Gratwohl A, Fluckiger U, Hirsch HH. Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature. Clinical Infectious Diseases.2008; 46(3):402-12.   [PubMed]

103. Khushalani NI, Bakri FG, Wentling D, Brown K, Mohr A, Anderson B, Keesler B, Ball D, Bernstein ZP, Bernstein SH, Czuczman MS, Segal BH, McCarthy PLJ. Respiratory syncytial virus infection in the late bone marrow transplant period: report of three cases and review. Bone Marrow Transplant 2001; 27:1071-1073. [PubMed]

104. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am Epidemiol 1969; 89:422-434.  [PubMed]

105. Kimura K, Mori S, Tomita K, Ohno K, Takahashi K, Shigeta S, Terada M. Antiviral activity of NMS03 against respiratory syncytial virus infection in vitro and in vivo. Antiviral Res 2000; 47:41-51. [PubMed]

106. Kishi Y, Kami M, Oki Y, Kazuyama Y, Kawabata M, Miyakoshi S, Morinaga S, Suzuki R, Mori S, Muto Y. Donor lymphocyte infusion for treatment of life-threatening respiratory syncytial virus infection following bone marrow transplantation. Bone Marrow Transplant 2000; 26:573-576. [PubMed]

107. Klassen TP, Rowe PC, Sutcliffe T, Ropp LJ, McDowell IW, Li MM. Randomized trial of salbutamol in acute bronchiolitis. J Pediatr 1991; 118:807-811. [PubMed]

108. Kneyber MC, van Woensel JB, Uijtendaal E, Uiterwaal CS, Kimpen JL. Dutch Antibiotics in RSV Trial (DART) Research Group. Azithromycin does not improve disease course in hospitalized infants with respiratory syncytial virus (RSV) lower respiratory tract disease: An randomized equivalence trial. Pediatric Pulmonology. 2008;43(2):142-9. [PubMed]

109. Krilov LR, Mandel FS, Barone SR, Fagin JC, Bronchiolitis Study Group. Follow-up of children with respiratory syncytial virus bronchiolitis in 1986 and 1987: potential effect of ribavirin on long term pulmonary function. Pediatr Infect Dis J 1997; 16:273-276.[PubMed]

110. Kurt-Jones EA, Popova L,. Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT, Anderson LJ, Finberg RW. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 2000; 1:398-401. [PubMed]

111. Lagos R, Devincenzo JP, Munoz A, Hultquist MSuzich JConnor EMLosonsky GA. Safety and antiviral activity of motavizumab, a respiratory syncytial virus (rsv)-specific humanized monoclonal antibody, when administered to rsv-infected children. Pediatr Infect Dis J 2009;2 8:835–837.  [PubMed]

112. Lewinsohn DM, Bowden RA, Mattson D, Crawford SW. Phase I study of intravenous ribavirin treatment of respiratory syncytial virus pneumonia after marrow transplantation. Antimicrob Agents Chemother 1996; 40:2555-2557. [PubMed]

113. Liss HP, Bernstein J. Ribavirin aerosol in the elderly. Chest 1988; 93:1239-1241. [PubMed]

114. Long CE, Voter KZ, Barker WH, Hall CB. Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo. Pediatr Infect Dis J 1997; 16:1023-1028. [PubMed]

115. Liu V. Dhillon GS. Weill D. A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients. Transplant Infectious Disease.2010; 12(1):38-44. [PubMed]

116. Lukens MV, van de Pol A, Coenjaerts FE, Jansen NJKamp VMKimpen JLRossen JWUlfman LHTacke CEViveen MC,Koenderman LWolfs TFvan Bleek GM. Al. A systemic neutrophil response precedes robust robust CD8+ T-cell activation during natural respiratory sysncytial virus infection in infants. J Virol 2010; 2374-2383.  [PubMed]

117. Malley R, DeVincenzo J, Ramilo O, Dennehy PH, Meissner HC, Gruber WC, Sanchez PJ, Jafri H, Balsley J, Carlin D, Buckingham S, Vernacchio L, Ambrosino DM. Reduction of respiratory syncytial virus (RSV) in tracheal aspirates in intubated infants by use of humanized monoclonal antibody to RSV F protein. J Infect Dis 1988; 178:1555-1561. [PubMed]

118. Martin MA, Bock MJ, Peallen MA, Wenzel RP. Respiratory syncytial virus infections in adult bone marrow transplant recipients. Lancet 1988; i:1341-1343. [PubMed]

119. McColl MD, Corser RB, Bremner J, Chopra R. Case report: respiratory syncytial virus infection in adult HSCT recipients: effective therapy with short duration nebulised ribavirin. Bone Marrow Transplant 1998;21:423-425. [PubMed]

120. McKimm-Breschkin J. VP-14637 ViroPharma. Cur Opinion in Investigational Drugs 2000;1:425-427. [PubMed]

121. Megged O. Schlesinger Y.  Down syndrome and respiratory syncytial virus infection.  Pediatric Infectious Disease Journal.  2010; 29(7):672-3.  [PubMed]

122. Meert KL, Sarnaik AP, Gelmini MJ, Lieb TM. Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial. Crit Care Med 1994; 22:566-572.[PubMed]  

123. Meissner HC, Fulton DR, Groothuis JR, Geggel RL, Marx GR, Hemming VG, Hougen R, Snydman DR. Controlled trial to evaluate protection of high-risk infants against respiratory syncytial virus disease by using standard intravenous immune globulin. Antimicrob Agents Chemother 1993; 37:1655-1658. [PubMed]

124. Moler FW, Steinhart CM, Ohmit SM, Stidham GL. Effectiveness of ribavirin in otherwise well infants with respiratory syncytial virus-associated respiratory failure. J Pediatr 1996; 128:422-428. [PubMed]

125. Mufson MA, Levine HD, Wasil RE, Mocega-Gonzalez HE, Krause HE. Epidemiology of respiratory syncytial virus infection among infants and children in Chicago. Am J Epidemiol 1973; 98:88-95. [PubMed]

126. Murawski MR, Bowen GN, Cerny AM, Anderson LJ, Haynes LM, Tripp RA, Kurt-Jones EA, Finberg RW.  Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. Journal of Virology. 2009;83(3):1492-500.  [PubMed]

127. Neilson KA Yunis EJ. Demonstration of respiratory syncytial virus in an autopsy series. Pediatr Path 1990;10:491-502.[PubMed]

128. Nikitenko AA, Raifeld YE, Wang TZ. The discovery of RFI-641 as a potent and selective inhibitor of the respiratory syncytial virus. Bioorganic & Med Chem Letters 2001; 11:1041-1044. [PubMed]

129. Ohmit SE, Moler FW, Monto AS, Khan AS. Ribavirin utilization and clinical effectiveness in children hospitalized with respiratory syncytial virus infection. J Clin Epidemiol 1996; 49:963-967.  [PubMed]

130. Openshaw PJ. Immunity and immunopathology to respiratory syncytial virus. Am J Respir Crit Care Med 1995; 152:S59-S62.[PubMed]

131. Openshaw P, Clarke S, Record F. Pulmonary eosinophilic response to respiratory syncytial virus infection in mice sensitized to the major surface glycoprotein G. Internatl Immunol 1992; 4:493-500. [PubMed]

132. Piedimonte G. Neural mechanisms of respiratory syncytial virus-induced inflammation and prevention of respiratory syncytial virus sequelae. Am J Respir Crit Care Med 2001; 163:S18-S21. [PubMed]

133. Piedimonte G, King KA, Holmgren NL, Bertrand PJ, Rodriguez MM, Hirsch RL. A humanized monoclonal antibody against respiratory syncytial virus (Palivizumab) inhibits RSV-induced neurogenic-mediated inflammation in rat airways. Pediatr Res 2000; 47:351-356. [PubMed]

134. Prince GA, Hemming VG, Horswood RL, Chanock RM. Immunophrophylaxis and immunotherapy of respiratory syncytial virus infection in the cotton rat. Virus Res 1985; 3:193-206. [PubMed]

135. Prince GA, Mathews A, Curtis SJ, Porter DD. Treatment of respiratory syncytial virus bronchiolitis and pneumonia in a cotton rat model with systemically administered monoclonal antibody (Palivizumab) and glucocorticosteroid. J Infect Dis 2000; 182:1326-1330. [PubMed]

136. Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus lower respiratory tract infection. Arch Pediatr and Adolesc Med 1996; 150:942-947. [PubMed]

137. Rimensberger PC, Burek-Kozlowska A, Morell A, Germann D, Eigenmann AK, Steiner F, Burger R, Kuenzli M, Schaad UB. Aerosolized immunogloulin treatment of respiratory syncytial virus infection in infants. Pediatr Infect Dis J 1996; 15:209-216.[PubMed]

138. Ripple MJ, You D, Honnegowda S, Giaimo JD, Sewell AB, Becnel DM, Cormier SA. Immunomodulation with IL-4R alpha antisense oligonucleotide prevents respiratory syncytial virus-mediated pulmonary disease. Journal of Immunology. 2010;185(8):4804-11.   [PubMed]

139. Rodriguez WJ, Gruber WC, Groothuis JR, Simoes EA, Rosas AJ, Leprow M, Kramer A, Hemming V. Respiratory syncytial virus immune globulin treatment of RSV lower respiratory tract infection in previously healthy children. Pediatrics 1997;100:937-942. [PubMed]

140. Rodriguez WJ, Gruber WC, Welliver RC, Groothuis JR, Simoes EA, Meissner HC, Hemming VG, Hall CB, Lepow ML, Rosas AJ, Robertsen C, Kramer A and Respiratory Syncytial Virus Immune Globulin Study Group. Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections. Pediatrics 1997;99:472-475. [PubMed]

141. Rodriguez WJ. Management strategies for respiratory syncytial virus infections in infants. J Pediatr 1999;135:S45-S50.[PubMed]

142. Rodriguez WJ, Arrobio J, Fink R, Kim HW, Milburn C. Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Arch Pediatr and Adolesc Med 1999; 153:469-474. [PubMed]

143. Roosevelt G, Sheehan K, Grupp-Phelan J, Tanz RR, Listermick R. Dexamethasone in bronchiolitis: a randomised controlled trial. Lancet 1996;348:292-295.  [PubMed]

144. Sanchez PJ. Immunoprophylaxis of respiratory syncytial virus disease. Pediatr Infect Dis J 2000;19:791-801. [PubMed]

145. Schlender J, Bossert B, Buchholz U, Conzelmann K. Bovine respiratory syncytial virus nonstructural proteins NS1 and NS2 cooperatively antagonize alpha/beta interferon-induced antiviral response. J Virol 2000;74:8234-8242. [PubMed]

146. Shay DK, Holman RC, Roosevelt GE, Clarke MJ, Anderson LJ. Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979-1997. J Infect Dis 2001;183:16-22. [PubMed]

147. Shay D, Holman R, Newman R, Liu L, Stout J, Anderson LJ. Bronchioloitis-associated hospitalizations among US children, 1980-1996. JAMA 1999; 282:1440-1446.  [PubMed]

148. Sidwell RW, Barnard DL. Respiratory syncytial virus infections: recent prospects for control. Antiviral Res 2006; 71:379–390.[PubMed]

149. Simoes EA, Groothuis JR, Tristram DA, Allessi K, Lehr MV, Siber GR, Welliver RC. Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high-risk children. J Pediatr 1995;129:214-219. [PubMed]

150. Simoes EA, Sondheimer HM, Top FH, Meissner HC, Welliver RC, Kramer AA, Groothuis JR. Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. J Pediatr 1998;133:492-499. [PubMed]

151. Simoes EA, Carbonell-Estrany X. Impact of severe disease caused by respiratory syncytial virus in children living in developed countries.Pediatr Infect Dis J 2003; 22:S13–S20.  [PubMed]

152. Smith DW, Frankel LR, Mathers LH, Tang ATS, Ariagno RL, Prober CG. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med 1991; 325:24-29. [PubMed]

153. Sorrentino M, Powers T, Palivizumab Outcomes Study Group. Effectiveness of palivizumab: evaluation of outcomes from the 1998 to 1999 respiratory syncytial virus season. Pediatr Infect Dis J 2000;19:1068-1071. [PubMed]

154. Spaarelid E, Ljungman P, Ekelof-Andstrom E, Aschan J, Ringden O, Winiarski J, Wahlin B, Andersson J. Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections. Bone Marrow Transplant 1997;19:905-908. [PubMed]

155. Sriskandan S, Shaunak S. Correspondence: respiratory syncytial infection in an adult with AIDS. Clin Infect Dis 1993;17:1065.[PubMed]

156. Sudo K, Miyazaki Y, Kojima N, et al. YM-53403, a unique antirespiratory syncytial virus agent with a novel mechanism of action.  Antiviral Res 2005; 65:125–131.  [PubMed]

157. Sullender WM. Respiratory syncytial virus genetic and antigenic diversity. Clinic Microbiol Rev 2000; 13:1-15. [PubMed]

158. Taber LH, Knight V, Gilbert BE. Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics 1983; 72:613-618. [PubMed]

159. Takimoto CH, Cram DL, Root RK. Respiratory syncytial virus infections on an adult medical ward. Arch Intern Med 1991; 151:706-708.  [PubMed]

160. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997; 99:93-99. [PubMed]

161. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003; 289:179–186. [PubMed]

162. Torok TJ, Clarke MJ, Holman RC, Anderson LJ. Temporal and spatial trends in respiratory syncytial virus activity in the United States, 1990-1996. RSV After 40 Years: An Anniversary Symposium Kiawah Island. [PubMed]

163. Tripp RA, Moore D, Winter J, Anderson LJ. Respiratory syncytial virus infection and G and/or SH protein expression contribute to substance P, which mediates inflammation and enhanced pulmonary disease in BALB/c mice. J Virol 2000;74:1614-1622. [PubMed]

164. Tripp RA, Jones LP, Haynes LM, HaoQiang Z, Murphy PM, Anderson LJ. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nature Immunol 2001; 2:732-738.  [PubMed]

165. Haynes LM, Caidi H, Radu GU, Miao C, Harcourt JL, Tripp RA, Anderson LJ. Therapeutic monocloncal antibody treatment targeting respiratory Syncytial virus (RSV) G protein mediates viral clearance and reduces the pathogenesis fo RSV infection in BALB/c mice. J Infect Dis 2009; 200:439-47. [PubMed]

166. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children.Cochrane Database Syst Rev 2007;(1):CD000181. [PubMed]

167. Walsh EE, Falsey AR, Hennessey PA. Respiratory syncytial virus and other infections in persons with chronic cardiopulmonary disease. Am J Respir Crit Care Med 1999; 160:791-795. [PubMed]

168. Walsh EE, McConnochie KM, Long CE, Hall CB. Severity of respiratory syncytial virus infection is related to virus strain. J Infect Dis 1997; 175:814-820. [PubMed]

169. Walsh EE, Hall CB, Briselli M, Brandriss MW, Schlesinger JJ. Immunization with glycoprotein subunits of respiratory syncytial virus to protect cotton rats against viral infection. J Infect Dis 1987; 155:1198-1204. [PubMed]

170. Walsh EE, Hruska J. Monoclonal antibodies to respiratory syncytial virus proteins: Identification of the fusion protein. J Virol 1983;47:171-177. [PubMed]

171. Welliver RC, Wong D, Sun M, Middleton Jr E, Vaughan R, Ogra PL. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med 1981; 205:841-846. [PubMed]

172. Welliver RC Sr. Checchia PA. Bauman JH. Fernandes AW. Mahadevia PJ. Hall CB. Fatality rates in published reports of RSV hospitalizations among high-risk and otherwise healthy children. [Review] Current Medical Research & Opinion. 2010; 26(9):2175-81.  [PubMed] 

173. Whimbey E, Champlin RE, Englund JA, Mirza NQ, Piedra PA, Goodrich JM, Przepiorka D, Luna DM, Morice RC, Neumann JL, Elting LS, Bodey GP. Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant 1995; 16:393-399. [PubMed]

174. Whimbey E, Champlin RE, Couch RB, Englund JA, Goodrich JM, Raad I, Przepiorka D, Lewis VA, Mirza N, Yousuf H, Tarrand JJ, Bodey GP. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996;22:778-782. [PubMed]

175. Whimbey E, Couch RB, Englund JA, Andreef MA, Goodrich JM, Raad I, Lewis VA, Mirza N, Luna MA, Baxter B, Tarrand JJ, Bodey GP. Respiratory syncytial virus pneumonia in hospitalized adult patients with leukemia. Clin Infect Dis 1995; 21:376-379.[PubMed]

176. Whimbey E, Englund JA, Couch RB. Community respiratory virus infections in immunocompromised patients with cancer. Am J Med 1997;102:10-18.  [PubMed]

177. Wu H, Pfarr DS, Johnson S, Brewah YAWoods RMPatel NKWhite WIYoung JFKiener PA.  Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. J Mol Biol 2007;368:652–665. [PubMed]

178. Zhang W, Yang H, Kong X, et al. Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med 2005; 11:56–62.  [PubMed]

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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:

  1. Children with complicated congenital heart disease, bronchopulmonary dysplasia, cystic fibrosis and other chronic lung disease
  2. Previously well premature infants (< 37 weeks gestation)
  3. Infants < 6 weeks of age
  4. Children with immunosuppressive conditions
  5. Severely ill children with or without mechanical ventilation
  6. 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



CLD = congenital lung disease     CHD = congenital heart disease

Muenchhoff M, et al.  Sex Differences in Pediatric Infectious Diseases.  J Infect Dis 2014;209:S120-6.

Chanock RM, et al.  Respiratory Syncytial Virus.  American Journal of Public Health 1962;52:918-925.



Clinical Manifestations





Respiratory Syncytial Virus