Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children. Globally, RSV is estimated to cause 3.2 million hospitalizations and 118,000 deaths in children younger than age 5 years.1 In the United States, RSV-attributable mortality is low and is typically associated with underlying complex medical conditions.2 However, RSV causes a substantial burden on the health care system each year, accounting for hospitalizations in 3 per 1,000 children, emergency department visits in 28 per 1,000, and outpatient clinic visits in 80 per 1,000 children younger than age 5 years every year.3 Mean hospitalization costs of full-term infants who are infected with RSV exceed $10,000 and increase 4-fold for infants with extreme prematurity (<29 weeks gestational age).4 Between 1997 and 2000, it was estimated that the economic burden of RSV-associated hospitalizations was $2.6 billion in the US alone.5 For every RSV infection in children younger than age 3 years, children miss an average of 1.9 days of school and parents miss 1.4 days of work.6 Thus, the direct and indirect costs of this infection are vast and likely underestimated.
Almost all children have been infected with RSV by age 2 years, and infections recur throughout the lifetime. In the US, RSV transmission typically lasts from November through March and peaks in the winter months. Transmission occurs via inhalation of large respiratory droplets or via contact with fomites and self-inoculation. The incubation period after infection is 4 to 6 days. The average duration of viral shedding is 11 days, but up to 13% of infected infants shed for more than 21 days. Prolonged shedding has been associated with younger patient age, severe disease, concurrent RSV infections in the same household,7 and immunocompromised states.
Nosocomial transmission has been reported for several decades and is particularly problematic in vulnerable patient populations, such as patients on pediatric wards or patients with immune compromise.8–10 Nosocomial outbreaks can be associated with significant morbidity and high attributable costs, particularly in neonates and young infants. To prevent nosocomial RSV transmission, the Centers for Disease Control and Prevention recommends contact isolation using gowns and gloves in addition to standard precautions.11 Other recommended strategies to prevent nosocomial transmission include meticulous hand hygiene, visitor restriction, and assigning personnel and equipment to specific patients.8
Upper Respiratory Tract Infection
RSV causes the spectrum of acute respiratory tract infection, from upper to lower respiratory disease. Primary infection is almost always symptomatic and commonly progresses to lower respiratory tract disease, which disproportionately affects neonates and young infants. Upper respiratory tract infections (URTIs) from RSV are characterized by cough, congestion, pharyngitis, low-grade fever, poor feeding, and copious nasal secretions. URTIs can be complicated by sinusitis and acute otitis media in up to 60% of patients, which may be either viral or bacterial in etiology.6
Lower Respiratory Tract Infection
Progression to lower respiratory tract disease is hallmarked by wheezing, crackles, tachypnea, hypoxia, nasal flaring, and other signs of respiratory distress. In infants, this most commonly presents as bronchiolitis, whereas older children and adults may present with a lobar viral pneumonia. The pathogenesis of RSV LRTI is characterized by epithelial cell necrosis, sloughing, mucus secretion, local inflammatory cell infiltration, airway hyperreactivity, and lower airway obstruction leading to air trapping. This leads to characteristic physical examination findings including diffuse crackles and wheezes with tachypnea, hypoxia, and respiratory distress. Chest imaging findings (Figure 1) may include lung hyperexpansion, diffuse interstitial infiltrates, atelectasis, or focal consolidation. Up to 15% of infants hospitalized with RSV progress to respiratory failure requiring intensive care unit (ICU) admission and escalating respiratory support including mechanical ventilation.12
Chest radiograph of an infant with respiratory syncytial virus bronchiolitis. Findings include hyperinflation, hazy interstitial opacities, and atelectasis.
Underlying medical conditions that increase the risk of severe RSV disease include prematurity, chronic lung disease, and hemodynamically significant congenital heart disease. Although less well studied, patients with primary or secondary immune deficiencies, trisomy 21, and cystic fibrosis also appear to be at increased risk of hospitalization from RSV.13 Social and epidemiological risk factors for severe RSV disease have been reported to include young chronological age, season of birth, male sex, daycare attendance, crowding, and a school-aged older sibling.14 Risk factors of unclear significance include socioeconomic status, parental education, second-hand smoke exposure, and lack of breast-feeding. Similarly, a personal or family history of atopy has not been definitively associated with increased risk of severe disease.14
Currently, palivizumab, a humanized monoclonal antibody directed against the RSV fusion protein, is recommended for RSV prophylaxis of certain infants and children with high risk to receive monthly during the RSV season.13 Palivizumab has been shown to significantly reduce RSV-associated hospitalizations in infants with extreme prematurity, congenital heart disease, and bronchopulmonary dysplasia.15,16 However, the high cost of palivizumab has been prohibitive to broader administration to other potentially at-risk populations; thus, improved prophylactic strategies and expanded access to them are needed in the future.
Apnea affects up to 24% of infants hospitalized with RSV infection.17 Apnea is typically nonobstructive and is presumed to be attributable to immature respiratory drive.18 Clinical predictors of apnea include history of prematurity and younger postnatal age.17–20 For these infants, apnea is commonly the presenting symptom at the time of hospitalization in addition to signs of lower respiratory tract involvement. These infants are less likely to present with rhinorrhea, coughing, or fever.20 The incidence of apnea peaks on days 4 to 5 of illness, and typically resolves within 5 days.20 RSV-associated apnea has not been associated with increased risk of future apneic events.
Other Reported Complications
Although RSV is not known to be a cardiotropic virus, fulminant RSV infection has been associated with cardiopulmonary failure, shock, arrhythmias, and the need for cardiopulmonary resuscitation.21 Cardiovascular complications have been observed in up to 9% of hospitalized infants with RSV infection,21 and are most common in patients with underlying cardiovascular disease. One possible explanation of these findings is increased pulmonary vascular resistance and increased myocardial strain leading to right-sided heart failure. Indeed, the transaminase elevation observed in some severely affected children has been attributed to hepatic venous congestion from right-sided heart failure.
Similarly, although RSV is not a neurotropic virus, fulminant RSV has been associated with central nervous system manifestations including central apnea, hypothermia, lethargy, and seizures.21 Seizures have been attributed to hyponatremia, which is a relatively common finding in patients with severe RSV disease and dehydration. Hypoxia, acidosis, and other electrolyte derangements also could be contributing factors in the development of neurologic manifestations.
Secondary Bacterial Pneumonia
The incidence of secondary bacterial pneumonia in patients infected with RSV is uncertain due to the difficulty in establishing diagnosis of bacterial disease. However, in infants who are infected with RSV requiring ICU admission for mechanical ventilation, endotracheal aspirates of lower airway secretions yield presumptive bacterial co-pathogens in 26% to 44% of patients studied.22–24 The most commonly identified copathogens are Haemophilus influenzae, followed by Staphylococcus aureus, Moraxella catarrhalis, and Streptococcus pneumoniae. Nosocomial pathogens, such as Pseudomonas aeruginosa, are also identified in a minority of patients and should be considered in patients who have been mechanically ventilated more than 48 hours. Bacterial co-infection has been associated with increased disease severity as indicated by significantly longer duration of mechanical ventilation.
Although bacterial coinfections are not uncommon in children hospitalized with RSV LRTIs, a recent prospective multicenter analysis demonstrated that antibiotics are still likely overused in this population. Of 188 children who were hospitalized with RSV-positive LRTIs, as many as one-third were treated unnecessarily with antibiotics.25 Thus, until risk factors for secondary bacterial infections are more clearly defined, a judicious approach to antimicrobial use in this patient population is likely prudent.
Other Concomitant Bacterial Infections
The incidence of other concomitant serious bacterial infections (SBIs) in febrile infants presenting with RSV infection is low, but not zero. A systematic review of studies describing infants younger than 60 to 90 days with RSV infection or bronchiolitis found a weighted rate of 3.3% URTI in this population.26 Bacteremia was less frequent and was typically associated with URTI, and there were no cases of bacterial meningitis identified.26 When directly compared to infants testing negative for RSV, a prospective analysis of 1,248 infants younger than 60 days found that infants who were RSV positive had a significantly lower risk of SBI (7% vs. 12.5%, risk difference: 5.5%; 95% confidence interval: 1.7%–9.4%).27 However, a more recent meta-analysis evaluating only febrile neonates younger than 30 days presenting to pediatric emergency departments found the rate of SBI was 11.5% in infants who are RSV positive compared to 15.3% in infants who were RSV negative, which was not significantly different (P = .46).28 Thus, although the frequency of SBI in infants who are RSV positive is relatively low, it is still appreciable and may not differ from infants who are RSV negative infants at younger than 30 days.
The advent of molecular diagnostics has enabled the detection of viral coinfections with high sensitivity, but research into the clinical significance of these findings has been conflicting.29 In the largest prospective analysis to date of 2,322 children hospitalized with RSV infection, viral coinfections were identified in 43% of patients using molecular diagnostic techniques.30 Approximately 25% had rhinovirus, 15% had adenovirus, and 1% had influenza virus.30 Overall, respiratory viral coinfections were not associated with disease severity. However, both RSV-adenovirus and RSV-influenza virus coinfections were associated with increased odds of life-threatening disease compared to RSV infection alone. These results merit further investigation.
Association with Childhood Wheezing and Asthma
Severe RSV infection in infancy has long been associated with the development of reactive airway disease and childhood asthma, but establishing a causal relationship has been elusive. A prospective analysis of 47 infants hospitalized with RSV found that the number of children with physician-diagnosed asthma was significantly higher in patients with prior RSV LRTI (23% vs 1%, P < .001) compared to age-matched controls.31 This cohort was subsequently observed until age 18 years, and patients with prior RSV LRTI still had increased prevalence of asthma (39% vs 9%, P < .001) into young adulthood.32 Stein et al.33 similarly found that infant RSV LRTI was associated with significantly increased risk of recurrent wheezing at age 6 years in a prospective analysis of 1,246 children enrolled in the Tucson Children's Respiratory Study. The risk, however, markedly decreased with age and was no longer significant by age 13 years. Further solidifying the relationship between infant RSV LRTI and childhood asthma, Carroll et al.34 performed a population-based retrospective analysis of 90,341 children enrolled in the Tennessee state Medicaid program. They found a dose-response relationship between the severity of infant bronchiolitis and the increased odds of both development of early childhood asthma and asthma severity.
Although these studies and others have demonstrated a clear epidemiologic relationship between early RSV LRTI and the development of childhood asthma, they have not established causation or a mechanism of action. Thus, it is possible that severe RSV disease is only a predictor of the true risk factor for asthma development, rather than being its actual cause. To test this hypothesis, Chawes et al.35 measured airway hyperresponsiveness in neonates who had not been infected with RSV and correlated it with the subsequent development of severe bronchiolitis. Using methacholine challenge and raised-volume rapid thoracoabdominal compression technique, they found that airway hyperresponsiveness preceded and was a predictor of severe bronchiolitis. These findings implied that a genetic and/or environmental predisposition to airway hyperreactivity may be a shared risk factor for the development of both severe RSV LRTI and childhood asthma. Supporting this conclusion, a randomized, single-blinded, placebo-controlled trial evaluating the administration of palivizumab to premature infants (33 to 35 weeks gestational age) found that, upon long-term follow-up through age 6 years, RSV prevention ultimately failed to impact asthma diagnoses or lung function.36
In summary, although a clear relationship exists between infant RSV LRTI and the development of childhood asthma, causation has not been established and this remains an area of active research.
Although RSV causes substantial disease burden, a spectrum of upper and lower respiratory tract manifestations, high direct and indirect costs, and significant global childhood mortality, an effective vaccine is not yet available. Although most RSV infections occur in toddlers and young children, disease severity disproportionately affects infants and neonates who are more likely to require hospitalization, ICU admission, and mechanical ventilation. Further research is needed to improve prophylactic strategies to prevent progression to severe RSV disease in these vulnerable populations.
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- Munywoki PK, Koech DC, Agoti CN, et al. Influence of age, severity of infection, and co-infection on the duration of respiratory syncytial virus (RSV) shedding. Epidemiol Infect. 2015;143:804–812. doi:. doi:10.1017/S0950268814001393 [CrossRef]
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