1. Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. Although the most effective management of this infection remains supportive care, many patients continue to be managed with therapies that lack the support of scientific evidence.

2. Although the quest for a safe and effective vaccine remains unsuccessful, the more vulnerable patients can be protected with passive prophylaxis. Because of limited clinical benefits and high costs, RSV prophylaxis should be limited to high-risk infants as directed by the most current evidence-based guidelines that, however, are not consistently followed.

3. The acute phase of this infection is often followed by episodes of wheezing that recur for months or years and usually lead to a physician diagnosis of asthma. The phenotype of post-RSV wheezing is different from atopic asthma, yet it is usually managed using the same pharmacologic therapy with often ineffective results.

Objectives

After reading this article, readers should be able to:

1. Understand the microbiology, epidemiology, pathophysiology, and clinical manifestations of RSV bronchiolitis in infants and children.

2. Know the scientific evidence relevant to prophylactic and therapeutic strategies currently available and recognize the lack of evidence concerning several pharmacologic agents commonly used in the management of bronchiolitis.

3. Be aware of alternative pharmacologic strategies currently being evaluated. Respiratory Syncytial Virus Bronchiolitis Essay.

4. Learn the epidemiologic and experimental information suggesting the existence of a link between early-life infection with RSV and the subsequent development of recurrent wheezing and asthma in childhood and adolescence.

Virology

Human respiratory syncytial virus (RSV) is a single-stranded RNA virus of the Paramyxoviridae family whose genome includes 10 genes that encode 11 proteins (Figure 1). Two surface proteins, the F (fusion) protein and the G (attachment glycoprotein) protein, are the major viral antigens and play a critical role in the virulence of RSV. The G protein mediates RSV attachment to the host cell, after which the F protein enables fusion of the host and viral plasma membranes to permit virus passage into the host cell. The F protein also promotes the aggregation of multinucleated cells through fusion of their plasma membranes, producing the syncytia for which the virus is named and allows the transmission of virus from cell to cell. RSV has 2 distinct antigenic subtypes, A and B, which are usually present in the communities during seasonal outbreaks. It remains controversial whether subtype A is more strongly associated with severe disease.

Epidemiology

RSV is the most frequent cause of bronchiolitis in infants and young children and accounts in the United States alone for approximately 125,000 hospitalizations and 250 infant deaths every year. Global estimates by the World Health Organization indicate that RSV accounts overall for more than 60% of acute respiratory infections in children. Furthermore, RSV is responsible for more than 80% of lower respiratory tract infections (LRTIs) in infants younger than 1 year and annually during the peak of viral season. In summary, RSV is by far the most frequent cause of pediatric bronchiolitis and pneumonia (Figure 2).

Nearly all children are infected at least once by the time they are age 2 years, but peak incidence occurs between ages 2 and 3 months and corresponds to nadir concentrations of protective maternal IgG transferred to the fetus through the placenta. Seasonal outbreaks occur each year throughout the world, although onset, peak, and duration vary from one year to the next. In the United States, the annual epidemics usually begin in November, peak in January or February, and end in May.

However, the epidemiology of RSV differs widely across latitudes and meteorologic conditions.Respiratory Syncytial Virus Bronchiolitis Essay.  For example, at sites with persistently warm temperatures and high humidity, RSV activity tends to be continuous throughout the year, peaking in summer and early autumn. In temperate climates, RSV activity is maximal during winter and correlates with lower temperatures. In areas where temperatures remain colder throughout the year, RSV activity again becomes nearly continuous. Thus, RSV activity in communities is affected by both ambient temperature and absolute humidity, perhaps reflecting meteorologic combinations that allow greater stability of RSV in aerosols.

Morbidity and mortality of RSV disease are higher in premature infants and in infants with chronic lung disease (eg, bronchopulmonary dysplasia, cystic fibrosis, and interstitial lung diseases) or hemodynamically significant congenital heart disease. Because preterm infants miss, in part or completely, the third trimester window during which the placenta expresses Fc receptors mediating the transfer of maternal IgG to the fetus, they are born with reduced humoral protection against infection and reach lower nadir concentrations of maternal IgG. This is compounded by T-cell–mediated responses that are inefficient because T cells also mature primarily during the last trimester of pregnancy.

Development of bronchopulmonary dysplasia or other chronic respiratory conditions amplifies the risk of severe infections by limiting pulmonary functional reserve, distorting airway architecture, and promoting a proinflammatory milieu. Additional risk factors for severe disease include age younger than 12 weeks, history of prematurity, male sex, crowding, lack of breastfeeding, congenital heart disease, and any immunodeficiency. Despite numerous studies that have explored whether environmental tobacco smoke exposure affects RSV morbidity, definitive evidence of this association is lacking, and its clinical significance remains controversial. Nevertheless, physicians should inquire about tobacco smoke exposure when assessing infants and children for bronchiolitis and advise caregivers about smoke cessation.

Previous infection with RSV does not convey persistent immunity even in the presence of significant antibody titers, although higher titers may attenuate the course of the disease. Consequently, subsequent infection is common, can recur within the same viral season, and occurs across all age groups. The first episodes of infection typically occur in the first 2 years after birth and tend to be the most severe because of the limited immunologic protection discussed above, smaller airway size, and unique structural and functional features of the developing respiratory tract (eg, lack of interalveolar pores and channels and different innervation patterns). Respiratory Syncytial Virus Bronchiolitis Essay.

Most subsequent infections remain confined to the upper respiratory tract and run a milder course, although the illness may still progress to an LRTI, especially in elderly and immunodeficient patients, usually characterized by more severe symptoms. The clinical manifestations of RSV pneumonia in immunocompromised patients vary, depending on the extent and severity of the underlying deficit, ranging from substantial morbidity and mortality in the first 3 months after bone marrow transplantation to a usually milder course in patients with AIDS.

Pathogenesis and Pathophysiology

Transmission of RSV infection occurs through inoculation of the nasopharyngeal or conjunctival mucosa with respiratory secretions from infected individuals. The virus remains viable on hard surfaces for up to 6 hours, on rubber gloves for 90 minutes, and on skin for 20 minutes. This prolonged survival highlights the need for hand washing and contact precautions as an essential (and cost-effective) practice to limit the spread of infection, especially in clinic settings. The incubation period ranges from 2 to 8 days, and immunocompetent individuals can shed the virus for up to 3 weeks, although on average this is limited to approximately 8 days. However, viral shedding from immunocompromised individuals can continue for several months because intracellular replication is not effectively contained by specific cell-mediated immunity.

RSV infection starts in the nasopharyngeal epithelium but then spreads rapidly by intercellular transmission through the lower airways, reaching the terminal bronchioles, where the replication of this virus is most efficient. Direct pathologic consequences of lytic viral replication include sloughing of necrotic epithelial cells, which exposes the dense subepithelial network of nociceptive nerve fibers, forming the afferent limb for the cough reflex. Respiratory Syncytial Virus Bronchiolitis Essay.The initial influx of polymorphonuclear neutrophils into the airways is rapidly replaced by predominantly lymphomononuclear infiltration of peribronchiolar tissues and increased microvascular permeability, leading to submucosal edema and swelling. Mucous secretions increase in quantity and viscosity and tend to pool because of the loss of ciliated epithelium, resulting in widespread mucous plugging.

This constellation of acute inflammatory changes that form the immediate response to exponential viral replication in the bronchioles leads to airway obstruction and air trapping, producing the classic clinical triad of polyphonic wheezing, patchy atelectasis, and bilateral hyperinflation. However, disease severity and duration are primarily a function of the immune response mounted by the host. Innate immune mechanisms provide the respiratory tract with a first barrier against the establishment of a productive infection. Subsequently, specific humoral and cell-mediated immunity play a critical role in clearing the infection and attenuating its course.

Although this response does not result in complete protection against subsequent infection, it decreases their severity. In infants, higher titers of maternally derived RSV-neutralizing antibody are associated with a much lower risk of hospitalization due to RSV, and this protective effect can be replaced or enhanced in high-risk infants by passive prophylaxis. Cytotoxic T lymphocytes are central in the control of active infection and viral clearance, which explains why immunocompromised individuals with deficient cell-mediated immunity experience more severe and prolonged RSV disease and shed the virus much longer.

Clinical Manifestations

RSV infection in children almost always causes clinical manifestations, but these manifestations can vary widely in severity, depending on the patient’s age, comorbidities, environmental exposures, and history of previous infections. Typically, the infection starts with signs and symptoms of mucosal inflammation and irritation of the upper respiratory tract (congestion, rhinorrhea, and sneezing). In the next few days, the clinical status evolves with involvement of the lower respiratory tract manifested by cough and increased work of breathing with use of accessory respiratory muscles to overcome the increased resistance of obstructed airways. As noted above, many of the clinical manifestations of airway obstruction are driven by the immune response against the virus rather than by viral replication and direct cytotoxicity. Therefore, wheezing and other typical signs of bronchiolitis may be reduced or even absent in immunosuppressed patients and be replaced by rapidly evolving parenchymal infiltrates that can lead to acute respiratory distress syndrome.

Inspection reveals respiratory distress ranging from minimal to profound respiratory failure associated with a variable degree of nasal flaring and intercostal retractions. Respiratory Syncytial Virus Bronchiolitis Essay. Auscultation reflects the vibration of conducting airways generated by turbulent airflow and is remarkable for a prolonged expiratory phase, diffuse polyphonic wheezing, and coarse crackles (rales) scattered throughout the lung fields. Pulse oxymetry and arterial blood gas analysis detect moderate to severe hypoxemia derived primarily from the perfusion of respiratory units that are poorly ventilated because of mucous plugging (ventilation-perfusion mismatch). Progressive carbon dioxide retention and respiratory acidosis signal the development of respiratory muscle fatigue and evolving respiratory failure that require ventilatory assistance.

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Infants are usually more severely affected and may also develop lethargy, fever, poor feeding, and otitis media, whereas older children typically manifest symptoms of the upper respiratory tract but may also develop tracheobronchitis. Apnea is a well-known complication of RSV infection in infants, and its incidence is as high as 20% in infants younger than 6 months who require hospitalization. When present, apnea usually is an early event that precedes lower respiratory tract signs and symptoms, suggesting the involvement of reflex neural activity triggered in the upper airways. The highest incidence of apnea occurs in premature infants and in infants younger than 1 month, probably because of the relative immaturity of ventilatory control. In most cases, however, apnea is self-limited and does not recur with subsequent infections.

The diagnosis of acute bronchiolitis should be based exclusively on the history and physical examination findings and does not require radiographic or laboratory studies. The specific cause can be confirmed by antigen detection tests, currently being replaced by more sensitive polymerase chain reaction–based assays. Arguably, this step in not essential because, especially during the epidemic peak and in the first year after birth, RSV is responsible for most cases of bronchiolitis and other pathogens are much less common. However, confirming the viral origin strengthens the rationale for withholding therapies known to be ineffective and provides prognostic clues concerning complications, such as recurrent wheezing and asthma, based on robust epidemiologic data. Respiratory Syncytial Virus Bronchiolitis Essay.