RSV infections: State of the art

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ABSTRACTRespiratory syncytial virus (RSV) is one of the most common lower respiratory disease in infants and young children worldwide. Despite its long history, a safe and effective cure for RSV remains elusive. Nonetheless, further understanding of RSV pathogenesis and risk factors have led to advances in prophylaxis and management. The leading risk factor for RSV is premature birth, primarily because fewer protective antibodies are transmitted from the mother to the infant. For full-term born infants, susceptibility to RSV increases as maternal IgG titers decline to a nadir at 2 to 3 months of age. Because of the unique pathophysiologic mechanisms involved in this infection, it is likely that future treatment strategies will focus on modulating the host immune response to the virus, rather than virucidal or virustatic molecules.



Understanding of respiratory syncytial virus (RSV) infection has increased substantially since its discovery, but a curative treatment remains elusive. Insights into the impact of gestational age, epidemiologic patterns, virus incubation and proliferation, pathogenesis and pathophysiology, and host immune response have set the stage for preventive measures and effective therapy. In today’s clinical practice, a specific humanized antibody is administered to high-risk infants, which is safe and effective in preventing RSV-related acute and postacute symptoms.


Reprinted with permission from Wolters Kluwer Health (Collins PL, et al. Respiratory syncytial virus and metapneumovirus. In: Knipe DM, Howley PM, eds. Fields Virology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:1089).
Figure 1. Electron photomicrograph of budding RSV virion used to indicate location and chain length of the RSV proteins.

Knowledge of the molecular structure of RSV is important because it gives clues as to how it infects the human airways (Figure 1). The virus is made of a single strand of RNA contained in a nucleocapsid made of only 11 proteins and covered by a lipid envelope. Essential for the virulence of RSV are the surface glycoproteins G and F (fusion) that attach to the host airway epithelial cells and merge the viral envelope to the membranes of multiple adjacent cells, creating the “syncytia” that give RSV its name. G and F proteins are also the principal antigens exposed to the host immune system, and therefore the patient’s neutralizing antibodies are primarily directed against these targets.1

Adapted from Ducoffre G, Cauchi P, Hendricks E. Respiratory syncytial virus epidemiology in Belgium in 1998, 1999 and 2000. Presented at World Congress of Perinatal Medicine, Barcelona Spain, September 23-27 2001.
Figure 2. Etiology of acute respiratory infections in children. RSV is by far the most frequent cause of pediatric bronchiolitis and pneumonia. RSV = respiratory syncytial virus, ARI = acute respiratory infection.

Human RSV is a Pneumovirus belonging to the Paramyxoviridae family. There are two strains of RSV (A and B) found in infants. Approximately 60% of all lower respiratory infections in preschool-aged children worldwide are caused by RSV (Figure 2).2 All the other viruses—including influenza, parainfluenza, metapneumovirus, and adenoviruses—as well as bacterial infections are much less common during the first years of life.


The burden of RSV continues to grow worldwide, particularly among the youngest segment of the population.2 During the first year of life, infants are not adequately protected from RSV by maternal immunoglobulins. Thus, approximately 80% of lower respiratory infections in children younger than 1 year are due to RSV with peak incidence occurring at 2 to 3 months of age. In the United States, bronchiolitis-associated hospitalizations in infants younger than 12 months more than doubled between 1980 and 1996, and in 1996, accounted for approximately 3% of all pediatric hospitalizations. Up to 120,000 RSV-related pediatric hospitalizations per year occur during a typical season.3

Mortality rates have improved significantly—at least in industrialized countries—and now are probably less than 1%.4 In the United States, RSV is estimated to cause fewer than 100 deaths annually, primarily because of better supportive care and the use of mechanical ventilation.

The seasonality of RSV varies by region. In the northern United States from October through March, RSV causes up to 90% of lower respiratory infection cases in infants. In the southern United States and farther into the southern hemisphere, the virus becomes endemic and can be present throughout the year with peak incidence occurring from August to September.2


The severity and frequency of RSV infection is influenced by well-known risk factors including environmental overcrowding, absence of breastfeeding, and immunosuppression. Children with chronic lung disease are predisposed to clinically significant RSV infection by their limited respiratory reserve, and 60% of those affected will be hospitalized. Hemo­dynamically significant congenital heart defects associated with higher pulmonary blood flow also increase risk for severe RSV disease, with more than 50% of children infected requiring hospitalization.4

Prematurity and increased RSV risk

Premature-born infants have a 10-fold increased risk of RSV infection and account for 25% to 30% of RSV hospitalizations annually.4 Prematurity as a risk factor for RSV is primarily tied to the physiology of placental immunoglobulin G (IgG) transfer. The human placenta is not permeable to IgG during the first half of pregnancy because of low expression of the Fc receptor needed to bind immunoglobulins and transfer them into the fetal circulation. Further, maternal IgG is recognized as a foreign protein by the newborn and is progressively removed from the circulation by the liver.5

Thus, the IgG decline continues postnatally, reaching the lowest concentration at 2 to 3 months of age because newborns are unable to synthesize their own antibodies. During this time, full-term born babies are at the highest risk for developing RSV infection. The risk is logically higher for premature infants who lack the full benefit of IgG transfer occurring during the last trimester, rendering antibody levels even lower at nadir. The greater the prematurity, the less the antibody protection and the more the predisposition to RSV infection.5


The hallmark signs of RSV bronchiolitis are wheezing, cough, and increased work of breathing caused by infection of the bronchiolar airways. However, the nasal phase of the infection may cause irritation and trigeminal nerve activation associated with sneezing, congestion, and apnea. Indeed, approximately 20% of infants manifest an apnea episode as the first symptom of infection.6

The specific etiology of RSV can be confirmed by antigen detection tests, currently being replaced by more sensitive polymerase chain reaction (PCR)-based assays. Chest radiography reveals obvious signs of RSV lower respiratory infection, typically patch atelectasis, increased peribronchial markings, and bilateral hyperinflation with flattening of the diaphragm. Current guidelines indicate that the diagnosis of acute bronchiolitis should be based exclusively on the history and physical exam; it does not require radiographic or laboratory studies.

Correct etiologic diagnosis, however, is crucial to avoid unnecessary therapies and rule out rare conditions that could be worsened by therapies commonly used for bronchiolitis. For example, infants with dilated cardiomyopathy and congestive heart failure may present with symptoms of wheezing that mimic an acute respiratory infection, but these patients are at risk of developing supraventricular tachycardia and even cardiopulmonary collapse associated with administration of beta-agonist agents. In such cases, a chest radiograph will show cardiomegaly suggesting a different diagnosis and therapy, and thus avoid significant complications.

Recurrent wheezing

Figure 3. This graph combines retrospective data from multiple studies suggesting an increased risk of subsequent wheezing in children who have had RSV infection in early life. The overall risk declines with age, but is still significant several years after the original infection.7-9

Children infected with RSV during their first year of life develop a higher risk of subsequent episodes of bronchial obstruction. Several retrospective studies conducted in the 1980s explored the incidence of lower respiratory symptoms continuing for years after initial RSV infection. Particularly unexpected was the finding that at least one-third of children hospitalized with RSV bronchiolitis will continue to wheeze beyond 6 to 8 years of age (Figure 3).7–9

More recent prospective studies of recurrent wheezing following RSV infection have been conducted. A Swedish study of 47 infants hospitalized with culture-proven RSV bronchiolitis showed significantly increased physician-diagnosed asthma (38%) compared with the 93 controls (2%) at age 7.5 years (P < .0001).10 Follow-up studies of the same cohort found increased risk for recurrent wheezing or asthma in the RSV group still present at age 13 years11 and 18 years12 compared with controls.


History of RSV infection is important both as a trigger of asthma attacks and in the inception of asthma. Family history of asthma is the most important marker of a genetic predisposition to develop asthma. A multivariate analysis of the Swedish cohort discussed above showed that children with neither previous RSV infection nor family history of asthma had approximately a 5% risk of developing asthma by age 7.5 years. None of the children with a family history of asthma but no history of RSV infection developed asthma during follow-up. Children who had an RSV infection without a familial predisposition to asthma had approximately a 20% risk of asthma development. Children with both previous RSV infection and a family history of asthma had the highest (~40%) risk of developing asthma.10

These results provide important information about asthma pathogenesis in early life. The main implication is that even if a child has a genetic predisposition to asthma development, clinical manifestations will not develop without exposure to environmental agents that allow the actual expression of the predisposing genes, such as pollution, unbalanced diet, or early-life RSV infection. On the other hand, children without genetic predisposition can present with clinical manifestations undistinguishable from atopic asthma if their respiratory tract is exposed to specific viral pathogens during crucial developmental windows in early life. Finally, the combination of genetic predisposition and adverse environmental exposures in infancy carries the highest risk of asthma.

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