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Monograph to the June 2007 issue

Current Issues in Pediatric Care: Infants



Identifying risk factors for severe RSV infection

Respiratory syncytial virus (RSV), a common pathogen in infancy that infects approximately two-thirds of children in their first year of life and nearly all children by age 2,1 generally causes acute respiratory tract illness limited to cold-like symptoms. In infants and children, RSV is a leading cause of lower respiratory tract infections, including bronchiolitis and pneumonia. Reinfection later in life is common, because the body does not generate lasting immunity to the pathogen.

In otherwise healthy children and adults, RSV causes symptoms similar to those of the common cold—upper respiratory infection, runny nose, and cough. In children with underlying bronchopulmonary dysplasia or other abnormalities of the respiratory or cardiopulmonary system, however, virulence increases, as does the risk of severe complications.

Premature birth is also a risk factor for severe RSV disease (Table 1). In the United States, RSV accounts for about 100,000 hospitalizations each year.1,2 In healthy children, approximately 30 children per 1,000 are hospitalized for an RSV-related illness. However, that number jumps significantly for children born prematurely.3

 
Table 1.
Rate of RSV infection in infants
born prematurely.
Table 1. Rate of RSV infection in infants born prematurely
Gestational age at birth is a significant factor in risk of serious RSV infection.3

Although supportive care is generally effective in treating hospitalized infants, with length of stay averaging five days, about 600,000 deaths occur each year worldwide due to RSV infection.4 Infection with RSV is especially dangerous for children with compromised immune systems, with an increased risk for hospital admission and prolonged and complicated hospitalizations.5


Etiology

The respiratory syncytial virus is a single-stranded RNA virus in the Paramyxoviridae family and is the only human pathogen in the genus Pneumovirus. Originally isolated in chimpanzees with coryza (or rhinorrhea and sneezing), the infection was first named chimpanzee coryza virus in 1956.6 Shortly after this early report, the virus was isolated from infants with lower respiratory tract infections.7 The human pathogen was given its current name in recognition of a propensity for infected cells to fuse together and form syncytia.

The virus is relatively stable and can survive on hard surfaces for up to four hours and on hands for approximately 30 minutes. Two surface glycoproteins determine the infectivity of the virus: G protein enables viral attachment to host cells, whereas F protein promotes the fusion of infected cells that in turn promote cell-to-cell transmission. Two subtypes of RSV (A and B) have been identified, and although epidemiologic evidence is inconclusive, there is suggestive evidence that some strains are more virulent than others. This would account for variations in season-to-season infectivity.


Epidemiology

The introduction of RSV prophylaxis for high-risk children has helped curb the onset of severe lower respiratory tract infections caused by RSV leading to hospitalizations. Still, RSV bronchiolitis is the leading cause of hospitalizations for infants younger than 1 year of age.8,9 More than half of all RSV-associated hospitalizations occur in children younger than 6 months, and more than two-thirds occur in children younger than 1 year, according to data from the CDC’s National Center for Infectious Disease.2 Further, RSV hospitalizations account for half of all pediatric hospitalizations for bronchiolitis and a quarter of all hospitalizations for pneumonia.10

In one study, RSV accounted for 718,008 emergency room visits over a three-year period, with a 29% admission rate, at a total cost of $202 million.8 Estimates from the mid-1980s suggested that approximately 4,500 deaths occur each year in the United States due to RSV. More recent estimates suggest that figure to be about 500 per year.11 Mortality may be higher in children at high risk for complications after RSV infection.

Several risk factors have been identified for increased risk of infection and increased virulence after infection. Certain environmental risk factors —such as exposure to second-hand smoke, living in a household with four or more members,5 daycare attendance12 and contact with older, school-aged siblings13,14—raise the risk of symptomatic RSV infection. Patient-specific risk factors identified include family history of asthma,13 low birth weight3 and multiple birth.15


Premature birth and RSV infection

Premature birth is a significant risk factor for virulent RSV infection and has been identified as a risk factor for hospitalization for RSV-related infection. This is especially true in infants born with underlying respiratory or cardiopulmonary deficiencies.3

In 2002, when about 4 million live births were recorded, there were 302,309 infants born prematurely,16 and the number of premature births continues to rise each year. Premature birth is significant because it can interrupt lung development, which may cause underdeveloped or altered lungs (Figure 1). Birth before 36 weeks of gestation interrupts the final stages of lung development. Specifically, the development of surfactants—critical in maintaining the integrity of alveoli during breathing—is halted. Without sufficient supply of surfactants, the alveoli may collapse during breathing, causing incomplete oxygen transfer.

Underdeveloped or altered lungs
Figure 1. Premature birth can cause interrupted or altered lung development
Figure 1. Premature birth can cause interrupted or altered lung development that can increase the chance of serious RSV infection.

© 2007, Artville/Getty Images

Interrupted development is also a risk factor for decreased lung volume and surface area. Children born prematurely may have increased smooth muscle, which increases airway hyperactivity and constriction. Increased smooth muscle, in turn, decreases the diameter of the airway, which increases obstruction during breathing. Children born prematurely may also have increased goblet cell proliferation in the lungs—the body’s natural response to attempt to increase oxygen flow may unwittingly promote plugging of the lungs.

Premature birth may also result in incomplete passage of immunity in utero. Maternal antibodies passed transplacentally are critical in the first year of life in establishing immunity against environmental pathogens. Without these important cellular immune markers, infants born prematurely may suffer from more pronounced viral replication in response to RSV exposure.


Other risk factors

Children with chronic underlying lung disease due to premature birth or another medical condition are also at risk for more symptomatic RSV infection. Chronic lung disease often necessitates supplemental oxygen therapy, which may damage the lungs in young infants. Morbidity and mortality due to RSV are increased in infants with chronic lung disease.

Clinical evidence suggests that the risk of symptomatic RSV infection in infants with chronic lung disease is higher (Table 2). In a cohort of Canadian children with chronic lung disease hospitalized with RSV infection, 30% were admitted to the intensive care unit, 17% required mechanical ventilation and 3.5% died,17 a mortality rate two to six times greater than average in infants hospitalized with RSV infection.18


RSV prophylaxis

Although advances in palliative care for infants with RSV have decreased morbidity and mortality and reduced hospitalization and length of stay in many cases, there is no actual cure at this time. Immunoprophylaxis against RSV remains the preferred option for selected high-risk infants and children.

Table 2
Table 2. The AAP recommends RSV prophylaxis for a limited subset of patients who are at high risk for complications from RSV infection
The AAP recommends RSV prophylaxis for a limited subset of patients who are at high risk for complications from RSV infection.20-22
 

Currently, two prophylactic options are available for preventing severe manifestations of RSV in high-risk children: RSV-IGIV, a polyclonal hyperimmune globulin prepared from donors with high serum titers of RSV-neutralizing antibody (Respigam, MedImmune) and palivizumab, a humanized murine monoclonal anti-F glycoprotein immunoglobulin G1 antibody with neutralizing and fusion inhibitory activity against RSV (Synagis, MedImmune).

According to AAP usage guidelines, selecting the appropriate prophylactic therapy should depend on the underlying disease, the preferred route of administration (RSV-IGIV is an intravenous product, whereas palivizumab is delivered intramuscularly) and other factors.19-21 Although both products are licensed for use in most high-risk children, only palivizumab is approved for use in children with hemodynamically significant congenital heart disease.

The AAP recommends taking precautions to reduce the potential for exposure to RSV, especially during winter and early spring when RSV may peak in incidence in parts of the United States. Included in those recommendations are suggestions to follow rigorous hand hygiene procedures, reduce daycare attendance and reduce, or preferably, eliminate second-hand smoke exposure.

In clinical trials for children with hemodynamically significant congenital heart disease, palivizumab reduced RSV-related hospitalization 55% overall, and in subgroup analysis, 78% in children with prematurity but no bronchopulmonary dysplasia and 39% in children with bronchopulmonary dysplasia.22 Children in the study who received palivizumab had fewer RSV hospital days, fewer days with increased oxygen, fewer days with moderate or severe lower respiratory tract infection and lower incidence of admission to the intensive care unit. This trial was a basis for FDA approval of palivizumab.


Conclusion

RSV infection typically causes mild to moderate upper and lower respiratory tract infection. However, in infants with compromised immune systems, virulence is far more dangerous, and in some cases, even fatal. Although there is no cure at this time, prophylaxis is available for some children at high risk for complications from RSV infection. Because prophylaxis is expensive and requires monthly injections prior to and during RSV season (which can be unpredictable), prophylaxis should be reserved for these high-risk infants.

References
  1. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140:543-546.
  2. Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. J Am Med Assoc. 1999;282:1440-1446.
  3. Boyce TG, Mellen BG, Mitchell EF Jr, et al. Rates of hospitalization for respiratory syncytial virus infection among children in Medicaid. J Pediatr. 2000;137:865-870.
  4. Howard TS, Hoffman LH, Stang PE, Simoes EA. Respiratory syncytial virus pneumonia in the hospital setting: length of stay, charges, and mortality. J Pediatr. 2000;137:227-232.
  5. Groothuis JR, Guitierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics. 1988;82:199-203.
  6. Blount RE Jr, Morris JA, Savage RE. Recovery of cytopathogenic agent from chimpanzees with coryza. Proc Soc Exp Biol Med. 1956;92:544-549.
  7. Chanock R, Roizman B, Myers R. Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). I. Isolation, properties and characterization. Am J Hyg. 1957:66:281-290.
  8. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143(5 suppl):S127-S132.
  9. Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr Infect Dis J. 2002;21:629-632.
  10. Heilman CA. From the National Institute of Allergy and Infectious Disease and the World Health Organization. Respiratory syncytial virus and parainfluenza viruses. J Infect Dis. 1990;161:402-406.
  11. Shay DK, Holman RC, Roosevelt GE, et al. Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979-1997. J Infect Dis. 2001;193:16-22. Epub 2000.
  12. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and young children. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4909a1.htm. Accessed March 22, 2007.
  13. Carbonell-Estrany X, Quero J, and the IRIS Study Group. Hospitalization rates for respiratory syncytial virus infection in premature infants born during two consecutive seasons. Pediatr Infect Dis J. 2001;20:874-879.
  14. Anderson LJ, Parker RA, Strika RA, et al. Day-care attendance and hospitalization for lower respiratory tract illness. Pediatrics. 1988;82:300-308.
  15. Simoes EA, King SJ, Lehr MV, Groothuis JR. Preterm twins and triplets. A high-risk group for severe respiratory syncytial virus infection. Am J Dis Child. 1993;147:303-306.
  16. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2002. Natl Vital Stat Rep. 2003;52:1-113.
  17. Navas L, Wang E, de Carvalho V, Robinson J. Improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. Pediatric Investigators Collaborative Network on Infections in Canada. J Pediatr. 1992:121:348-354.
  18. La Via WV, Marks MI, Stutman HR. Respiratory syncytial virus puzzle: clinical features, pathophysiology, treatment, and prevention. J Pediatr. 1992:121:503-510.
  19. Committee on Infectious Disease and Committee on Fetus and Newborn Health. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus. Pediatrics. 112:1442-1446.
  20. Committee on Infectious Disease and Committee on Fetus and Newborn Health. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics. 1998;102:1211-1216.
  21. Committee on Infectious Disease and Committee on Fetus and Newborn Health. Respiratory syncytial virus immune globulin intravenous: indications for use. Pediatrics. 1997;99:645-650.
  22. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduced hospitalizations from respiratory syncytial virus infection in high-risk infants. Pediatrics. 1998:102:531-537.


[Introduction]
[Skin conditions in infancy: common dermatitis and complex manifestations]
[Identifying risk factors for severe RSV infection]

Copyright 2007, SLACK Incorporated. Revised 25 July 2007.