Pediatric Respiratory Disease: Diagnosis, Prophylaxis and Treatment in the Premature and Late Preterm Infant

Influenza Vaccination: Applying The Latest Data To Your Practice
Introduction

RSV: As Important as Ever
Gary Goodman, MD


A Primer on Preemies: Developmental Biology and Respiratory Illness
Dan L. Stewart, MD


Challenges in the Diagnosis and Management of RSV Infection
Paul A. Checchia, MD


Optimizing RSV Prophylaxis and Improving Continuity of Care for Infants at Risk
Michael L. Forbes, MD

Introduction


By the age of 5 years, nearly every child will have had at least one respiratory infection, and one of the most common pathogens associated with bronchiolitis is respiratory syncytial virus (RSV). However, multiple viruses may coexist, and infection with bacterial and viral pathogens is also possible. Premature infants are at a higher risk than full-term infants for RSV, and the health care burden for treatment and management of RSV infection in premature infants is higher.

An expert panel was convened at the 2008 Pediatric Academic Society (PAS) meeting in Honolulu, Hawaii, to discuss the epidemiology of RSV, the effect of lung development and function on infection risk in preterm infants, the challenges to diagnose and manage RSV in term and preterm infants, and optimize RSV prophylaxis and continuity of care for improved patient health.

I would like to thank the faculty members for their participation in the symposium at PAS and in the development of this monograph.

Tim Hayes, MD, PhD
Medical Director
Vindico Medical Education

Gary S. Goodman, MD

Gary S. Goodman, MD,
Medical Director, Pediatric Intensive Care Unit and Hospitalist Service
CHOC at Mission
Mission Viejo, CA.

Paul A. Checcia, MD

Paul A. Checcia, MD,
Medical Director, Pediatric Cardiac Intensive Care Unit
St. Louis Children’s Hospital
Washington University
St. Louis, MO.

Dan L. Stewart, MD

Dan L. Stewart, MD,
Professor of Pediatrics
University of Louisville School of Medicine
Louisville, KY.

Michael L. Forbes, MD

Michael L. Forbes, MD,
Pediatric & Adolescent Intensivist
Director, Clinical Research & Outcomes Analysis
Pediatric Critical Care Medicine
Akron Children’s Hospital
Akron, OH.

RSV: As Important as Ever


Gary Goodman, MD
Children average 6-10 acute respiratory infections per year, and respiratory syncytial virus is a common cause of respiratory infection that requires hospitalization.
- Gary Goodman, MD

Respiratory infections are the most common illnesses found in children and are the most common causes of hospitalization of children younger than 12 months of age. Children average 6-10 acute respiratory infections per year,1 and respiratory syncytial virus (RSV) is a common cause of respiratory infection that requires hospitalization. The number of RSV and bronchiolitis-related hospitalizations rose steadily from 1980 to 1996, with an estimated 1.65 million hospitalizations in children <5 years of age reported in the USA over the 17-year period (Figure1).1 Between 1997 and 2002, the rate of hospitalization related to RSV infection in children less than one year old increased 25% (Figure 2).2

Figure 1: Annual Bronchiolitis Hospitalizations
Figure 1: Annual Bronchiolitis Hospitalizations

Figure 2: RSV Hospitalizations Continue to Increase
Figure 2: RSV Hospitalizations Continue to Increase


RSV History

RSV was first isolated from chimpanzees in 1955. In 1960, RSV was recognized as a pathogen in children, and during the 1960’s a formalin inactivated vaccine was developed to try to protect children. The vaccine, however, worsened the disease. A safe and successful vaccine has not yet been developed.

In the 1990’s, the clinical approach to RSV changed. Rapid RSV testing was developed and physicians could quickly diagnose children with RSV infections.

The FDA approved RSV immunoglobulin, the first prophylactic medication for RSV, in 1996. In 1998, the FDA approved palivizumab, a synthetic monoclonal antibody against RSV.

Other Viruses and Multiple Viruses

The most common pathogen associated with bronchiolitis is RSV.3 There are, however, a number of other viruses that can cause bronchiolitis, such as parainfluenza virus type III, adenovirus, human metapneumo virus, and human bocavirus. Both human metapneumo virus and human bocavirus have been clearly associated with an illness in children similar to bronchiolitis. Children who are RSV-negative can be tested for these other viruses.

For many years physicians identified one infectious agent as the cause of the patient’s clinical illness. In recent years, however, physicians have begun to recognize complex infections with multiple pathogens. Often both viral and bacterial pathogens coexist, such as varicella and group A Streptococcus; influenza and Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus [MRSA]); and RSV with both Streptococcus pneumoniae and Haemophilus influenzae. Alternatively, several viruses may coexist, such as RSV and rhinovirus, a risk factor for admission of infants with severe bronchiolitis to the pediatric intensive care unit.

Premature Infants

Although many children contract RSV, premature infants are at higher risk for RSV infection than full-term infants. Approximately 500,000 children are born preterm—less than 37 weeks gestational age—each year in the United States.4

A study on the rate of hospital readmission following discharge of infants born less than 36 weeks gestational age revealed that of 260,000 infants born prematurely, 15% required readmission to the hospital. The most common cause of readmission was acute respiratory disease, and RSV infection was the most common principle diagnosis leading to readmission.5 Moreover, infants born less than 32 weeks gestational age who contracted an RSV-positive lower respiratory tract infection had more subsequent hospital admissions, spent more days in the hospital, and experienced more coughing and wheezing compared to infants who did not have a RSV lower respiratory tract infection.6

A study of lung function in premature infants found that infants born less than 32 weeks gestational age who contracted the RSV or Human metapneumovirus infection had higher airway resistance, more days of wheezing, and an increased requirement for bronchodilator.7

Finally, a study of chronic manifestations of RSV disease found that otherwise healthy premature infants born 32-35 weeks gestational age and hospitalized for RSV had more subsequent hospital admissions, more inpatient days, more physician contacts, and more outpatient visits in the first two years after birth than children who did not contract RSV.8

Conclusion

The annual rates of hospitalization due to RSV and bronchiolitis have increased steadily since 1980. Though RSV is the most common pathogen associated with bronchiolitis, other viruses are also associated with bronchiolitis. Multiple infections and multiple pathogens can cause of bronchiolitis, and often viral and bacterial pathogens coexist.

Premature infants are at a higher risk for RSV infection, are at an increased risk of hospital readmission and spend more days in the hospital than term infants. In addition, premature infants infected with RSV have higher airway resistance and spend more days wheezing.

Many challenges are associated with RSV infection. Children have a limited natural immunity to RSV and reinfection is common. Both hypoxemia and apnea are uniquely associated with RSV infections. No effective or safe vaccine has been developed; treatment is only supportive and focus on relieving symptoms.

References

  1. Shay DK, Holman RC, Newman RD et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999; 282:1440-1446.
  2. McLaurin KK, Leader S. Pediatric Academic Societies Annual Meeting. May 14-17; 2005. Washington, D.C.
  3. Cooper AC, Banasiak NC, Allen PJ. Pediatric Nursing. 2003;29(6):452-456.
  4. Martin JA, Hamilton BE, Sutton PD et al. Births: Final Data for 2005. Natl Vital Stat Rep. 2006; 56:1-103.
  5. Underwood MA, Danielson B, Gilbert WM. Cost, causes and rates of rehospitalization of preterm infants. Journal of Perinatology. 2007; 27:614-619.
  6. Broughton S, Roberts A, Fox G et al. Prospective study of healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants. Thorax. 2005; 60:1039-1044.
  7. Broughton S, Sylvester KP, Fox G et al. Lung function in prematurely born infants after viral lower respiratory tract infections. Pediatric Infect Dis J. 2007; 26:1019-1024.
  8. Greenough A, Broughton S. Chronic manifestations of respiratory syncytial virus infection in premature infants. Pediatric Infect Dis J. 2005; 24:S184-S188.

A Primer on Preemies: Developmental Biology and Respiratory Illness


Dan L. Stewart, MD
A major complication observed in preterm infants increased risk is increased vulnerability to both viral and bacterial infections when compared to term infants.
— Dan L. Stewart, MD

Preterm infants, defined as infants who have completed less than 37 weeks of gestation, can have significant comorbidities, such as feeding problems, body temperature instability, elevated bilirubin levels, sepsis, and hypoglycemia. A major complication of prematurity is increased vulnerability to both viral and bacterial infections compared to term infants. Thus, respiratory problems, such as pneumonia, transient tachypnea of the newborn, surfactant deficiency, and pulmonary hypertension are more common in preterm infants.1-2

Lung Development

Many factors can delay or interfere with normal lung development and the alveolarization process, such as mechanical ventilation, antenatal and postnatal steroids, pro-inflammatory mediators, hyperoxia, hypoxia, and poor nutrition.7 Early in lung development the airways are tubular and lined by cuboidal epithelium. Later in development the airways become more saccular. Premature birth interrupts normal lung development resulting in abnormal airways with smaller caliber, increased smooth muscle, and increased goblet cells compared with term infants (Figure1). 4-6 Moreover, at 34 weeks gestation the lung volume is only 52% that of a term infant’s lung; at 30 weeks gestation the preterm lung volume is only 36% that of the term lung volume (Figure2). The surface area of the lung at 34 weeks gestation is 44% of the term infant; at 30 weeks it is 27% of the term infant. Alveoli can be present at 32 weeks but generally are not present until 36 weeks of gestational age,3 and alveolar wall thickness of a premature infant at 34 weeks gestation is 34% greater than that of the term infant, while at 30 weeks gestation it is 61% greater (Figure 3).1

Figure 1: Premature Birth can Alter Airways
Figure 1: Premature Birth can Alter Airways

Figure 2: Premature Birth Interrupts Lung Development
Figure 2: Premature Birth Interrupts Lung Development

Figure 3: Modeled Lung Estimates with Development
Figure 3: Modeled Lung Estimates with Development


Challenges of RSV Infection

Premature infants have smaller lung volume, less surface area, and fewer alveoli with greater wall thickness; they also have a higher risk than term infants of hospitalization due to infection with respiratory syncytial virus (RSV). In one study, the hospitalization rate for term infants due to infection with RSV was 3%, compared with 5.7% for premature infants born 33-36 weeks gestation, and 6.6% for premature infants born 29-33 weeks gestation.8 Moreover, RSV infection requiring hospitalization in infancy has been shown to be an independent risk factor for abnormal lung function in young adults. The effects of RSV persist into late childhood and, in some cases, early adulthood.11

Premature infants have smaller lung volume, less surface area, and fewer alveoli with greater wall thickness and have a higher risk than term infants of hospitalization due to infection with respiratory syncytial virus.
— Dan L. Stewart, MD

The increased risk of RSV infection in premature and low birth weight infants may also be due in part to lower RSV-specific immune risk factors, such as IgG levels and transplacental antibody ratios. 9 RSV-specific antibodies decrease quickly after birth; at one month, RSV-specific antibodies decrease to 73%, and by three months RSV-specific antibodies decrease to 8%.

Although it correlates with premature gestational age, low birth weight is an independent risk factor for RSV infection and increased mortality.9, 12 RSV is often the cause of bronchiolitis, and the rate of bronchiolitis-associated deaths increase 5-times in premature infants born 32-35 weeks gestation, and 17-times in premature infants born less than 32 weeks gestation.15

Finally, premature infants with severe chronic lung disease who acquire RSV infection face many obstacles to their recovery. A study of premature infants with chronic lung disease and RSV found 80% of patients required supplemental oxygen, 32% were admitted to the ICU, 17% required mechanical ventilation, and 3.5% died within 2 weeks.16

Conclusion

Infants born less than 37 weeks gestation are at significant risk for RSV infection as well as additional respiratory problems. This increase is due in part to a delay in lung development, which results in abnormal airways, smaller lung volume, smaller lung surface area and increased alveolar wall thickness. Another reason is lower RSV-specific immune factors, such as IgG levels and transplacental antibody ratios.

Premature infants infected with RSV face many challenges, including an increased hospitalization rate compared to term infants. Depending on gestational age, the hospitalization rate can be more than double the rate of term infants. In addition, hospitalization in infancy due to RSV has been shown to correlate with abnomral lung function in early adulthood.

Premature lung development, low birth weight, immunological deficiencies, and poor physiologic and functional capacity of premature infants, are all risk factors for RSV, and result in increased morbidity and mortality.

References

  1. Engle WA, Tomashek KM, Wallman C et al. “Late-preterm” infants: a population at risk. Pediatrics. 2007; 120:1390-1401.
  2. Shapiro-Mendoza CK et al. Risk factors for neonatal morbidity and mortality among “healthy,” late preterm newborns. Semin Perinatol. 2006; 30:54-60.
  3. Langston C, Kida K, Reed M, Thurlbeck WM. Human lung growth in late gestation and in the neonate. Am Rev Respir Dis. 1984; 129: 607-613.
  4. Hoo AF, Dezateux C, Henschen M et al. Development of airway function in infancy after preterm delivery. J Pediatr. 2002;141:652-658.
  5. Mansell AL, Driscoll JM, James LS. Pulmonary follow-up of moderately low birth weight infants with and without respiratory distress syndrome. J Pediatr. 1987;110:111-115.
  6. Hislop AA, Haworth SG. Airway size and structure in the normal fetal and infant lung and the effect of premature delivery and artificial ventilation. Am Rev Respir Dis. 1989;140:1717-1726.
  7. Resnik R, Creasy RK, Iams JD. Maternal-Fetal Medicine:Principles and Practice 5th Edition.2004. Philadelphia. Chap 16. 212.
  8. Boyce TG, Mellen BG, Mitchel EF Jr. et al. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr. 2000;137:865–870.
  9. Okoko JB, Wesumperuma HL, Hart CA. The influence of prematurity and low birthweight on transplacental antibody transfer in a rural West African population. Trop Med Int Health. 2001 Jul;6(7):529-34.
  10. Hacimustafaoglu M, Celebi S, Aynaci E. The progression of maternal RSV antibodies in the offspring. Arch Dis Child. 2004;89:52-53.
  11. Korppi M, Piippo-Savolainen E, Korhonen K, Remes S. Respiratory morbidity 20 years after RSV infection in infancy. Pediatr Pulmonol. 2004 Aug;38(2):155-60.
  12. Buckingham SC, Quasney MW, Bush AJ, DeVincenzo JP. Respiratory syncytial virus infections in the pediatric intensive care unit: clinical characteristics and risk factors for adverse outcomes. Pediatr Crit Care Med. 2001 Oct;2(4):318-23.
  13. Rona RJ, Gulliford MC, Chinn S. Effects of prematurity and intrauterine growth on respiratory health and lung function in childhood. BMJ. 1993 Mar 27;306(6881):817-20.
  14. Chan KN, Noble-Jamieson CM, Elliman A et al. Lung function in children of low birth weight. Arch Dis Child. 1989 Sep;64(9):1284-93.
  15. Holman RC, Shay DK, Curns AT et al. Risk factors for bronchiolitis-associated deaths among infants in the United States. Pediatr Infect Dis J. 2003;22:483-490.
  16. 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.

Challenges in the Diagnosis and Management of RSV Infection


Paul A. Checchia, MD

Infection from respiratory syncytial virus (RSV) is the leading cause of viral death in infants. Each year about 500 deaths are associated with RSV, 80% of which occur in infants younger than 1 year of age.2 The rate of RSV-related death in infants younger than one year of age is about ten times the rate of influenza-related death in this age group (Figure 1).1

Several factors increase the severity of RSV infection, including premature birth, chronic lung disease, congenital heart disease, low birth weight, and immunodeficiencies (Figure2).3-4

Figure 1: RSV Infection: The Leading Cause of Mortality in Infancy
Figure 1: RSV Infection: The Leading Cause of Mortality in Infancy

Figure 2: Children at Increased Risk of Severe RSV Infection
Figure 2: Children at Increased Risk of Severe RSV Infection


Infection Control

The transmission rate of RSV is 26%. The most important factor in nosocomial infection control is assiduous hand-washing by medical personnel. Screening for RSV infection on admission and cohorting infected patients can also reduce nosocomial spread of RSV. However, debate exists regarding the national standard of time to 2 negative cultures within a 7 day period.5-6

Up to 83% of children with RSV are reinfected each year, more than 50% of all preschool children will experience repeated lower respiratory illness such as bronchiolitis. Infection with RSV is not protective against subsequent exposures.
— Paul A. Checchia, MD

Up to 83% of children with RSV are reinfected each year, and more than 50% of all preschool children will experience repeated lower respiratory illness such as bronchiolitis. Contracting RSV is not protective against subsequent infections.7 One reason for the high rate of repeat infections is that the immune response does not recognize important protective epitopes following the initial exposure. High risk infants and young children who have not developed immunity to RSV should receive monthly doses of palivizumab throughout the infection season.

Cardiac Risks

Children with congenital heart disease are at increased risk for serious infection from RSV. At the same time, RSV infection can cause cardiac complications. RSV infection in patients with congenital heart disease is associated with increased morbidity and mortality, and, following cardiac surgery employing cardiopulmonary bypass, these patients are at the highest risk for complications, leading to increased morbidity and mortality.19-22 For example, cardiac surgery performed during the symptomatic period of RSV infection is associated with a high risk of postoperative pulmonary hypertension. Physicians should consider not performing elective procedures during RSV season, and should delay surgical procedures up to 5 weeks following active infection.23

RSV infection in patients with congenital heart disease is associated with increased morbidity and mortality, and following cardiac surgery employing cardiopulmonary bypass these patients are at the highest risk for complications, leading to increased morbidity and mortality.
— Paul A. Checchia, MD

RSV is associated with a spectrum of disease ranging from pulmonary manifestations to a sepsis-like syndrome.8-11 Patients with cardiac symptoms can suffer from arrhythmias and cardiac failure secondary to presumed myocarditis.12-18 A study conducted on the association between RSV and myocardial injury found that 54% of 22 children admitted to the PICU for RSV infection had elevated troponin levels, indicating myocardial injury. Patients who had elevated troponin were younger, with 75% of positive assays occurring in patients less than 3 months of age. There was an association between an elevated troponin levels and the need for mechanical ventilation, occurrence of a cardiovascular event, such as CPR, and volume resuscitation or inotropes. Post hoc analysis found that troponin levels were elevated prior to the cardiac event.24 Thus, myocardial involvement is common in infants without congenital heart disease who have severe RSV infection.

Treatment Options

Multiple therapies have been used to relieve airway obstruction associated with RSV infection, including chest physiotherapy, bronchodilators, heliox mixtures, corticosteroids, mucolytics, ribavirin, and exogenous surfactants. However, these therapies have had mixed results, and physicians have few options other than to intubate, ventilate, and let the lungs heal themselves without causing additional damage.

Albuterol is a bronchodilator that can potentially reduce the work of breathing and increase patient comfort. Data are conflicting regarding whether bronchodilators decrease complication rates or length of hospitalization. The best responders to albuterol are patients with underlying bronchopulmonary dysplasia or reactive airway disease.5, 26-29 Racemic epinephrine is an alpha and beta2-adrenergic agonist that has shown equivalent or better outcomes compared to pure albuterol. In one study, 30% of patients treated with racemic epinephrine required hospitalization compared to 75% of patients treated with albuterol.5 In a more recent study, children with mild RSV had similar responses whether treated with albuterol or racemic epinephrine.

The use of steroids for first time wheezing due to RSV is not recommended. Clinical trials provide little evidence to support the use of steroids in the treatment of RSV bronchiolitis.30

Conclusion

Though there are many factors that can increase the severity of RSV, physicians can take precautions to ensure they do not cause additional complications. Infection control is important, and careful hand washing, RSV screening, and cohorting of patients are recommended for physicians to avoid nosocomial infection. Elective cardiac surgery should not be performed during RSV season and surgery should be delayed following RSV infection since RSV patients have a higher morbidity and mortality following these procedures.

No specific therapy has been found to be effective for RSV lower respiratory infections. Supportive care promoting hydration, gas exchange (oxygentation and ventilation) and appropriate antibiotic etherapy for bacterial co infections is the current standard of care.

References

  1. 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.
  2. Shay DK et al. Bronchiolitis-Associated Mortality and Estimates of Respiratory Syncytial Virus-Associated Deaths Among US Children, 1979-1997. J Infect Dis. 2001;183(1):16-22.
  3. Weisman LE. Populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions. Pediatr Infect Dis J. 2003; 22:S33-S39.
  4. Panitch HB. Viral respiratory infections in children with technology dependence and neuromuscular disorders. Pediatr Infect Dis J. 2004; 23:S222-S227.
  5. Weisman LE. Nosocomial Respiratory Syncytial Virus Infections: The “Cold War” Has Not Ended. Clinical Infectious Disease. 2000;31:590-596.
  6. Prevention of Respiratory Syncytial Virus Infections: Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV. Pediatrics. 1998;102(5):1211-1215.
  7. Feign RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, 4th Edition. 1998. Philadelphia. Chap. 185. 2095.
  8. Dagan R, Hall CB, Powell KR, Menegus MA. Epidemiology and laboratory diagnosis of infection with viral and bacterial pathogens in infants hospitalized for suspected sepsis. J Pediatr. 1989; 115:351-356.
  9. Njoku DB, Kliegman RM. Atypical extrapulmonary presentations of severe respiratory syncytial virus infection requiring intensive care. Clin Pediatr (Phila). 1993; 32:455-460.
  10. Kim KK, Frankel LR. The need for inotropic support in a subgroup of infants with severe life-threatening respiratory syncytial viral infection. J Investig Med. 1997; 45:469-473.
  11. Wahab AA, Dawod ST, Raman HM. Clinical characteristics of respiratory syncytial virus infection in hospitalized healthy infants and young children in Qatar. J Trop Pediatr. 2001; 47:363-366.
  12. Huang M et al. Ventricular arrhythmia associated with respiratory syncytial viral infection. Pediatr Cardiol. 1998; 19:498-500.
  13. Menahem S. Respiratory syncytial virus and supraventricular tachycardia in an infant. Int J Cardiol. 1991; 32:249-251.
  14. Armstrong DS. Cardiac arrhythmias as a manifestation of acquired heart disease in association with paediatric respiratory syncitial virus infection. J Paediatr Child Health. 1993; 29:309-311.
  15. Olesch CA, Bullock AM. Bradyarrhythmia and supraventricular tachycardia in a neonate with RSV. J Paediatr Child Health. 1998; 199-201.
  16. Donnerstein RL, Berg RA, Shehab Z, Ovadia M. Complex atrial tachycardias and respiratory syncytial virus infections in infants. J Pediatr. 1994; 125:23-28.
  17. Menahem S, Uren EC. Respiratory syncytial virus and heart block--cause and effect? Aust N Z J Med. 1985; 15:55-57.
  18. Bairan AC, Cherry JD, Fagan LF, Codd JE Jr. Complete heart block and respiratory syncytial virus infection. Am J Dis Child. 1974; 127:264-265.
  19. 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.
  20. Altman CA, Englund JA, Demmler G et al. Respiratory syncytial virus in patients with congenital heart disease: a contemporary look at epidemiology and success of preoperative screening. Pediatr Cardiol. 2000; 21:433-438.
  21. Moler FW, Khan AS, Meliones JN et al. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Crit Care Med. 1992; 20:1406-1413.
  22. MacDonald NE, Hall CB, Suffin SC et al. Respiratory syncytial viral infection in infants with congenital heart disease. N Engl J Med. 1982; 307:397-400.
  23. Khongphatthanayothin A, Wong PC, Samara Y et al. Impact of respiratory syncytial virus infection on surgery for congenital heart disease: postoperative course and outcome. Crit Care Med. 1999; 27:1974-1981.
  24. Checchia PA, Appel HJ, Kahn S et al. Myocardial injury in children with respiratory syncytial virus infection. Pediatr Crit Care Med. 2000; 146-150.
  25. Moynihan JA, Brown L, Sehra R, Checchia PA. Cardiac troponin I as a predictor of respiratory failure in children hospitalized with respiratory syncytial virus (RSV) infections: a pilot study. Am J Emerg Med. 2003; 21:479-482.
  26. Hammer J, Numa A, Newth CJ. Albuterol responsiveness in infants with respiratory failure caused by respiratory syncytial virus infection. J Pediatr. 1995; 127:485-490.
  27. Schuh S, Canny G, Reisman JJ et al. Nebulized albuterol in acute bronchiolitis. J Pediatr. 1990; 117:633-637.
  28. Gadomski AM, Perkis V, Horton L et al. Nebulized albuterol in acute bronchiolitis. Pediatrics. 1994; 93:907-912.
  29. Flores G, Horwitz RI. Efficacy of 2 – Agonists in Bronchiolitis: A Reappraisal and Meta-Analysis. Pediatrics. 1997; 100(2):233-239.
  30. Roosevelt G, Sheehan K, Grupp-Phelan et al. Dexamethasone in bronchiolitis: a randomised controlled trial. Lancet. 1996; 348:292-295.

Optimizing RSV Prophylaxis and Improving Continuity of Care for Infants at Risk


Michael L. Forbes, MD

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality in infants. However, not all infants are at equal risk for severe RSV infection. It is important for physicians to identify and manage patients at high risk to help prevent hospitalization.

High Risk Patients

Focused risk assessment allows doctors to identify patients who are vulnerable to RSV infection and can benefit from intervention.
— Michael L. Forbes, MD

Focused risk assessment allows doctors to identify patients who are vulnerable to RSV infection and who can benefit from intervention. Patients with bronchopulmonary dysplasia, chronic lung disease, and congenital heart disease are at a higher risk of severe respiratory disease such as bronchiolitis and bronchopneumonia. In addition, a study of infants hospitalized due to bronchiolitis showed that patients with these preexisting conditions had significant morbidity.1 Eighty percent of patients in the study required supplemental O2, 32% required ICU admission, 17% required mechanical ventilation, and the mortality rate was 3.5% (Figure 1).

Infants younger than 3 months of age have a higher rate of hospitalization than children older than 3 months of age, and the younger patients had longer hospitalizations and more days on oxygen, ventilator support, bronchodilators, and corticosteroids (Figure 2).2 In addition, previously healthy premature infants hospitalized due to RSV infection have significantly more subsequent health care resource utilization and mortality compared to infants not hospitalized (Figure 3).4

Figure 1: Once Hospitalized
Figure 1: Once Hospitalized

Figure 2: Hospitalized Infants Were...
Figure 2: Hospitalized Infants Were

Figure 3: Uniquely Vulnerable Infants become Disproportionate Health care Resource Utilizers
Figure 3: Uniquely Vulnerable Infants become Disproportionate Health care Resource Utilizers


Immunoprophylaxis Strategies

Immunoprophylaxis of RSV with monoclonal antibody (palivizumab) has been shown to reduce the rate of hospitalization of high risk infants and children by 39%-80%.5 Questions still remain, however, about whether the timing of administration affects hospitalization rates. A retrospective analysis of reports from 1996-2003 that evaluated the incidence of hospitalizations following pre- and post-discharge prophylaxis with palivizumab concluded that there was no apparent benefit to providing immunoprophylaxis with palivizumab to every infant before discharge. Outpatient rates of prophylaxis are rising.6 The percentage of infants who received their first palivizumab dose in the outpatient setting after hospital discharge increased from 33% in the 2000–2001 season to 52% in the 2003–2004 season (Figure 4).8 However, there is no evidence to suggest outpatient prophylaxis reduces hospitalization rates, and reimbursement may be a driver of the increased rate of outpatient prophylaxis. For example, hospitals reimbursed palivizumab doses for under diagnosis-related costs more than for total inpatient hospitalization costs.4

Figure 4: Outpatient Dosing has increased Prior to 2006 Red Book Guidelines Change
Figure 4: Outpatient Dosing has increased Prior to 2006 Red Book Guidelines Change

A 2-year study of 40,000 births in Canada identified 401 patients with significant chronic heart disease. Twenty one patients were eligible for prophylaxis, and no ineligible patients received prophylaxis. In this study it was determined that optimized prophylaxis strategies may be appropriate for a target group of at risk patients.7 However, a collaboration of many healthcare practitioners was needed for proper patient-group identification and prophylaxis.

Conclusion

A collaborative effort of many health care practitioners is required for proper patient-group identification and prophylaxis.
— Michael L. Forbes, MD

Not all premature infants are equally at risk for RSV infection, and infection is a major cause of morbidity, mortality, and healthcare resourse utilization. Patients with preexisting conditions, such as chronic lung disease, are at higher risk of developing severe respiratory disease. In addition, infants less than 3 months of age are hospitalized more often than infants >3 months of age.

Immunoprophylaxis can reduce the rate of hospitalization by up to 80%. There is, however, little information on whether delaying immunoprophylaxis from pre- to post-discharge has an effect on hospital readmissions.

Physicians need to focus on prevention of RSV for at risk patients, including using immunoprophylaxis to reduce the rate of hospitalization. Studies investigating the timing (pre- or post-discharge) of immunoprophlyaxis are required to determine its effect on the rate of hospitalization and long term morbidity.

References

  1. 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.
  2. Resch B, Gusenleitner W, Müller W. The impact of respiratory syncytial virus infection: a prospective study in hospitalized infants younger than 2 years. Infection. 2002;30:193-197.
  3. Boyce TG, Mellen BG, Mitchel EF Jr. et al. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr. 2000;137:865–870.
  4. Sampalis JS. Morbidity and mortality after RSV-associated hospitalizations among premature Canadian infants. J Pediatr. 2003; 143:S150-S156.
  5. Mejias et al. Respiratory Syncytial Virus Prophylaxis. Neoreviews. 2005; 6:26-31.
  6. Geskey JM, Ceneviva GD, Brummel GL et al. Administration of the first dose of palivizumab immunoprophylaxis against respiratory syncytial virus in infants before hospital discharge: what is the evidence for its benefit? Clin Ther. 2004; 26:2130-2137.
  7. Warren A, Langley JM, Thomas W, Scott J. Optimizing the delivery and use of a new monoclonal antibody in children with congenital heart disease: a successful provincial respiratory syncytial virus prophylaxis program. Can J Cardiol. 2007; 23:463-466.
  8. Speer ME et al. Palivizumab outcomes registry 2000 to 2004: Delayed prophylaxis in children at high risk of respiratory syncytial virus (rsv) disease. Neonatology Today. April 2007:2;4:1-5.

Influenza Vaccination: Applying The Latest Data To Your Practice
Introduction

RSV: As Important as Ever
Gary Goodman, MD


A Primer on Preemies: Developmental Biology and Respiratory Illness
Dan L. Stewart, MD


Challenges in the Diagnosis and Management of RSV Infection
Paul A. Checchia, MD


Optimizing RSV Prophylaxis and Improving Continuity of Care for Infants at Risk
Michael L. Forbes, MD

Introduction


By the age of 5 years, nearly every child will have had at least one respiratory infection, and one of the most common pathogens associated with bronchiolitis is respiratory syncytial virus (RSV). However, multiple viruses may coexist, and infection with bacterial and viral pathogens is also possible. Premature infants are at a higher risk than full-term infants for RSV, and the health care burden for treatment and management of RSV infection in premature infants is higher.

An expert panel was convened at the 2008 Pediatric Academic Society (PAS) meeting in Honolulu, Hawaii, to discuss the epidemiology of RSV, the effect of lung development and function on infection risk in preterm infants, the challenges to diagnose and manage RSV in term and preterm infants, and optimize RSV prophylaxis and continuity of care for improved patient health.

I would like to thank the faculty members for their participation in the symposium at PAS and in the development of this monograph.

Tim Hayes, MD, PhD
Medical Director
Vindico Medical Education

Gary S. Goodman, MD

Gary S. Goodman, MD,
Medical Director, Pediatric Intensive Care Unit and Hospitalist Service
CHOC at Mission
Mission Viejo, CA.

Paul A. Checcia, MD

Paul A. Checcia, MD,
Medical Director, Pediatric Cardiac Intensive Care Unit
St. Louis Children’s Hospital
Washington University
St. Louis, MO.

Dan L. Stewart, MD

Dan L. Stewart, MD,
Professor of Pediatrics
University of Louisville School of Medicine
Louisville, KY.

Michael L. Forbes, MD

Michael L. Forbes, MD,
Pediatric & Adolescent Intensivist
Director, Clinical Research & Outcomes Analysis
Pediatric Critical Care Medicine
Akron Children’s Hospital
Akron, OH.

RSV: As Important as Ever


Gary Goodman, MD
Children average 6-10 acute respiratory infections per year, and respiratory syncytial virus is a common cause of respiratory infection that requires hospitalization.
- Gary Goodman, MD

Respiratory infections are the most common illnesses found in children and are the most common causes of hospitalization of children younger than 12 months of age. Children average 6-10 acute respiratory infections per year,1 and respiratory syncytial virus (RSV) is a common cause of respiratory infection that requires hospitalization. The number of RSV and bronchiolitis-related hospitalizations rose steadily from 1980 to 1996, with an estimated 1.65 million hospitalizations in children <5 years of age reported in the USA over the 17-year period (Figure1).1 Between 1997 and 2002, the rate of hospitalization related to RSV infection in children less than one year old increased 25% (Figure 2).2

Figure 1: Annual Bronchiolitis Hospitalizations
Figure 1: Annual Bronchiolitis Hospitalizations

Figure 2: RSV Hospitalizations Continue to Increase
Figure 2: RSV Hospitalizations Continue to Increase


RSV History

RSV was first isolated from chimpanzees in 1955. In 1960, RSV was recognized as a pathogen in children, and during the 1960’s a formalin inactivated vaccine was developed to try to protect children. The vaccine, however, worsened the disease. A safe and successful vaccine has not yet been developed.

In the 1990’s, the clinical approach to RSV changed. Rapid RSV testing was developed and physicians could quickly diagnose children with RSV infections.

The FDA approved RSV immunoglobulin, the first prophylactic medication for RSV, in 1996. In 1998, the FDA approved palivizumab, a synthetic monoclonal antibody against RSV.

Other Viruses and Multiple Viruses

The most common pathogen associated with bronchiolitis is RSV.3 There are, however, a number of other viruses that can cause bronchiolitis, such as parainfluenza virus type III, adenovirus, human metapneumo virus, and human bocavirus. Both human metapneumo virus and human bocavirus have been clearly associated with an illness in children similar to bronchiolitis. Children who are RSV-negative can be tested for these other viruses.

For many years physicians identified one infectious agent as the cause of the patient’s clinical illness. In recent years, however, physicians have begun to recognize complex infections with multiple pathogens. Often both viral and bacterial pathogens coexist, such as varicella and group A Streptococcus; influenza and Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus [MRSA]); and RSV with both Streptococcus pneumoniae and Haemophilus influenzae. Alternatively, several viruses may coexist, such as RSV and rhinovirus, a risk factor for admission of infants with severe bronchiolitis to the pediatric intensive care unit.

Premature Infants

Although many children contract RSV, premature infants are at higher risk for RSV infection than full-term infants. Approximately 500,000 children are born preterm—less than 37 weeks gestational age—each year in the United States.4

A study on the rate of hospital readmission following discharge of infants born less than 36 weeks gestational age revealed that of 260,000 infants born prematurely, 15% required readmission to the hospital. The most common cause of readmission was acute respiratory disease, and RSV infection was the most common principle diagnosis leading to readmission.5 Moreover, infants born less than 32 weeks gestational age who contracted an RSV-positive lower respiratory tract infection had more subsequent hospital admissions, spent more days in the hospital, and experienced more coughing and wheezing compared to infants who did not have a RSV lower respiratory tract infection.6

A study of lung function in premature infants found that infants born less than 32 weeks gestational age who contracted the RSV or Human metapneumovirus infection had higher airway resistance, more days of wheezing, and an increased requirement for bronchodilator.7

Finally, a study of chronic manifestations of RSV disease found that otherwise healthy premature infants born 32-35 weeks gestational age and hospitalized for RSV had more subsequent hospital admissions, more inpatient days, more physician contacts, and more outpatient visits in the first two years after birth than children who did not contract RSV.8

Conclusion

The annual rates of hospitalization due to RSV and bronchiolitis have increased steadily since 1980. Though RSV is the most common pathogen associated with bronchiolitis, other viruses are also associated with bronchiolitis. Multiple infections and multiple pathogens can cause of bronchiolitis, and often viral and bacterial pathogens coexist.

Premature infants are at a higher risk for RSV infection, are at an increased risk of hospital readmission and spend more days in the hospital than term infants. In addition, premature infants infected with RSV have higher airway resistance and spend more days wheezing.

Many challenges are associated with RSV infection. Children have a limited natural immunity to RSV and reinfection is common. Both hypoxemia and apnea are uniquely associated with RSV infections. No effective or safe vaccine has been developed; treatment is only supportive and focus on relieving symptoms.

References

  1. Shay DK, Holman RC, Newman RD et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999; 282:1440-1446.
  2. McLaurin KK, Leader S. Pediatric Academic Societies Annual Meeting. May 14-17; 2005. Washington, D.C.
  3. Cooper AC, Banasiak NC, Allen PJ. Pediatric Nursing. 2003;29(6):452-456.
  4. Martin JA, Hamilton BE, Sutton PD et al. Births: Final Data for 2005. Natl Vital Stat Rep. 2006; 56:1-103.
  5. Underwood MA, Danielson B, Gilbert WM. Cost, causes and rates of rehospitalization of preterm infants. Journal of Perinatology. 2007; 27:614-619.
  6. Broughton S, Roberts A, Fox G et al. Prospective study of healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants. Thorax. 2005; 60:1039-1044.
  7. Broughton S, Sylvester KP, Fox G et al. Lung function in prematurely born infants after viral lower respiratory tract infections. Pediatric Infect Dis J. 2007; 26:1019-1024.
  8. Greenough A, Broughton S. Chronic manifestations of respiratory syncytial virus infection in premature infants. Pediatric Infect Dis J. 2005; 24:S184-S188.

A Primer on Preemies: Developmental Biology and Respiratory Illness


Dan L. Stewart, MD
A major complication observed in preterm infants increased risk is increased vulnerability to both viral and bacterial infections when compared to term infants.
— Dan L. Stewart, MD

Preterm infants, defined as infants who have completed less than 37 weeks of gestation, can have significant comorbidities, such as feeding problems, body temperature instability, elevated bilirubin levels, sepsis, and hypoglycemia. A major complication of prematurity is increased vulnerability to both viral and bacterial infections compared to term infants. Thus, respiratory problems, such as pneumonia, transient tachypnea of the newborn, surfactant deficiency, and pulmonary hypertension are more common in preterm infants.1-2

Lung Development

Many factors can delay or interfere with normal lung development and the alveolarization process, such as mechanical ventilation, antenatal and postnatal steroids, pro-inflammatory mediators, hyperoxia, hypoxia, and poor nutrition.7 Early in lung development the airways are tubular and lined by cuboidal epithelium. Later in development the airways become more saccular. Premature birth interrupts normal lung development resulting in abnormal airways with smaller caliber, increased smooth muscle, and increased goblet cells compared with term infants (Figure1). 4-6 Moreover, at 34 weeks gestation the lung volume is only 52% that of a term infant’s lung; at 30 weeks gestation the preterm lung volume is only 36% that of the term lung volume (Figure2). The surface area of the lung at 34 weeks gestation is 44% of the term infant; at 30 weeks it is 27% of the term infant. Alveoli can be present at 32 weeks but generally are not present until 36 weeks of gestational age,3 and alveolar wall thickness of a premature infant at 34 weeks gestation is 34% greater than that of the term infant, while at 30 weeks gestation it is 61% greater (Figure 3).1

Figure 1: Premature Birth can Alter Airways
Figure 1: Premature Birth can Alter Airways

Figure 2: Premature Birth Interrupts Lung Development
Figure 2: Premature Birth Interrupts Lung Development

Figure 3: Modeled Lung Estimates with Development
Figure 3: Modeled Lung Estimates with Development


Challenges of RSV Infection

Premature infants have smaller lung volume, less surface area, and fewer alveoli with greater wall thickness; they also have a higher risk than term infants of hospitalization due to infection with respiratory syncytial virus (RSV). In one study, the hospitalization rate for term infants due to infection with RSV was 3%, compared with 5.7% for premature infants born 33-36 weeks gestation, and 6.6% for premature infants born 29-33 weeks gestation.8 Moreover, RSV infection requiring hospitalization in infancy has been shown to be an independent risk factor for abnormal lung function in young adults. The effects of RSV persist into late childhood and, in some cases, early adulthood.11

Premature infants have smaller lung volume, less surface area, and fewer alveoli with greater wall thickness and have a higher risk than term infants of hospitalization due to infection with respiratory syncytial virus.
— Dan L. Stewart, MD

The increased risk of RSV infection in premature and low birth weight infants may also be due in part to lower RSV-specific immune risk factors, such as IgG levels and transplacental antibody ratios. 9 RSV-specific antibodies decrease quickly after birth; at one month, RSV-specific antibodies decrease to 73%, and by three months RSV-specific antibodies decrease to 8%.

Although it correlates with premature gestational age, low birth weight is an independent risk factor for RSV infection and increased mortality.9, 12 RSV is often the cause of bronchiolitis, and the rate of bronchiolitis-associated deaths increase 5-times in premature infants born 32-35 weeks gestation, and 17-times in premature infants born less than 32 weeks gestation.15

Finally, premature infants with severe chronic lung disease who acquire RSV infection face many obstacles to their recovery. A study of premature infants with chronic lung disease and RSV found 80% of patients required supplemental oxygen, 32% were admitted to the ICU, 17% required mechanical ventilation, and 3.5% died within 2 weeks.16

Conclusion

Infants born less than 37 weeks gestation are at significant risk for RSV infection as well as additional respiratory problems. This increase is due in part to a delay in lung development, which results in abnormal airways, smaller lung volume, smaller lung surface area and increased alveolar wall thickness. Another reason is lower RSV-specific immune factors, such as IgG levels and transplacental antibody ratios.

Premature infants infected with RSV face many challenges, including an increased hospitalization rate compared to term infants. Depending on gestational age, the hospitalization rate can be more than double the rate of term infants. In addition, hospitalization in infancy due to RSV has been shown to correlate with abnomral lung function in early adulthood.

Premature lung development, low birth weight, immunological deficiencies, and poor physiologic and functional capacity of premature infants, are all risk factors for RSV, and result in increased morbidity and mortality.

References

  1. Engle WA, Tomashek KM, Wallman C et al. “Late-preterm” infants: a population at risk. Pediatrics. 2007; 120:1390-1401.
  2. Shapiro-Mendoza CK et al. Risk factors for neonatal morbidity and mortality among “healthy,” late preterm newborns. Semin Perinatol. 2006; 30:54-60.
  3. Langston C, Kida K, Reed M, Thurlbeck WM. Human lung growth in late gestation and in the neonate. Am Rev Respir Dis. 1984; 129: 607-613.
  4. Hoo AF, Dezateux C, Henschen M et al. Development of airway function in infancy after preterm delivery. J Pediatr. 2002;141:652-658.
  5. Mansell AL, Driscoll JM, James LS. Pulmonary follow-up of moderately low birth weight infants with and without respiratory distress syndrome. J Pediatr. 1987;110:111-115.
  6. Hislop AA, Haworth SG. Airway size and structure in the normal fetal and infant lung and the effect of premature delivery and artificial ventilation. Am Rev Respir Dis. 1989;140:1717-1726.
  7. Resnik R, Creasy RK, Iams JD. Maternal-Fetal Medicine:Principles and Practice 5th Edition.2004. Philadelphia. Chap 16. 212.
  8. Boyce TG, Mellen BG, Mitchel EF Jr. et al. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr. 2000;137:865–870.
  9. Okoko JB, Wesumperuma HL, Hart CA. The influence of prematurity and low birthweight on transplacental antibody transfer in a rural West African population. Trop Med Int Health. 2001 Jul;6(7):529-34.
  10. Hacimustafaoglu M, Celebi S, Aynaci E. The progression of maternal RSV antibodies in the offspring. Arch Dis Child. 2004;89:52-53.
  11. Korppi M, Piippo-Savolainen E, Korhonen K, Remes S. Respiratory morbidity 20 years after RSV infection in infancy. Pediatr Pulmonol. 2004 Aug;38(2):155-60.
  12. Buckingham SC, Quasney MW, Bush AJ, DeVincenzo JP. Respiratory syncytial virus infections in the pediatric intensive care unit: clinical characteristics and risk factors for adverse outcomes. Pediatr Crit Care Med. 2001 Oct;2(4):318-23.
  13. Rona RJ, Gulliford MC, Chinn S. Effects of prematurity and intrauterine growth on respiratory health and lung function in childhood. BMJ. 1993 Mar 27;306(6881):817-20.
  14. Chan KN, Noble-Jamieson CM, Elliman A et al. Lung function in children of low birth weight. Arch Dis Child. 1989 Sep;64(9):1284-93.
  15. Holman RC, Shay DK, Curns AT et al. Risk factors for bronchiolitis-associated deaths among infants in the United States. Pediatr Infect Dis J. 2003;22:483-490.
  16. 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.

Challenges in the Diagnosis and Management of RSV Infection


Paul A. Checchia, MD

Infection from respiratory syncytial virus (RSV) is the leading cause of viral death in infants. Each year about 500 deaths are associated with RSV, 80% of which occur in infants younger than 1 year of age.2 The rate of RSV-related death in infants younger than one year of age is about ten times the rate of influenza-related death in this age group (Figure 1).1

Several factors increase the severity of RSV infection, including premature birth, chronic lung disease, congenital heart disease, low birth weight, and immunodeficiencies (Figure2).3-4

Figure 1: RSV Infection: The Leading Cause of Mortality in Infancy
Figure 1: RSV Infection: The Leading Cause of Mortality in Infancy

Figure 2: Children at Increased Risk of Severe RSV Infection
Figure 2: Children at Increased Risk of Severe RSV Infection


Infection Control

The transmission rate of RSV is 26%. The most important factor in nosocomial infection control is assiduous hand-washing by medical personnel. Screening for RSV infection on admission and cohorting infected patients can also reduce nosocomial spread of RSV. However, debate exists regarding the national standard of time to 2 negative cultures within a 7 day period.5-6

Up to 83% of children with RSV are reinfected each year, more than 50% of all preschool children will experience repeated lower respiratory illness such as bronchiolitis. Infection with RSV is not protective against subsequent exposures.
— Paul A. Checchia, MD

Up to 83% of children with RSV are reinfected each year, and more than 50% of all preschool children will experience repeated lower respiratory illness such as bronchiolitis. Contracting RSV is not protective against subsequent infections.7 One reason for the high rate of repeat infections is that the immune response does not recognize important protective epitopes following the initial exposure. High risk infants and young children who have not developed immunity to RSV should receive monthly doses of palivizumab throughout the infection season.

Cardiac Risks

Children with congenital heart disease are at increased risk for serious infection from RSV. At the same time, RSV infection can cause cardiac complications. RSV infection in patients with congenital heart disease is associated with increased morbidity and mortality, and, following cardiac surgery employing cardiopulmonary bypass, these patients are at the highest risk for complications, leading to increased morbidity and mortality.19-22 For example, cardiac surgery performed during the symptomatic period of RSV infection is associated with a high risk of postoperative pulmonary hypertension. Physicians should consider not performing elective procedures during RSV season, and should delay surgical procedures up to 5 weeks following active infection.23

RSV infection in patients with congenital heart disease is associated with increased morbidity and mortality, and following cardiac surgery employing cardiopulmonary bypass these patients are at the highest risk for complications, leading to increased morbidity and mortality.
— Paul A. Checchia, MD

RSV is associated with a spectrum of disease ranging from pulmonary manifestations to a sepsis-like syndrome.8-11 Patients with cardiac symptoms can suffer from arrhythmias and cardiac failure secondary to presumed myocarditis.12-18 A study conducted on the association between RSV and myocardial injury found that 54% of 22 children admitted to the PICU for RSV infection had elevated troponin levels, indicating myocardial injury. Patients who had elevated troponin were younger, with 75% of positive assays occurring in patients less than 3 months of age. There was an association between an elevated troponin levels and the need for mechanical ventilation, occurrence of a cardiovascular event, such as CPR, and volume resuscitation or inotropes. Post hoc analysis found that troponin levels were elevated prior to the cardiac event.24 Thus, myocardial involvement is common in infants without congenital heart disease who have severe RSV infection.

Treatment Options

Multiple therapies have been used to relieve airway obstruction associated with RSV infection, including chest physiotherapy, bronchodilators, heliox mixtures, corticosteroids, mucolytics, ribavirin, and exogenous surfactants. However, these therapies have had mixed results, and physicians have few options other than to intubate, ventilate, and let the lungs heal themselves without causing additional damage.

Albuterol is a bronchodilator that can potentially reduce the work of breathing and increase patient comfort. Data are conflicting regarding whether bronchodilators decrease complication rates or length of hospitalization. The best responders to albuterol are patients with underlying bronchopulmonary dysplasia or reactive airway disease.5, 26-29 Racemic epinephrine is an alpha and beta2-adrenergic agonist that has shown equivalent or better outcomes compared to pure albuterol. In one study, 30% of patients treated with racemic epinephrine required hospitalization compared to 75% of patients treated with albuterol.5 In a more recent study, children with mild RSV had similar responses whether treated with albuterol or racemic epinephrine.

The use of steroids for first time wheezing due to RSV is not recommended. Clinical trials provide little evidence to support the use of steroids in the treatment of RSV bronchiolitis.30

Conclusion

Though there are many factors that can increase the severity of RSV, physicians can take precautions to ensure they do not cause additional complications. Infection control is important, and careful hand washing, RSV screening, and cohorting of patients are recommended for physicians to avoid nosocomial infection. Elective cardiac surgery should not be performed during RSV season and surgery should be delayed following RSV infection since RSV patients have a higher morbidity and mortality following these procedures.

No specific therapy has been found to be effective for RSV lower respiratory infections. Supportive care promoting hydration, gas exchange (oxygentation and ventilation) and appropriate antibiotic etherapy for bacterial co infections is the current standard of care.

References

  1. 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.
  2. Shay DK et al. Bronchiolitis-Associated Mortality and Estimates of Respiratory Syncytial Virus-Associated Deaths Among US Children, 1979-1997. J Infect Dis. 2001;183(1):16-22.
  3. Weisman LE. Populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions. Pediatr Infect Dis J. 2003; 22:S33-S39.
  4. Panitch HB. Viral respiratory infections in children with technology dependence and neuromuscular disorders. Pediatr Infect Dis J. 2004; 23:S222-S227.
  5. Weisman LE. Nosocomial Respiratory Syncytial Virus Infections: The “Cold War” Has Not Ended. Clinical Infectious Disease. 2000;31:590-596.
  6. Prevention of Respiratory Syncytial Virus Infections: Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV. Pediatrics. 1998;102(5):1211-1215.
  7. Feign RD, Cherry JD (eds). Textbook of Pediatric Infectious Diseases, 4th Edition. 1998. Philadelphia. Chap. 185. 2095.
  8. Dagan R, Hall CB, Powell KR, Menegus MA. Epidemiology and laboratory diagnosis of infection with viral and bacterial pathogens in infants hospitalized for suspected sepsis. J Pediatr. 1989; 115:351-356.
  9. Njoku DB, Kliegman RM. Atypical extrapulmonary presentations of severe respiratory syncytial virus infection requiring intensive care. Clin Pediatr (Phila). 1993; 32:455-460.
  10. Kim KK, Frankel LR. The need for inotropic support in a subgroup of infants with severe life-threatening respiratory syncytial viral infection. J Investig Med. 1997; 45:469-473.
  11. Wahab AA, Dawod ST, Raman HM. Clinical characteristics of respiratory syncytial virus infection in hospitalized healthy infants and young children in Qatar. J Trop Pediatr. 2001; 47:363-366.
  12. Huang M et al. Ventricular arrhythmia associated with respiratory syncytial viral infection. Pediatr Cardiol. 1998; 19:498-500.
  13. Menahem S. Respiratory syncytial virus and supraventricular tachycardia in an infant. Int J Cardiol. 1991; 32:249-251.
  14. Armstrong DS. Cardiac arrhythmias as a manifestation of acquired heart disease in association with paediatric respiratory syncitial virus infection. J Paediatr Child Health. 1993; 29:309-311.
  15. Olesch CA, Bullock AM. Bradyarrhythmia and supraventricular tachycardia in a neonate with RSV. J Paediatr Child Health. 1998; 199-201.
  16. Donnerstein RL, Berg RA, Shehab Z, Ovadia M. Complex atrial tachycardias and respiratory syncytial virus infections in infants. J Pediatr. 1994; 125:23-28.
  17. Menahem S, Uren EC. Respiratory syncytial virus and heart block--cause and effect? Aust N Z J Med. 1985; 15:55-57.
  18. Bairan AC, Cherry JD, Fagan LF, Codd JE Jr. Complete heart block and respiratory syncytial virus infection. Am J Dis Child. 1974; 127:264-265.
  19. 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.
  20. Altman CA, Englund JA, Demmler G et al. Respiratory syncytial virus in patients with congenital heart disease: a contemporary look at epidemiology and success of preoperative screening. Pediatr Cardiol. 2000; 21:433-438.
  21. Moler FW, Khan AS, Meliones JN et al. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Crit Care Med. 1992; 20:1406-1413.
  22. MacDonald NE, Hall CB, Suffin SC et al. Respiratory syncytial viral infection in infants with congenital heart disease. N Engl J Med. 1982; 307:397-400.
  23. Khongphatthanayothin A, Wong PC, Samara Y et al. Impact of respiratory syncytial virus infection on surgery for congenital heart disease: postoperative course and outcome. Crit Care Med. 1999; 27:1974-1981.
  24. Checchia PA, Appel HJ, Kahn S et al. Myocardial injury in children with respiratory syncytial virus infection. Pediatr Crit Care Med. 2000; 146-150.
  25. Moynihan JA, Brown L, Sehra R, Checchia PA. Cardiac troponin I as a predictor of respiratory failure in children hospitalized with respiratory syncytial virus (RSV) infections: a pilot study. Am J Emerg Med. 2003; 21:479-482.
  26. Hammer J, Numa A, Newth CJ. Albuterol responsiveness in infants with respiratory failure caused by respiratory syncytial virus infection. J Pediatr. 1995; 127:485-490.
  27. Schuh S, Canny G, Reisman JJ et al. Nebulized albuterol in acute bronchiolitis. J Pediatr. 1990; 117:633-637.
  28. Gadomski AM, Perkis V, Horton L et al. Nebulized albuterol in acute bronchiolitis. Pediatrics. 1994; 93:907-912.
  29. Flores G, Horwitz RI. Efficacy of 2 – Agonists in Bronchiolitis: A Reappraisal and Meta-Analysis. Pediatrics. 1997; 100(2):233-239.
  30. Roosevelt G, Sheehan K, Grupp-Phelan et al. Dexamethasone in bronchiolitis: a randomised controlled trial. Lancet. 1996; 348:292-295.

Optimizing RSV Prophylaxis and Improving Continuity of Care for Infants at Risk


Michael L. Forbes, MD

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality in infants. However, not all infants are at equal risk for severe RSV infection. It is important for physicians to identify and manage patients at high risk to help prevent hospitalization.

High Risk Patients

Focused risk assessment allows doctors to identify patients who are vulnerable to RSV infection and can benefit from intervention.
— Michael L. Forbes, MD

Focused risk assessment allows doctors to identify patients who are vulnerable to RSV infection and who can benefit from intervention. Patients with bronchopulmonary dysplasia, chronic lung disease, and congenital heart disease are at a higher risk of severe respiratory disease such as bronchiolitis and bronchopneumonia. In addition, a study of infants hospitalized due to bronchiolitis showed that patients with these preexisting conditions had significant morbidity.1 Eighty percent of patients in the study required supplemental O2, 32% required ICU admission, 17% required mechanical ventilation, and the mortality rate was 3.5% (Figure 1).

Infants younger than 3 months of age have a higher rate of hospitalization than children older than 3 months of age, and the younger patients had longer hospitalizations and more days on oxygen, ventilator support, bronchodilators, and corticosteroids (Figure 2).2 In addition, previously healthy premature infants hospitalized due to RSV infection have significantly more subsequent health care resource utilization and mortality compared to infants not hospitalized (Figure 3).4

Figure 1: Once Hospitalized
Figure 1: Once Hospitalized

Figure 2: Hospitalized Infants Were...
Figure 2: Hospitalized Infants Were

Figure 3: Uniquely Vulnerable Infants become Disproportionate Health care Resource Utilizers
Figure 3: Uniquely Vulnerable Infants become Disproportionate Health care Resource Utilizers


Immunoprophylaxis Strategies

Immunoprophylaxis of RSV with monoclonal antibody (palivizumab) has been shown to reduce the rate of hospitalization of high risk infants and children by 39%-80%.5 Questions still remain, however, about whether the timing of administration affects hospitalization rates. A retrospective analysis of reports from 1996-2003 that evaluated the incidence of hospitalizations following pre- and post-discharge prophylaxis with palivizumab concluded that there was no apparent benefit to providing immunoprophylaxis with palivizumab to every infant before discharge. Outpatient rates of prophylaxis are rising.6 The percentage of infants who received their first palivizumab dose in the outpatient setting after hospital discharge increased from 33% in the 2000–2001 season to 52% in the 2003–2004 season (Figure 4).8 However, there is no evidence to suggest outpatient prophylaxis reduces hospitalization rates, and reimbursement may be a driver of the increased rate of outpatient prophylaxis. For example, hospitals reimbursed palivizumab doses for under diagnosis-related costs more than for total inpatient hospitalization costs.4

Figure 4: Outpatient Dosing has increased Prior to 2006 Red Book Guidelines Change
Figure 4: Outpatient Dosing has increased Prior to 2006 Red Book Guidelines Change

A 2-year study of 40,000 births in Canada identified 401 patients with significant chronic heart disease. Twenty one patients were eligible for prophylaxis, and no ineligible patients received prophylaxis. In this study it was determined that optimized prophylaxis strategies may be appropriate for a target group of at risk patients.7 However, a collaboration of many healthcare practitioners was needed for proper patient-group identification and prophylaxis.

Conclusion

A collaborative effort of many health care practitioners is required for proper patient-group identification and prophylaxis.
— Michael L. Forbes, MD

Not all premature infants are equally at risk for RSV infection, and infection is a major cause of morbidity, mortality, and healthcare resourse utilization. Patients with preexisting conditions, such as chronic lung disease, are at higher risk of developing severe respiratory disease. In addition, infants less than 3 months of age are hospitalized more often than infants >3 months of age.

Immunoprophylaxis can reduce the rate of hospitalization by up to 80%. There is, however, little information on whether delaying immunoprophylaxis from pre- to post-discharge has an effect on hospital readmissions.

Physicians need to focus on prevention of RSV for at risk patients, including using immunoprophylaxis to reduce the rate of hospitalization. Studies investigating the timing (pre- or post-discharge) of immunoprophlyaxis are required to determine its effect on the rate of hospitalization and long term morbidity.

References

  1. 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.
  2. Resch B, Gusenleitner W, Müller W. The impact of respiratory syncytial virus infection: a prospective study in hospitalized infants younger than 2 years. Infection. 2002;30:193-197.
  3. Boyce TG, Mellen BG, Mitchel EF Jr. et al. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr. 2000;137:865–870.
  4. Sampalis JS. Morbidity and mortality after RSV-associated hospitalizations among premature Canadian infants. J Pediatr. 2003; 143:S150-S156.
  5. Mejias et al. Respiratory Syncytial Virus Prophylaxis. Neoreviews. 2005; 6:26-31.
  6. Geskey JM, Ceneviva GD, Brummel GL et al. Administration of the first dose of palivizumab immunoprophylaxis against respiratory syncytial virus in infants before hospital discharge: what is the evidence for its benefit? Clin Ther. 2004; 26:2130-2137.
  7. Warren A, Langley JM, Thomas W, Scott J. Optimizing the delivery and use of a new monoclonal antibody in children with congenital heart disease: a successful provincial respiratory syncytial virus prophylaxis program. Can J Cardiol. 2007; 23:463-466.
  8. Speer ME et al. Palivizumab outcomes registry 2000 to 2004: Delayed prophylaxis in children at high risk of respiratory syncytial virus (rsv) disease. Neonatology Today. April 2007:2;4:1-5.