Pediatric Respiratory Disease: Defining the Risk and Reducing the Burden of Respiratory Syncytial Virus

Introduction Defining the Risk and Burden of RSV Infection Michael L. Forbes, MD, FAAP Managing Respiratory Disease in the Pediatric Patient Gary Goodman, MD Multidisciplinary Strategies for Successful RSV Prophylaxis John J. LaBella, MD Discussion

Introduction

Respiratory syncytial virus (RSV), a pediatric respiratory disease, is the primary cause of infant hospitalization in the United States. Estimates from the Centers for Disease Control and Prevention indicate that more than 220,000 infants are hospitalized due to RSV infection each year. Very young children, especially those born preterm, have a high RSV infection rate in the first year of life. Among symptomatic preschool children, nearly two-thirds (62%) have been infected with RSV. In the scope of pervasive, recurring health issues, RSV-related illness remains a significant, under-appreciated public health problem, the epidemiological and clinical impact of which is primarily pediatric, but also occurs acutely and chronically in adults.

To increase awareness of RSV disease as a significant health burden, especially in preterm infants, Vindico Medical Education organized a panel of experts to share their expertise in November 2008. They reviewed the epidemiology as well as the medical economic burden of RSV infection. Treatment options and prophylaxis were also discussed. American Academy of Pediatrics guidelines for RSV risk factors and prophylaxis were evaluated. Advice for ensuring prophylaxis of all high-risk infants was given.

I thank the panel for their contributions to the development of this monograph. Readers can expect to increase their understanding of the economic burden attributable to RSV and the importance of prophylaxis, and learn how to successfully implement prophylaxis in their practices.

Michael L. Forbes, MD, FAAP
Course Chair

Defining the Risk and Burden of RSV Infection

Michael L. Forbes, MD, FAAP

As preterm infants are uniquely vulnerable to respiratory syncytial virus (RSV), it is noteworthy to examine the prevalence of premature births. According to the National Center for Health Statistics, mortality rates for late preterm (between 34 and 36 weeks of gestation) infants were 3 times those for full-term infants in 2005.¹ Approximately 4 million children are born every year in the United States, and premature infants account for 12.5% of these births. Approximately 200,000 of these premature infants are late preterm. Approximately 50,000 are in the 28- to 31-week gestational age, and 1300 infants were born before 20 weeks’ gestation. Moreover, 60,000 infants born in 2002 weighed less than 1500 g.² Therefore, the summary indicates that the number of preterm births decreases as the gestational age decreases. However, since this population will continue to increase, developing a strategy for optimal management of premature infants is vital.

The Public Health Impact of Prematurity

The United States has continued to invest in preterm care. The average cost of care for late preterm infants upon discharge is $10,000, which is double that of full-term infants. Regarding infants born between 26 and 28 weeks’ gestation, the average cost of care at the time of discharge is $240,000, which is almost 50-fold higher than the average cost of care of a full-term infant.³

The United States spends $5 billion each year caring for infants in the first year of life, with 50% spent on preterm infants, a uniquely vulnerable population that accounts for only 12.5% of all infants born in this country. That cost per infant is 4 times their incidence in the population. By contrast, $600 million, approximately 25% of the United States cost of preterm care, can immunize all of the children in the world against measles, whooping cough, tetanus, tuberculosis, polio, and diphtheria. Thus, the investment in improving preterm care is substantial and worthwhile.

Pathophysiology of RSV

As members of a common family of mammalian pathogens, orthomyxoviruses and paramyxoviruses cause similar symptoms. The common clinical features of infection are cough, coryza, and fever. Infection involving the terminal bronchioles is a common consequence of RSV infection. Bronchiolitis, however, can be contracted due to infection from RSV, influenza, and many other common winter viruses.

Clinical features of bronchiolitis include:

• Nasal flaring
• Hypoxemia and cyanosis
• Expiratory grunt
• Expiratory wheezing, prolonged expiration, rales, and rhonchi
• Chest wall retractions
• Tachypnea with apneic episodes

Epidemiology of RSV

Approximately 50% of children in the first year of life will be infected with RSV. Of those, 30% to 70% will develop lower respiratory illness, but the frequency of hospitalization is only 1% to 3%. Once they are infected, these children display a unique vulnerability and become disproportionate utilizers of health care resources. RSV infections occur in nearly everyone by 2 years of age.⁴ In children from birth to 12 months of age, 68% have been infected with primary RSV. In children aged 13 to 24 months, 97.1% have been affected by primary RSV.⁴ RSV does not confer immune memory, and thus infection from RSV can occur more than once each season.

A cohort study based on data from the Belgian sentinel network’s epidemiology surveillance of the 2000-2001 RSV seasons examined the clinical epidemiology of RSV in symptomatic preschool children. It was found that RSV accounts for the majority of upper and lower respiratory tract infections in children.⁵ Sixty-two percent of symptomatic preschool children were infected with RSV, while 38% were infected with other viruses.⁵

Bronchiolitis, predominantly due to RSV, is the most common reason infants are discharged nationally, according to the National Hospital Discharge Survey, 1997–1999.^6,7 Of 684,675 infant discharges reported, 220,379 discharges were due to RSV-related bronchiolitis and 181,662 discharges were related to unspecified bronchiolitis.^7,8 Overall, more than 400,000 discharges were due to bronchiolitis every year, underscoring the significant disease burden of RSV and other pathogens that cause bronchiolitis. ^6,7

A study at Boston Children’s Hospital examined the reasons children present to the emergency department (ED). Acute respiratory infections were the most common, with the mean incidence at 6923 cases, and the mean rate-per-thousand of 398 children.⁸ Overall, children younger than 7 years presented to the Boston Children’s Hospital ED 37.6% of the time due to an acute respiratory infection, compared to presenting with influenza 9.2% of the time, adenovirus 4.6% of the time, and parainfluenza virus 2.8% of the time.⁸ The majority of those respiratory infections were caused by RSV.

An IED epidemiologic study, which addressed the disease burden of bronchiolitis, utilized a 19-panel multiplex-reverse transcriptase polymerase chain reaction (RT-PCR) to identify pathogens and illustrated coinfection rates for influenza A, influenza B, RSV, human metapneumovirus, and the parainfluenza viruses. It was found that some pathogens independently cause life-changing or life-threatening infection, whereas other pathogens, such as Mycoplasma pneumonia, Bordetella pertussis, and Bordetella parapertussis, are almost always coinfectants.⁹ The coinfection rate in the study was 12.5%, and the fraction of coinfections per pathogen varied. The coinfection rate with RSV was at 25%, compared with the coinfection rates of influenza A at 18% and parainfluenza virus 3 at 36%.⁹

In summary, RSV-related illness remains a significant, under-appreciated public health care burden, the epidemiological and clinical impact of which is primarily pediatric.

Seasonality of RSV

The seasonality of RSV is well known but incompletely understood. Based on data collected during the 2006-2007 and 2007-2008 seasons, the RSV season is earliest and longest in Florida, ranging from July to approximately February. In the South, it begins between October and November.¹⁰ In the Northeast it begins between November and December, and later in the Midwest and West. By April or May, in the majority of the country, the process begins to attenuate.¹⁰

Burden of RSV

In 2002, Resch and colleagues examined the impact of RSV infection in a prospective study in hospitalized infants younger than 2 years to determine the differential impact of severe RSV disease. The study used nasopharyngeal aspirates and RSV-Ag detection, and all infants born at less than 29 weeks’ gestation received palivizumab. Of 281 hospitalizations, 21% of infants tested positive for RSV.¹¹

In a 2002 Healthcare Utilization Project-National Inpatient Sample by Pelletier, an estimated 149,000 patients (<2 years of age) were hospitalized for bronchiolitis, with a mean hospital length of stay of 3.3 days.¹² The costs associated with bronchiolitis and RSV are becoming apparent in the health care community. According to data from the National Inpatient Sample, when the primary diagnosis was RSV or unspecified bronchiolitis, approximately $390 million was spent annually; the mean cost was about $3208 for a mean length of stay of 3.3 days.¹² Looking at all children with bronchiolitis, including children who do not present with respiratory failure but may present with arrhythmias, severe hypoxia, or apnea, the cost rose incrementally.¹²

In a study conducted by Thompson and colleagues, mortality related to RSV was compared to mortality related to influenza by examining a national database from the Centers for Disease Control and Prevention. Mortality rates for influenza were higher for age groups of 1 year to 4 years and 5 years to 49 years. However, the mortality rate due to RSV for infants younger than 1 year was about 10-fold higher than that of influenza in these children.¹³ These data suggest that infants younger than 1 year are uniquely vulnerable to infection with RSV and thus require special attention.

In a study that attempted to determine reasons that infants with RSV are hospitalized, it was found that RSV-related hospitalization was independent of gestational age (Figure 1).¹⁴ The relative risk for RSV-related hospitalization for infants born at 28 weeks’ gestation, 29 to 32 weeks’ gestation, and 33 to 35 weeks’ gestation was 2.1, 1.9, and 1.8, respectively. Thus, the relative risk of hospitalization for preterm infants was approximately twice the risk for full-term infants and, contrary to what was previously believed, this risk of hospitalization is independent of gestational age, which could be due to physician practice and concern.

On the other hand, mortality appears to be a function of gestational age (Figure 2). The odds ratio for death due to bronchiolitis in infants born within 32 weeks is 17.3, and infants in the 32- to 35-week gestational age group have an odds ratio of 4.7. Therefore, once hospitalized, the mortality rate of infants increases as gestational age decreases.¹⁵

Low birth weight is also a factor associated with increased mortality. Multivariate analysis shows that infants born weighing less than 1500 g have an odds ratio of 13.9 and infants weighing between 1500 g and 2499 g have an odds ratio of 3.0. Thus, once hospitalized, infants with low birth weight have a dramatically increased risk of mortality due to bronchiolitis.¹⁵

An understanding of morbidity associated with hospitalization is essential. Several studies provide a window into the percentage of hospitalizations for RSV and, more specifically, RSV hospitalizations leading to intensive care unit (ICU) admission and requiring ventilation in high-risk groups.^16-23 In one study examining hospitalization for RSV, it was found that the proportion of term infants hospitalized for RSV was 1% to 3%, while the proportion of premature infants hospitalized for RSV was 10.6%. The ICU admission rate for term infants hospitalized for RSV was 11%, while the rate of premature infants was 28% to 31%. The proportion of full-term RSV-infected infants requiring mechanical ventilation was 4.6%, compared to 12% to 22% of premature infants. In preterm infants with bronchopulmonary dysplasia (BPD) or congenital heart disease requiring medical therapy, the rates are even higher. Thus, the disease burden associated with this pathogen is noteworthy.

Once hospitalized, there is a 2- to 3-fold increase in the rate of hospitalizations afterward compared to full-term controls (Table 1).²⁴ In a study that involved a 2-year follow-up, it was found that total days spent in the hospital were higher compared to control patients who were never hospitalized due to RSV and, referring to outpatient data, the number of visits with pulmonologists and/or other specialists indicated an increased utilization of the health care system (Table 1).²⁴

In summary, RSV is associated with a significant health care burden. Preterm infants are uniquely vulnerable to infection, and once infected, they become disproportionate utilizers of the health care system.

References

1. Mathews TJ, Macdorman MF. Infant mortality statistics from the 2005 period linked birth/infant death data set. National Vital Statistics Reports. 2008 Jul 30;57(2):1-32.
2. Martin JA, Kochanek KD, Strobino DM, Guyer B, MacDorman MF. Annual summary of vital statistics--2003. Pediatrics. 2005 Mar;115(3):619-34.
3. Cuevas KD, Silver DR, Brooten D, Youngblut JM, Bobo CM. The cost of prematurity: hospital charges at birth and frequency of rehospitalizations and acute care visits over the first year of life: a comparison by gestational age and birth weight. The American Journal of Nursing. 2005 Jul;105(7):56-64; quiz 65.
4. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. American Journal of Diseases of Children. 1986 Jun;140(6):543-6.
5. Simoes EA, Carbonell-Estrany X. Impact of severe disease caused by respiratory syncytial virus in children living in developed countries. The Pediatric Infectious Disease Journal. 2003 Feb;22(2 Suppl):S13-8; discussion S18-20.
6. Leader S, Kohlhase K. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. The Pediatric Infectious Disease Journal. 2002 Jul;21(7):629-32.
7. National Center for Health Statistics, Centers for Disease Control and Prevention, United States Department of Health and Human Services. Atlanta, GA.
8. Bourgeois FT, Valim C, Wei JC, McAdam AJ, Mandl KD. Influenza and other respiratory virus-related emergency department visits among young children. Pediatrics. 2006 Jul;118(1):e1-8.
9. Weigl JA, Puppe W, Meyer CU, Berner R, Forster J, Schmitt HJ, Zepp F. Ten years' experience with year-round active surveillance of up to 19 respiratory pathogens in children. European Journal of Pediatrics. 2007 Sep;166(9):957-66. Epub 2007 Jun 14.
10. Centers for Disease Control and Prevention (CDC). Brief report: respiratory syncytial virus activity--United States, July 2006-November 2007. MMWR: Morbidity and Mortality Weekly Report. 2007 Dec 7;56(48):1263-5.
11. 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 Aug;30(4):193-7.
12. Pelletier AJ, Mansbach JM, Camargo CA Jr. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics. 2006 Dec;118(6):2418-23.
13. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003 Jan 8;289(2):179-86.
14. Boyce TG, Mellen BG, Mitchel EF Jr, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. The Journal of Pediatrics. 2000 Dec;137(6):865-70.
15. Holman RC, Shay DK, Curns AT, Lingappa JR, Anderson LJ. Risk factors for bronchiolitis-associated deaths among infants in the United States. The Pediatric Infectious Disease Journal. 2003 Jun;22(6):483-90.
16. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999 Oct 20;282(15):1440-6.
17. Hall CB. Respiratory syncytial virus. In: Feigin RD, Cherry JD, eds. Textbook of Pediatric Infectious Diseases. 4^th ed. Philadelphia, PA: WB Saunders;1998:2084-2110.
18. The IMpact-RSV Study Group. Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. Pediatrics. 1998 Sep;102(3):531-7.
19. Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top FH Jr, Connor EM, Sondheimer HM; Cardiac Synagis Study Group. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. The Journal of Pediatrics. 2003 Oct;143(4):532-40.
20. Law BJ, MacDonald N, Langley J, et al. Severe respiratory syncytial virus infection among otherwise healthy prematurely born infants: What are we trying to prevent? Paediatric Child Health. 1998;3:402-4.
21. 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. The Journal of Pediatrics. 1992 Sep;121(3):348-54.
22. Altman CA, Englund JA, Demmler G, Drescher KL, Alexander MA, Watrin C, Feltes TF. Respiratory syncytial virus in patients with congenital heart disease: a contemporary look at epidemiology and success of preoperative screening. Pediatric Cardiology. 2000 Sep-Oct;21(5):433-8.
23. Moler FW, Khan AS, Meliones JN, Custer JR, Palmisano J, Shope TC. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Critical Care Medicine. 1992 Oct;20(10):1406-13.
24. Sampalis JS. Morbidity and mortality after RSV-associated hospitalizations among premature Canadian infants. The Journal of Pediatrics. 2003 Nov;143(5 Suppl):S150-6.

Managing Respiratory Disease in the Pediatric Patient

Gary Goodman, MD

Respiratory syncytial virus (RSV) remains the leading cause of hospitalization in infants younger than 1 year. Current therapeutic options for treating children with RSV are limited. There are a number of factors to consider in the management of RSV and bronchiolitis.

Etiology of Bronchiolitis

RSV is the leading cause of bronchiolitis, accounting for 50% to 80% of lower respiratory infections that occur each winter. It is the most important respiratory pathogen in children. However, other viruses, such as influenza, human metapneumovirus, adenovirus, parainfluenza virus, and bocavirus, also can cause bronchiolitis. This should be considered when managing patients who have a diagnosis of bronchiolitis, yet their test results were negative for RSV.

Also, bronchiolitis is not always due to infection by a single virus. A number of studies have demonstrated dual viral infections. In fact, a study of patients admitted to the intensive care unit (ICU) discovered that, in patients who were coinfected with RSV and rhinovirus, there was a 2.7-fold increase in the risk of admission to the pediatric intensive care unit (PICU) compared with patients who were infected with only RSV.¹ A recent study conducted in Seattle demonstrated that 23% of admissions were due to multiple viruses.² A single virus was isolated in 71% of patients. RSV is the most common virus isolated independently, occurring 77% of the time.²

Bacterial coinfection may also occur. In fact, 40% of patients with RSV and respiratory failure admitted to the ICU had tracheal cultures that were positive for a bacterial pathogen including Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. ³ Thus, although it is not advisable to use antibiotics when they are not necessary, the possibility of a bacterial coinfection should be examined when managing bronchiolitis.

In summary, although infection with RSV is the leading cause of bronchiolitis, bronchiolitis can be caused by other viruses, coinfection with other viruses, or coinfection with bacteria. Therefore, when a patient presents with bronchiolitis, testing must be performed to determine the true etiology of the disease, so that the appropriate treatment is administered.

Infection Control and Isolation

The American Academy of Pediatrics (AAP) guidelines suggest that, based on outpatient treatment and evaluation of patients with bronchiolitis, RSV diagnostic testing may not be as necessary when a child presents to the physician’s office. However, for patients admitted to the hospital, diagnostic testing may be beneficial for several reasons.⁴ For example, viral diagnostic testing will result in the appropriate isolation and cohorting of patients and staff, which minimizes the risk of transmission of viral agents. Also, if a specific viral pathogen is identified, then the unnecessary use of antibiotics could be avoided. Optimally, antibiotics should be utilized for treatment only when evidence of a specific bacterial pathogen exists. Furthermore, early diagnostic testing can identify a specific virus, such as influenza, allowing for the initiation of appropriate antiviral therapy.

Diagnostic testing is also important for the collecting and reporting of RSV infection rates, which has been proposed as a quality-of-care performance indicator for inpatient pediatric units. Moreover, diagnostic testing aids in identifying emerging agents that cause bronchiolitis and pneumonia in children. It will also assist in defining epidemiological trends in RSV infection. Lastly, diagnostic tests will assess the effectiveness of RSV prophylaxis.⁴ Current infection control recommendations also include wearing a gown and gloves for contact precautions and a mask for droplet precautions for patients who may be infected with influenza or adenovirus. Hand washing remains the single most important method in the prevention of the spread of infection.

Supportive Care

Supportive care is important in the management of RSV infection. In a study examining the determinants of hospital stay for patients with bronchiolitis, it was shown that the majority of these patients (82%) present to the hospital with feeding difficulties due to their respiratory distress. Therefore, adequate hydration and nutrition are vital for these patients. Seventy percent of infants hospitalized for bronchiolitis require oxygen 6 hours after hospitalization.⁵ Thus, oxygen support is also important. AAP clinical practice guidelines for bronchiolitis recommend maintaining oxygen saturations at 90% or above, although there is controversy as to whether this value is too low.^6-8 In the duration of the hospital stay, the need for supplemental oxygen slowly declines (Figure 1). In fact, it is the rate-limiting factor for hospital discharge.⁵ In a study involving an extensive review of 16 patients, it was found that many infants appeared ready for discharge in terms of their respiratory distress, but, due to the low oxygen levels measured by pulse oximetry, they remained in the hospital on supplemental oxygen. It was observed in this study that the length of hospital stay is extended by 1.6 days based on pulse oximetry readings compared to when the clinical evaluation indicated that the patients may be discharged.⁵

Clinical Manifestations of RSV

Small airway obstruction

The most common respiratory manifestations of RSV are wheezing and small airway obstruction. Although there is no absolute treatment, several options for management of this manifestation exist.^9-12 Aerosol delivery is an option, although there is currently no optimal aerosol delivery system. A face mask or a hood may also be effective, both of which are well tolerated.

Bronchodilators such as albuterol and epinephrine are also options. Many clinical trials compared the efficacy of albuterol with that of racemic epinephrine.¹⁰ Several years ago, the data seemed to support racemic epinephrine as the preferred bronchodilator. However, a more recent study concluded that albuterol administered in the emergency department was a more successful bronchodilator for children with bronchiolitis.¹⁰ It is advisable to initiate treatment with either albuterol or racemic epinephrine and, if the patient does not respond, stop the treatment and change to the alternative. Ipratropium bromide is another bronchodilator used to treat children with asthma; however, limited data on its efficacy in patients with RSV infection exist. Nebulized 3% hypertonic saline also has been shown to be a safe and effective treatment for patients with RSV infection. Lastly, pilot studies on the effect of inhaled furosemide have demonstrated limited clinical benefit but found it was safe.

Extrapulmonary manifestations of RSV

Although RSV is primarily a respiratory pathogen, there are extrapulmonary manifestations of RSV disease as well.¹³ The most common secondary organ affected by RSV is the heart. This effect is observed in 2 dimensions. Effects on cardiac function are observed, as some patients have hypotension and require ionotropic support. In an analysis of 22 patients admitted to the PICU, elevated troponin levels were observed in 54.5% of patients, and 22.7% required ionotropic support.¹⁴ Patients may also have complex cardiac arrhythmias, both supraventricular and ventricular tachycardias, that are associated with RSV infection. Central apnea is also associated with RSV, as is neurological complications such as seizures and focal neurologic abnormalities. Hyponatremia is associated with RSV, as it can lead to inappropriate antidiuretic hormone syndrome. Hepatitis has also been associated with RSV.

Antiviral Therapy

Antiviral therapy has not been successful in the treatment of RSV infection. Ribavirin was used extensively for only a limited time due to the complexity of its administration, its lack of efficacy, and significant complications in children who were on mechanical ventilation. However, ribavirin is still used in children who are at extremely high risk for RSV infection, especially those who are immunocompromised.

A small study was conducted recently in 31 patients, 7 of whom had received transplants and 24 of whom had medical conditions such as malignancy, congenital heart disease, and prematurity. All patients were given IV palivizumab, 15 mg/kg daily (an off-label indication), and 25 patients (80%) also received ribavirin. Twenty-nine patients (93.6%) survived, results that were better than what was to be expected in this high-risk population.¹⁵ Therefore, for a select population of patients with RSV disease, antiviral therapy could be effective.

Novel Treatment for Patients with Respiratory Failure

A number of emerging therapies have potential for treatment of RSV infection, especially in the PICU, where physicians are trying to avoid mechanical ventilation due to respiratory distress. These novel therapies include nasal continuous positive airway pressure (CPAP), helium-oxygen mixtures, and surfactant replacement.

Traditionally, it has been believed that nasal CPAP is not the ideal treatment for children who are hyperinflated and have small airways disease. Conversely, 3 clinical studies demonstrated that nasal CPAP can improve clinical scores in carbon dioxide elimination, unload the respiratory muscles, improve respiratory distress symptoms, and improve ventilation in patients with bronchiolitis and hypercapnea.^16-18

Helium-oxygen mixtures decrease the density of the air that patients breathe, which improves airflow by decreasing resistance.¹⁶ In a study of a mixture of 30% oxygen and 70% helium, marked reductions in tachycardia and tachypnea were observed. A decreased length of stay in the PICU for children treated with helium-oxygen therapy was also observed.¹⁶

The efficacy of the combination of helium-oxygen mixtures and nasal CPAP has also been examined. A Modified Woods Clinical Asthma Score revealed that, compared to the nontreatment group, patients receiving nasal CPAP alone with air and oxygen, and nasal CPAP along with helium-oxygen mixture experienced a decrease in clinical asthma scores.¹⁶ Examination of the partial pressure of carbon dioxide revealed that there was a decrease in respiratory failure when patients were given CPAP alone, and then pCO₂ levels decreased further, nearly 10 points, when helium-oxygen mixtures were added to CPAP.

There has been an interest in surfactant therapy for patients who have required mechanical ventilation. Three clinical trials involving 79 patients demonstrated a trend toward a decrease in the duration of mechanical ventilation by approximately 2.6 days, a further decrease in the length of stay in the ICU by 3.3 days, and short-term benefits of surfactant therapy on both pulmonary mechanics and gas exchange.¹⁹ Thus, surfactant therapy may also play a beneficial therapeutic role in respiratory failure, but additional studies are required to further define the therapeutic value of this treatment.

RSV Prophylaxis

Because therapy for RSV is limited, the potential prevention of RSV infection with vaccines and with passive immunoprophylaxis should be investigated, especially for infants at risk. During the 1960s, a formalin-inactivated RSV (FI-RSV) vaccine was tested, which was unsuccessful. Children treated with FI-RSV vaccines who were subsequently infected with RSV developed serious respiratory illness.²⁰ Seventy percent of the patients who received the FI-RSV vaccine developed RSV-related pneumonia, compared to only 4% of patients in the control group who did not receive the vaccine.²⁰ Eighty percent of the patients who received the vaccine required hospitalization, whereas only 5% of those in the control group did, and 2 deaths occurred in the treatment group.²⁰ This negative experience with the initial vaccine has delayed development efforts and raised concerns about the safety of a potential RSV vaccine. Alternative prevention strategies include passive immunoprophylaxis for RSV prevention. An RSV hyperimmune globulin was the first such product, approved by the FDA in February 1996.²¹ The dosage was 750 mg/kg, IV, once per month, and its use resulted in a 41% reduction in hospital admissions for patients who were premature and had chronic lung disease.²¹ In 1998, an updated version of RSV prophylaxis became available in the form of a synthetic monoclonal antibody against the fusion-protein of RSV, delivered in a monthly dose of 15 mg/kg. It accounted for a 78% reduction of hospital admissions in premature infants, a 39% reduction in hospital admissions for patients with chronic lung disease,²² and, in a separate study, a 45% reduction in hospital admissions for patients with congenital heart disease.²³ The guidelines developed by AAP specifically address 3 large groups of infants who are at risk for RSV disease and are eligible for prophylaxis. Those groups include infants who are born prematurely, infants with chronic lung disease, and infants with congenital heart disease. AAP has added modifiers including gestational age, chronological age, and environmental risk factors. When the total population of 4.1 million infants born each year in the United States is examined, it is obvious that only a small percentage of patients would benefit from RSV prophylaxis, given the current guidelines. Of those 4.1 million, about 500,000 babies (12%) are born prematurely at less than 37 weeks’ gestation, 32,700 (1%) are born with congenital heart disease, and only 7500 are born with bronchopulmonary dysplasia (Figure 2). Thus it follows that, in terms of RSV prophylaxis, the emphasis is not on the large group of healthy children born each year, but rather on a select group of children at high risk.

In summary, RSV is a pervasive disease that should not be ignored. It is the main cause of bronchiolitis, but there are also other possible causes of bronchiolitis that should be considered. Supportive care, therapy, and prophylaxis for bronchiolitis have improved, but an absolute solution remains to be determined.

References

1. Richard N, Komurian-Pradel F, Javouhey E, Perret M, Rajoharison A, Bagnaud A, Billaud G, Vernet G, Lina B, Floret D, Paranhos-Baccalà G. The impact of dual viral infection in infants admitted to a pediatric intensive care unit associated with severe bronchiolitis. The Pediatric Infectious Disease Journal. 2008 Mar;27(3):213-7.
2. Stempel HE, Martin ET, Kuypers J, Englund JA, Zerr DM. Multiple viral respiratory pathogens in children with bronchiolitis. Acta Paediatrica. 2009 Jan;98(1):123-6. Epub 2008 Sep 9.
3. Thorburn K, Harigopal S, Reddy V, Taylor N, van Saene HK. High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis. Thorax. 2006 Jul;61(7):611-5. Epub 2006 Mar 14.
4. Harris JA, Huskins WC, Langley JM, Siegel JD; Pediatric Special Interest Group of the Society for Healthcare Epidemiology of America. Health care epidemiology perspective on the October 2006 recommendations of the Subcommittee on Diagnosis and Management of Bronchiolitis. Pediatrics. 2007 Oct;120(4):890-2.
5. Unger S, Cunningham S. Effect of oxygen supplementation on length of stay for infants hospitalized with acute viral bronchiolitis. Pediatrics. 2008 Mar;121(3):470-5.
6. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006 Oct;118(4):1774-93.
7. Schroeder AR, Marmor AK, Pantell RH, Newman TB. Impact of pulse oximetry and oxygen therapy on length of stay in bronchiolitis hospitalizations. Archives of Pediatrics & Adolescent Medicine. 2004 Jun;158(6):527-30.
8. Bass JL, Gozal D. Oxygen therapy for bronchiolitis. Pediatrics. 2007 Mar;119(3):611.
9. Amirav I, Oron A, Tal G, Cesar K, Ballin A, Houri S, Naugolny L, Mandelberg A. Aerosol delivery in respiratory syncytial virus bronchiolitis: hood or face mask? The Journal of Pediatrics. 2005 Nov;147(5):627-31.
10. Walsh P, Caldwell J, McQuillan KK, Friese S, Robbins D, Rothenberg SJ. Comparison of nebulized epinephrine to albuterol in bronchiolitis. Academic Emergency Medicine. 2008 Apr;15(4):305-13.
11. Kuzik BA, Al-Qadhi SA, Kent S, Flavin MP, Hopman W, Hotte S, Gander S. Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. The Journal of Pediatrics. 2007 Sep;151(3):266-70, 270.e1. Epub 2007 Jun 29.
12. Bar A, Srugo I, Amirav I, Tzverling C, Naftali G, Kugelman A. Inhaled furosemide in hospitalized infants with viral bronchiolitis: a randomized, double-blind, placebo-controlled pilot study. Pediatric Pulmonology. 2008 Mar;43(3):261-7.
13. Eisenhut M. Extrapulmonary manifestations of severe respiratory syncytial virus infection--a systematic review. Critical Care. 2006;10(4):R107.
14. Checchia PA, Appel HJ, Kahn S, Smith FA, Shulman ST, Pahl E, Baden HP. Myocardial injury in children with respiratory syncytial virus infection. Pediatric Critical Care Medicine. 2000 Oct;1(2):146-50.
15. Chávez-Bueno S, Mejías A, Merryman RA, Ahmad N, Jafri HS, Ramilo O. Intravenous palivizumab and ribavirin combination for respiratory syncytial virus disease in high-risk pediatric patients. Pediatric Infectious Disease Journal. 2007 Dec;26(12):1089-93.
16. Martinón-Torres F, Rodríguez-Núñez A, Martinón-Sánchez JM. Nasal continuous positive airway pressure with heliox versus air oxygen in infants with acute bronchiolitis: a crossover study. Pediatrics. 2008 May;121(5):e1190-5. Epub 2008 Apr 14.
17. Cambonie G, Milési C, Jaber S, Amsallem F, Barbotte E, Picaud JC, Matecki S. Nasal continuous positive airway pressure decreases respiratory muscles overload in young infants with severe acute viral bronchiolitis. Intensive Care Medicine. 2008 Oct;34(10):1865-72. Epub 2008 Jul 8.
18. Thia LP, McKenzie SA, Blyth TP, Minasian CC, Kozlowska WJ, Carr SB. Randomised controlled trial of nasal continuous positive airways pressure (CPAP) in bronchiolitis. Archives of Disease in Childhood. 2008 Jan;93(1):45-7. Epub 2007 Mar 7.
19. Ventre K, Haroon M, Davison C. Surfactant therapy for bronchiolitis in critically ill infants. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005150. DOI: 10.1002/14651858.CD005150.pub2.
20. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. American Journal of Epidemiology. 1969 Apr;89(4):405-21.
21. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, Parrott RH. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. American Journal of Epidemiology. 1969 Apr;89(4):422-34.
22. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. The PREVENT Study Group. Pediatrics. 1997 Jan;99(1):93-9.
23. Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. Pediatrics. 1998 Sep;102(3):531-7.
24. Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top FH Jr, Connor EM, Sondheimer HM; Cardiac Synagis Study Group. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. The Journal of Pediatrics. 2003 Oct;143(4):532-40.

Multidisciplinary Strategies for Successful RSV Prophylaxis

John J. LaBella, MD

According to surveys, 50% to 70% of infants at high risk are candidates for respiratory syncytial virus (RSV) prophylaxis in the neonatal intensive care unit (NICU) and receive their dose of prophylaxis. Accordingly, 30% to 50% of these infants have not been identified, and it is then the responsibility of their primary care physician (PCP) to identify and track these children who did not receive a dose prior to hospital discharge.¹ It is advisable for office-based physicians to have a specific member of their staff be responsible for tracking these patients. Infants born prematurely are at high risk, due to their altered airway anatomy and absence of maternal antibodies. Also, children with a pre-existing lung condition are at high risk. This population may include premature children with classic bronchopulmonary dysplasia (BPD) or even full-term infants with meconium aspiration or airway anomaly. Also, children who are immunocompromised would have difficulty clearing an RSV infection and therefore also considered high risk. If infected, these children have the potential to experience a more severe course of infection that would lead to hospitalization. Therefore, it is vital to identify these children as candidates for RSV prophylaxis.^2,3

American Academy of Pediatrics Guidelines for RSV Prophylaxis Using Palivizumab

The American Academy of Pediatrics (AAP) has established guidelines for determining candidates for RSV prophylaxis (Figure 1).⁴ Infants born at 28 weeks’ gestation or less without chronic lung disease or congenital heart disease and younger than 12 months at the start of the RSV season would be appropriate candidates for palivizumab prophylaxis. Infants born extremely prematurely receive prophylaxis in the NICU during not only the current season, but also the following season if they will still be younger than 1 year. If a child was born in another community and is new to a PCP’s practice, the PCP should immediately identify the patient as a candidate for RSV prophylaxis.

A more obscure case to consider for prophylaxis would be a child who was born between 29 and 32 weeks’ gestation and is younger than 6 months old, born in the summer, and does not have chronic lung disease or premature complications. In other words, a child can be considered at risk simply based on his or her chronological age. The AAP guidelines recommend that these children receive prophylaxis for RSV if they are 6 months of age or younger at the beginning of RSV season.

Another age group the AAP addresses is children who are born between 32 and 35 weeks’ gestation and who are younger than 6 months old at the start of RSV season. Due to the significant number of these children (220,000) born each year and the high cost associated with monthly prophylaxis, the AAP recommends administering palivizumab to these children only when 2 additional risk factors listed below are present.

For patients with congenital heart disease and patients with chronic lung disease, the AAP guidelines recommend palivizumab during not only the season they are born, but also the subsequent season. Also, any child younger than 2 years who has ongoing congenital heart lesions requiring ongoing medical therapy or infants with primary lung disease in infancy that remains active the following season should be considered for prophylaxis.

Risk Factors for RSV Infection

Risk factors for RSV infection are viewed differently by different groups. The traditional risk factors, which are also those put forth by the AAP, are child care attendance, the presence of older siblings in the home, congenital airway anomalies, severe neuromuscular disease, and tobacco smoke.

The issue of tobacco smoke as a risk factor is controversial. The AAP considers it a modifiable risk factor that could be reduced or eliminated, creating a more cost-effective way to prevent RSV disease. But data suggest that exposure to tobacco smoke during pregnancy itself could raise the risk of a severe RSV event in the infant.^5-7 Because of that, tobacco smoke must be considered separately.

Additional risk factors include low birth weight, young age at season onset, family history of wheezing or asthma, multiple births, male gender, minimal breast feeding, crowded living conditions, and maternal education level.^5,8-11 Studies conducted in Spain and Canada reached the same conclusion regarding classic risk factors, but different findings in terms of the strength of the statistical associations.^7,10 Afterward, however, the group in Spain re-examined the risk factors as independent, rather than additive, and found that being born prior to the onset of the season, being in the same household as children in school or day care attendance, or having smoke exposure independently raised the risk for RSV. These data may aid in leading to a change in attitude regarding the requirement for the presence of 2 risk factors for immunoprophylaxis of infants born between 32 and 35 weeks’ gestation.

Relevance of RSV Prevention

The issue of whether premature infants born between 32 and 35 weeks’ gestation should be administered prophylaxis remains debatable. Considering the health care utilization data, children between 32 and 35 weeks’ gestation with their primary infection, compared with not only full-term children, but also children born less mature, have higher rates of intensive care unit admissions, higher usage of critical-care support in terms of ventilation, and longer hospital stays. This uniquely vulnerable group warrants special attention because, if the primary infection can be prevented, then health care costs can be decreased. Thus, it appears as though preventing the primary infection is the appropriate course of action. The European predictive model based on risk factors may aid in identification of infants with the highest risk for RSV hospitalization.

Special Circumstances

There are special circumstances in which it will be appropriate to administer prophylaxis to patients who do not meet the AAP guidelines. For example, if a nosocomial outbreak occurs in an NICU, then prophylaxis of the entire unit would be appropriate. Although there are limited data supporting this action, many hospitals will make a clinical judgment in this type of situation. There are also additional high-risk scenarios, such as nosocomial infections, cystic fibrosis, bone marrow transplant/solid organ transplant candidates/recipients, and congenital anomalies.^12-16

With more extensive newborn screening being performed in the United States, more asymptomatic infants with an underlying lung disorder, such as cystic fibrosis, can be identified. Preventing an RSV infection in that population of patients can reduce long-term morbidity; preliminary data suggest that it may be effective.

Solid organ and bone marrow transplant recipients are immunosuppressed. Thus, there is potential value in preventing infection in that group. A recent United States survey did not demonstrate consensus in terms of the measures implemented by organ transplant centers to prevent infection in this population. Some centers are administering prophylaxis, whereas some are awaiting more research. This is an area where additional information is required.

Lastly are the special circumstances of children with congenital disorders. Prophylaxis of this population should be considered on a case-by-case basis.

Patient Identification and Tracking Programs

What is most important is recognizing the need to have all available information from the NICU and an awareness of when these high-risk groups visit the office, so that their need for RSV prophylaxis will not go unheeded.

Special attention should be paid to children who are born in May who may be candidates the following fall and children born before 29 weeks’ gestation, who will be candidates the following year. This is a large group of patients to track. Solutions that nurses have for organizing the information and tracking the patients may vary. Data suggest which systems may be more effective than others. Internet-based tools, in which all of the patient information is available and can be accessed directly from the office, are effective. Education programs have also been shown to be successful. Also, local surveillance and the Centers for Disease Control and Prevention Web site can define when the seasonality begins and ends in specific communities.

Product Procurement

Palivizumab is an expensive monoclonal antibody. A PCP must be aware of the different health care systems and their requirements for prior authorization for RSV prophylaxis. This will overcome the barrier of prior authorization. Another barrier is working with families to overcome the high cost of palivizumab. The families may have copayments or high deductibles that may require special consideration. The PCP may have to work with the family and arrange payment plans. It is also important to be aware of the policies of the pharmacy. Many pharmacy policies vary in terms of forms and shipment, and the office coordinator of the PCP must understand the process of the particular pharmacy to prevent delays in treatment.

Dosing Delivery Options: Where?

Where should prophylaxis begin? Does the NICU, pediatric ICU, or newborn nursery give the first dose?¹⁷ How much time should elapse before administering the second dose? Who should deliver the second dose? The answers to these questions are individual practice decisions. Some practices refer the children back to a hospital-based or specialty clinic for on-going follow-up and consultation, while most practitioners continue and coordinate the care in-office. Approximately 10% of practices recommend a home-nursing visit. Data accumulated over the past 6 to 8 years demonstrated that the compliance rate, measured by the total number of doses intended to give, versus the number of doses actually given, is higher in the case of a home nurse.¹⁸ Increased compliance reduces rates of emergency department visits and admissions to the hospital.^19-21 However, when compliance is low, there are higher rates of emergency department visits and hospitalizations.^22,23

Dosing Decisions: When?

Dosing decisions can be confusing, with cost-effectiveness a subject of debate. When the commitment to prophylaxis is made, when should it begin? The “season” is fairly predictable, but it is important to understand seasonal variability.²⁴ National recommendations of the AAP/COID–Red Book guidelines, suggesting a season onset of November 1 and a dosing protocol of 5 doses, are helpful, but these guidelines do not apply to certain areas, for example, south Florida or Texas. Data suggest that the season not only varies from year to year, but also depends on the location of the patient base. Tools are available to support timing and dosing requirements if prior-authorization becomes a challenge.

Compliance Concerns

Once the intention to prophylax is made, completion of the immunoprophylaxis series is mandatory. Without complete treatment, compliance breakthrough infections may occur, placing the child at risk. Immunoprophylaxis can and should bbe coadministered with routine immunization practices. A child can receive monthly prophylaxis even when he or she is ill. Prophylaxis does not stimulate the immune system. Thus, there is virtually no type of visit to the office that should cause suspending or deferring prophylaxis for a child. Other vaccines can be deferred if fever or reactions are concerns. If the child is in the office and it has been more than 25 to 28 days since his or her last dose, the next dose should always be given.

“Team Effort”

Coordinated care is the cornerstone that is responsible for success of the entire process. The interaction between the physician, the pharmacist, and third-party payors is a complex but necessary process. If compliance cannot be maintained, the effectiveness of the program will be compromised and the hospitalization of an infant may occur that perhaps could have been avoided.

References

1. Speer ME, Boron M, McLaurin K, Cohen A, Rankin M, Groothuis J. Palivizumab Outcomes Registry 2000 to 2004: Delayed Prophylaxis in Children at High Risk of Respiratory Syncytial Virus (RSV) Disease. Neonatology Today. 2007 April;2(4):1-5.
2. Weisman LE. Populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions. Pediatric Infectious Disease Journal. 2003 Feb;22(2 Suppl):S33-7; discussion S37-9.
3. Panitch HB. Viral respiratory infections in children with technology dependence and neuromuscular disorders. Pediatric Infectious Disease Journal. 2004 Nov;23(11 Suppl):S222-7.
4. American Academy of Pediatrics. Respiratory Syncytial Virus. In: Pickering LK, ed. Red Book®. 27th ed. 2006:560-566.
5. Carbonell-Estrany X, Quero J; IRIS Study Group. Hospitalization rates for respiratory syncytial virus infection in premature infants born during two consecutive seasons. Pediatric Infectious Disease Journal. 2001 Sep;20(9):874-9.
6. Boyce TG, Mellen BG, Mitchel EF Jr, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. The Journal of Pediatrics. 2000 Dec;137(6):865-70.
7. Law BJ, Langley JM, Allen U, Paes B, Lee DS, Mitchell I, Sampalis J, Walti H, Robinson J, O'Brien K, Majaesic C, Caouette G, Frenette L, Le Saux N, Simmons B, Moisiuk S, Sankaran K, Ojah C, Singh AJ, Lebel MH, Bacheyie GS, Onyett H, Michaliszyn A, Manzi P, Parison D. The Pediatric Investigators Collaborative Network on Infections in Canada study of predictors of hospitalization for respiratory syncytial virus infection for infants born at 33 through 35 completed weeks of gestation. The Pediatric Infectious Disease Journal. 2004 Sep;23(9):806-14.
8. Holman RC, Shay DK, Curns AT, Lingappa JR, Anderson LJ. Risk factors for bronchiolitis-associated deaths among infants in the United States. The Pediatric Infectious Disease Journal. 2003 Jun;22(6):483-90.
9. Carbonell-Estrany X, Quero J, Bustos G, Cotero A, Doménech E, Figueras-Aloy J, Fraga JM, García LG, García-Alix A, Del Río MG, Krauel X, Sastre JB, Narbona E, Roqués V, Hernández SS, Zapatero M. Rehospitalization because of respiratory syncytial virus infection in premature infants younger than 33 weeks of gestation: a prospective study. IRIS Study Group. The Pediatric Infectious Disease Journal. 2000 Jul;19(7):592-7.
10. Figueras-Aloy J, Carbonell-Estrany X, Quero J; IRIS Study Group. Case-control study of the risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born at a gestational age of 33-35 weeks in Spain. The Pediatric Infectious Disease Journal. 2004 Sep;23(9):815-20.
11. Stensballe LG, Kristensen K, Simoes EA, Jensen H, Nielsen J, Benn CS, Aaby P; Danish RSV Data Network. Atopic disposition, wheezing, and subsequent respiratory syncytial virus hospitalization in Danish children younger than 18 months: a nested case-control study. Pediatrics. 2006 Nov;118(5):e1360-8.
12. Groothuis J, Bauman J, Malinoski F, Eggleston M. Strategies for prevention of RSV nosocomial infection. Journal of Perinatology. 2008 May;28(5):319-23. Epub 2008 Mar 27.
13. Speer ME, Fernandes CJ, Boron M, Groothuis JR. Use of Palivizumab for prevention of hospitalization as a result of respiratory syncytial virus in infants with cystic fibrosis. The Pediatric Infectious Disease Journal. 2008 Jun;27(6):559-61.
14. Giebels K, Marcotte JE, Podoba J, Rousseau C, Denis MH, Fauvel V, Laberge S. Prophylaxis against respiratory syncytial virus in young children with cystic fibrosis. Pediatric Pulmonology. 2008 Feb;43(2):169-74.
15. Thomas NJ, Hollenbeak CS, Ceneviva GD, Geskey JM, Young MJ. Palivizumab prophylaxis to prevent respiratory syncytial virus mortality after pediatric bone marrow transplantation: a decision analysis model. Journal of Pediatric Hematology/Oncology. 2007 Apr;29(4):227-32.
16. Michaels MG, Fonseca-Aten M, Green M, Charsha-May D, Friedman B, Seikaly M, Sánchez PJ. Respiratory syncytial virus prophylaxis: A survey of pediatric solid organ transplant centers. Pediatric Transplantation. 2008 Sep 10. [Epub ahead of print]
17. Geskey JM, Ceneviva GD, Brummel GL, Graff GR, Javier MC. Administration of the first dose of palivizumab immunoprophylaxis against respiratory syncytial virus in infants before hospital discharge: what is the evidence for its benefit? Clinical Therapeutics. 2004 Dec;26(12):2130-7.
18. Paul DA, Leef KH, Chidekel A, Tran K, Eppes S, Stefano JL. Home delivery of palivizumab: outcomes and compliance in regional preterm infants. Delaware Medical Journal. 2002 Jan;74(1):11-5.
19. Golombek SG, Berning F, Lagamma EF. Compliance with prophylaxis for respiratory syncytial virus infection in a home setting. The Pediatric Infectious Disease Journal. 2004 Apr;23(4):318-22.
20. Hand IL, Noble L, Geiss D, Shotkin A. Respiratory syncytial virus immunoprophylaxis in an urban population: a comparison of delivery strategies and outcomes. The Pediatric Infectious Disease Journal. 2008 Feb;27(2):175-6.
21. Frogel M, Nerwen C, Boron M, Cohen A, VanVeldhuisen P, Harrington M, Groothuis J; Palivizumab Outcomes Registry Group. Improved outcomes with home-based administration of palivizumab: results from the 2000-2004 Palivizumab Outcomes Registry. The Pediatric Infectious Disease Journal. 2008 Oct;27(10):870-3.
22. Mansbach J, Kunz S, Acholonu U, Clark S, Camargo CA Jr. Evaluation of compliance with palivizumab recommendations in a multicenter study of young children presenting to the emergency department with bronchiolitis. Pediatric Emergency Care. 2007 Jun;23(6):362-7.
23. Moynihan JA, Kim TY, Young T, Checchia PA. Rate of palivizumab administration in accordance with current recommendations among hospitalized children. Journal of Pediatric Health Care. 2004 Sep-Oct;18(5):224-7.
24. Panozzo CA, Fowlkes AL, Anderson LJ. Variation in timing of respiratory syncytial virus outbreaks: lessons from national surveillance. The Pediatric Infectious Disease Journal. 2007 Nov;26(11 Suppl):S41-5.