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(Chest. 2005;128:2765-2771.)
© 2005 American College of Chest Physicians

Impact of Palivizumab on Admission to the ICU for Respiratory Syncytial Virus Bronchiolitis*

A National Survey{dagger}

Dario Prais, MD; Dana Danino, BmedSc; Tommy Schonfeld, MD; Jacob Amir, MD; for the Israeli RSV Monitoring Group

* From the Department of Pediatrics C (Drs. Prais and Amir) and Pediatric Intensive Care Unit (Dr. Schonfeld), Schneider Children’s Medical Center of Israel, Petah Tiqva J. Sackler Faculty of Medicine, Tel Aviv University; and Bruce Rappaport Faculty of Medicine (Dr. Danino), Israel Institute of Technology, Technion, Haifa, Israel. {dagger} A list of the members of the Israeli RSV Monitoring Group is located in the Appendix.

Correspondence to: Dario Prais, MD, Department of Pediatrics C, Schneider Children’s Medical Center of Israel, Petah Tiqva 49202, Israel; e-mail: dariop{at}clalit.org.il


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Study objectives: To assess the effect of palivizumab licensing for respiratory syncytial virus (RSV) prophylaxis on national pediatric ICU (PICU) admissions and on the need for mechanical ventilation due to RSV bronchiolitis in Israel.

Design: Prospective national surveillance survey.

Setting: All PICUs in Israel.

Patients or participants: All patients admitted to a PICU because of acute bronchiolitis in two consecutive RSV seasons (November 2000 to April 2001 and November 2001 to April 2002).

Methods: Data on demographic and epidemiologic factors and RSV prophylaxis status were collected for every infant with bronchiolitis who was admitted to a PICU in Israel in the year before and after issuance of the Israel Ministry of Health recommendation for palivizumab prophylaxis (January 2001).

Results: One hundred five patients were admitted to a PICU because of RSV bronchiolitis in the year before the recommendations were issued, and 123 patients were admitted in the year after they were issued. Mechanical ventilation was required by 33 and 42 children, respectively. Gestational age was > 32 weeks in 92.9% and 83.9% of the admitted patients, respectively, and 89% and 91% of the patients, respectively, were free of chronic lung disease (CLD). In both periods, 83% of the children who were admitted to a PICU did not meet the American Academy of Pediatrics criteria for RSV prophylaxis.

Conclusions: Most of the children with severe RSV bronchiolitis needing PICU admission from 2000 to 2002 born at term did not have CLD and were not candidates for RSV prophylaxis according to the current recommendations.

Key Words: bronchiolitis • palivizumab • pediatric ICU • respiratory syncytial virus


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Almost all children become infected with respiratory syncytial virus (RSV) within 2 years after birth.1 Although the infection usually presents as a mild upper respiratory tract disease, up to 1% of infected children require hospitalization. Overall, RSV accounts for 50 to 90% of all hospitalizations for bronchiolitis in children.2 In patients with a known underlying disease, such as chronic lung disease (CLD) or congenital heart disease, and in premature children, RSV bronchiolitis can quickly become a severe, life-threatening, lower respiratory tract infection.34

Since 1996, the following two passive immunization techniques have been available: RSV IV immunoglobulins (Ig) (RSV-IGIV, RespiGam; Massachusetts Public Health Biological Laboratories; Boston, MA; and MedImmune, Inc; Gaithersburg, MD) and a humanized monoclonal antibody preparation against the F glycoprotein of RSV (palivizumab, Synagis; MedImmune, Inc). In controlled clinical trials, monthly prophylaxis during the RSV season reduced the hospitalization rate in the high-risk population.567 On the basis of these findings, in 1998 the American Academy of Pediatrics (AAP) recommended that RSV prophylaxis should be considered for the following patients8:

  1. Infants < 2 years old with CLD who warranted medical therapy (ie, supplemental oxygen, bronchodilators, diuretics, or corticosteroids) within 6 months before the anticipated RSV season;
  2. Infants born at ≤ 28 weeks of gestation who do not meet the first criterion, up to 12 months of age; and
  3. Infants born at 29 to 32 weeks of gestation who do not meet the first criterion, up to 6 months of age.

The revised indications for RSV prophylaxis published by the AAP in 2003 include two other high-risk groups9:

  1. Infants born at 32 to 35 weeks of gestation who meet two or more of the following risk criteria: attend child care; have school-aged siblings; exposed to environmental air pollutants; have congenital abnormalities of the airways; or have severe neuromuscular disease.
  2. Children < 24 months of age with hemodynamically significant cyanotic or acyanotic congenital heart disease.

Before the RSV season of 2001 to 2002, the Israel Ministry of Health (IMH) published its indications for RSV prophylaxis with palivizumab.10 The guidelines stipulated that palivizumab should be administered to all infants with the following risk factors: have oxygen-dependent CLD, age up to 2 years; have CLD, age up to 1 year; and birth at ≤ 28 weeks of gestation, age up to 6 months.

In an earlier study, our group reported that the great majority of patients with RSV bronchiolitis who are admitted to pediatric ICUs (PICUs) or require mechanical ventilation do not meet the AAP criteria for RSV prophylaxis.11 Moreover, others12 have found that the majority of deaths due to bronchiolitis in the United States from 1996 to 1998 occurred among infants of normal birth weight who were not candidates for RSV prophylaxis. The aim of the present study was to assess the effect of palivizumab licensing for RSV prophylaxis on national PICU admissions and on the need for mechanical ventilation for RSV bronchiolitis in Israel.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
This prospective study was conducted in all 13 PICUs in Israel. The study sample included all patients who had been admitted to a PICU because of clinical symptoms indicative of acute bronchiolitis from November 2000 to April 2001 (period 1), the year before the IMH recommendations were issued, and from November 2001 to April 2002 (period 2), the year after they were issued. In the second season, palivizumab was available throughout the country and was administered in a hospital-based setting. Part of the data from the first period has already been published by our group.11

Cases of RSV bronchiolitis in both periods were identified by the authors, by personal communication, or by weekly visits or phone calls with a senior staff member of every PICU in Israel during the RSV season. A detailed questionnaire was completed at each PICU admission for all patients with clinical symptoms of acute bronchiolitis. In addition, the PICU admission registries were examined periodically to prevent omissions or errors. The following characteristics were recorded: age; gender; gestational age; birth weight; perinatal medical history; medical treatment since discharge from the neonatal department; present medical treatment; presence of CLD; oxygen requirement prior to PICU admission; palivizumab prophylaxis; indication for PICU admission; medical treatment; RSV status; total number of days of PICU hospitalization; total number of days receiving mechanical ventilation; and death. RSV status was determined by nasopharyngeal aspirate and standard RSV enzyme immunoassay, as reported.13 CLD was defined as oxygen dependence at a gestational age of 36 weeks. Congenital heart disease was considered to be cyanotic when a right-to-left shunt was present, delivering deoxygenated blood from the right side of the heart into the arterial circulation.

Individual hospital policies were followed with regard to the specific indications for PICU admission and medical management, which were unrelated to the study. National statistics on the number of annual live births, the rate and incidence of preterm deliveries, and neonatal ICUs admissions and discharges were obtained from the Israel Neonatal Network (Israel Center for Disease Control).14 The study was approved by the institutional review board at the institution of the main investigator (DP).

The effect of the availability of prophylaxis was assessed by comparing the data of the two periods. Analyses were performed on the total number of patients admitted to the PICUs and, separately, on the patients who were mechanically ventilated and the patients who died. Statistical analysis was performed with Pearson {chi}2 and Fisher exact tests.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
One hundred twenty-nine children were admitted to the 13 PICUs in Israel because of acute bronchiolitis during period 1 (from 2000 to 2001), and 167 children were admitted during period 2 (from 2001 to 2002). Of these patients, 105 children (81.4%) and 123 children (73.7%), respectively, were RSV-positive. The remainder were RSV-negative, including two patients in period 1 and one patient in period 2 with unknown RSV status. There was no statistically significant difference between the periods for this factor (p = 0.127). An analysis of the seasonal distribution of PICU admissions for RSV bronchiolitis revealed that in both periods 75 to 85% of the RSV-positive patients were admitted to PICUs from December to February, and 100% were admitted from November to April. All of the patients with proven RSV-negative status were admitted to PICUs from November to March (approximately 10 cases per month). The data for period 2 are shown in Figure 1 . Because our study focused on palivizumab prophylaxis (a specific monoclonal antibody against RSV), the non-RSV- positive patients (ie, those with RSV-negative and unknown status) were excluded from the analysis.



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  		Figure 1.. Seasonal distribution of admissions to the PICUs for bronchiolitis from November 2001 to April 2002.

 
The demographic characteristics of the RSV-positive patients in both periods are presented in Table 1 . There were no statistically significant differences in any of these features between the two periods. The average age at PICU admission was 5.3 months (range, 0.4 to 84 months; median, 2.27 months) for period 1 and 5 months (range, 0.5 to 203 months; median, 1.7 months) for period 2; 77.2% and 88.2% of the children, respectively, were < 6 months of age. The mean (± SD) birth weight was 2,559 ± 845 g in period 1 and 2,645 ± 963 g in period 2; birth weight was > 2,500 g in 56.4% and 55.4% of the children, respectively. The mean duration of PICU hospitalization was 8 days in period 1 and 7.3 days in period 2. Children who required mechanical ventilation had a longer PICU stay (14 and 13.1 days, respectively) than those who did not.


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  		Table 1.. Demographic Characteristics of the RSV Bronchiolitis Patients in the Two Periods*

 
Table 2 shows the distribution of the gestational ages of the patients admitted to a PICU in the two periods. More than half the children in both periods (60% and 57.7%, respectively) were born at term; 83.8% and 82.9% were born after 32 weeks of gestation.


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  		Table 2.. Distribution of Gestational Age of Patients With RSV Bronchiolitis Admitted to PICUs During the Two Periods*

 
Table 3 shows the presence of CLD among patients during the two study periods categorized by admission to a PICU and mechanical ventilation. CLD was absent in 89% of the admitted patients in period 1 and in 91% of patients in period 2. Three of the 11 patients with CLD who were admitted to a PICU in each period were oxygen-dependent; all 3 patients received mechanical ventilation in period 1, and 2 received it in period 2. Half of the non-oxygen-dependent patients with CLD required treatment with corticosteroids, bronchodilators, and/or diuretics at home.


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  		Table 3.. Presence of CLD Among Patients During the Two Study Periods Categorized by Admission to PICU and Mechanical Ventilation*

 
Mechanical ventilation was required in 33 patients (31.4%) during period 1 for a mean duration of 9.1 days (range, 1 to 27 days), and in 42 children (34.1%) during period 2 for a mean duration of 7.5 days (range, 1 to 28 days). CLD was present in 12% and 9.5% of the patients, respectively, who needed ventilation in each period (Table 3).

During the first period, nine children (8.6%) with congenital heart disease were admitted to the PICU, five of whom were cyanotic (ie, with tetralogy of Fallot, hypoplastic left heart, truncus arteriosus, and atrioventricular canal) and four of whom were acyanotic (ie, with ventricular septal defect, atrial septal defect, and patent ductus arteriosus). Mechanical ventilation was needed in three of the cyanotic children, of whom two died, and in one of the four acyanotic children. During period 2, 14 children (11.4%) with congenital heart disease were admitted to a PICU. Only one patient was cyanotic (truncus arteriosus). Four of the 13 acyanotic patients needed mechanical ventilation.

Seven patients died during the two periods; their characteristics are presented in Table 4 . The mortality rate was not significantly different between periods 1 and 2 (p = 0.215), but the absolute number of patients was too small to reach a conclusion. In addition, in period 2, there was one more child with RSV-negative bronchiolitis who died.


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  		Table 4.. Mortality Due to RSV Bronchiolitis in Patients Admitted to PICUs in Israel

 
The classification of the infants according to the previous AAP guidelines for the use of RSV immunoprophylaxis is presented in Table 5 . Eighty-three percent of the children admitted to the PICU because of RSV bronchiolitis in the two periods did not meet any of the AAP criteria (Fig 2 ). This was also true for 85% of the children in period 1 and in 69% of those in period 2 who needed mechanical ventilation (p = 0.170).


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  		Table 5.. ICU Admission and Mechanical Ventilation in Patients with RSV Bronchiolitis Classified According to AAP Criteria*

 


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  		Figure 2.. PICU admissions of patients with RSV bronchiolitis, classified according to the AAP criteria for RSV prophylaxis, as follows: (1) patients < 2 years of age with CLD who required oxygen therapy within 6 months of the start of RSV season; (2) patients < 2 years of age with CLD who required medical therapy within 6 months of the start of RSV season; (3) infants born at < 29 weeks of gestation who did not meet first two criteria, up to 12 months of age; and (4) infants born at 29 to 32 weeks of gestation who did not meet the first two criteria, up to 6 months of age.

 
When the study sample was classified according to the IMH recommendations for RSV prophylaxis, the following results were obtained. In the first period, 86.7% of patients admitted to a PICU with bronchiolitis and 85% of the patients who required mechanical ventilation did not meet the local criteria for RSV prophylaxis. The corresponding rates for period 2 were 90.3% and 90.5%, respectively (p < 0.001).

The RSV season of 2001 to 2002 was the first time that the prophylaxis program was offered in Israel. Twelve of the RSV-positive patients admitted to the PICU because of bronchiolitis during that period met the IMH recommendations for prophylaxis, but only 3 of them were properly immunized. All three patients to whom palivizumab was administered were admitted to the PICU. One patient received mechanical ventilation for 22 days and died on day 23 of sepsis.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
In the present national surveillance survey, we compared PICU admissions and the need for mechanical ventilation for the treatment of RSV bronchiolitis between the following two consecutive seasons: before and after the introduction of palivizumab in Israel. Seventeen percent of the patients admitted to a PICU in both periods were candidates for RSV prophylaxis according to the AAP guidelines. For period 1, 13.3%; and for period 2, 9.7% (p < 0.01) were candidates for RSV prophylaxis according to the IMH recommendations. The difference in the rates associated with the AAP and the IMH guidelines is probably attributable to the broader criteria of the AAP guidelines.

The present study takes an alternative look at the epidemiology of severe RSV disease. It did not ask which patients were at greater risk of severe disease, but rather, among those with severe disease what risk factors were present. We sought to investigate the potential impact of palivizumab therapy on the burden of PICU admissions due to RSV infections. We evaluated the PICU admissions for RSV bronchiolitis with respect to the recognized risk factors associated with an increased severity of RSV disease, namely, prematurity and CLD. The study showed that the majority of children who were admitted to the PICU lacked these risk factors, probably because the majority of infants in the general population are not premature and do not have CLD.

In 1997, the PREVENT study6 reported that the administration of IV RSV Ig (RespiGam; Massachusetts Public Health Biological Laboratories) to preterm infants with or without bronchopulmonary dysplasia led to a 41% reduction in RSV-related hospitalizations and to a 53% reduction in the total number of hospitalization days, in addition to a reduction in oxygen requirement and in the severity of lower respiratory tract illness. The Impact study7 tested the use of palivizumab and noted the following similar results: a 55% reduction in RSV-related hospitalizations (10.6% vs 4.8%, respectively), in addition to a reduction in the number of hospitalization days, in oxygen requirement, and in severity of disease. Overall, 3% of the placebo-treated children were admitted to the ICU in contrast to 1.3% of the palivizumab group (p = 0.026). These results demonstrate the low frequency of PICU admissions due to RSV bronchiolitis, even in a cohort of premature children. As the impact of this group on the general pediatric population was small because of their reduced absolute numbers, their impact on general morbidity was small as well.

In the United States, a national study12 of bronchiolitis-associated infant deaths during from 1996 to 1998 concluded that although preterm infants and infants weighing < 2500 g at birth are at an increased risk of dying of bronchiolitis, the majority of deaths due to bronchiolitis occur in infants of normal birth weight. Therefore, interventions for infants in high-risk groups will not prevent the majority of deaths due to bronchiolitis.

Although the national cost-effectiveness of RSV prophylaxis is beyond the scope of the present study, it certainly warrants further investigation. The findings of many of the related studies conducted so far have been inconclusive.151617 Other studies18192021222324 have reported that RSV prophylaxis would increase the net cost of care if palivizumab were administered to the population according to the AAP recommendations. Most of the economic analyses have failed to demonstrate overall savings in health-care dollars because of the high cost of prophylaxis for all at-risk children.

Our survey has some limitations. First, we could not be sure that all patients who were admitted to the PICUs because of acute bronchiolitis were enrolled in the study. However, we assume that the weekly personal communication of the author with a staff member in each unit was probably effective in identifying most of them. Second, our study included only two specific seasons. Further studies over several consecutive years are needed in order to account for year-to-year variability.

The most appropriate target population for RSV prophylaxis is still undefined. The criteria for RSV prophylaxis are changing and have been reconsidered.9 For example, following a large randomized clinical trial showing the benefit of palivizumab therapy in children with hemodynamically significant congenital heart disease, this patient group was included in the target population for prophylaxis.25 However, there are probably other potential candidates for RSV prophylaxis, such as children with CLD unrelated to prematurity (eg, those with meconium aspiration, persistent pulmonary hypertension, pulmonary hypoplasia, and congenital diaphragmatic hernia), interstitial lung diseases, severe respiratory tract obstruction (eg, tracheal stenosis, tracheobronchomalacia, and status/post stent insertion), immune deficiencies (eg, HIV and DiGeorge syndrome), and neuromuscular diseases (eg, Werdnig-Hoffmann disease). Surveys of these patient groups as well as epidemiologic studies to identify predisposing factors for severe RSV disease, even in full-term infants, are still needed.

In summary, most of the RSV bronchiolitis patients admitted to the PICU do not fit the current recommendations for palivizumab administration. Because the majority of patients are born at term and do not have CLD, RSV prophylaxis according to those guidelines is not expected to reduce the national burden of RSV bronchiolitis in the PICU.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
Members of the Israeli RSV Monitoring Group
J. Amir, Schneider Children’s Medical Center of Israel, Petah Tiqva; Z. Barzilay, The Chaim Sheba Medical Center, Tel Hashomer; T. Bernstein, Soroka Medical Center, Beer Sheva; H. Bibi, Barzilai Medical Center, Ashkelon; G. Eshel, Assaf Harofeh Medical Center, Zerifin; A. Gazit A, Western Galilee Hospital, Nahariya; I. Kasis, Rambam Medical Center, Haifa; D. Kleid, Shaare Zedek Medical Center, Jerusalem; A. Korneci, Dana Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv; Y. Marzel, HaEmek Medical Center, Afula; G. Paret, The Chaim Sheba Medical Center, Tel Hashomer; D. Prais, Schneider Children’s Medical Center of Israel, Petah Tiqva; T. Schonfeld, Schneider Children’s Medical Center of Israel, Petah Tiqva; Y. Sivan, Dana Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv; S. Sofer, Soroka Medical Center, Beer Sheva; E. Somekh, Wolfson Hospital, Holon; E. Tabachnik, Kaplan Medical Center, Rehovot; D. Wolf, Hadassah Medical Center, Jerusalem; I. Yatziv, Hadassah Medical Center, Jerusalem; Z. Zonis, Western Galilee Hospital, Nahariya.


   Acknowledgements
 
We thank Gloria Ganzach and Phyllis Curchack Kornspan for their editorial support.


   Footnotes
 
Abbreviations: AAP = American Academy of Pediatrics; CLD = chronic lung disease; IMH = Israel Ministry of Health; PICU = pediatric ICU; RSV = respiratory syncytial virus

This work was performed in partial fulfillment of the MD thesis requirements of author Dana Danino.

Received for publication August 31, 2004. Accepted for publication May 25, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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