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ORIGINAL STUDIES

Effect of palivizumab prophylaxis in decreasing respiratory syncytial virus hospitalizations in premature infants

PEDRAZ, CARMEN MD; CARBONELL-ESTRANY, XAVIER PhD; FIGUERAS-ALOY, JOSÉ MD, PhD; QUERO, JOSÉ MD, PhD THE IRIS STUDY GROUP

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The Pediatric Infectious Disease Journal: September 2003 - Volume 22 - Issue 9 - p 823-827
doi: 10.1097/01.inf.0000086403.50417.7c
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Abstract

INTRODUCTION

Respiratory syncytial virus (RSV) is a leading cause of rehospitalization in preterm infants and represents a major burden to public healthcare worldwide. 1–6 Palivizumab, a humanized monoclonal IgG antibody against the F protein of RSV, 7–12 was approved for use in Europe in August 1999. Before approval two previous studies were performed during the 1998 to 1999 and 1999 to 2000 respiratory seasons in Spain in preterm infants with and without chronic lung disease (CLD). Study objectives were to determine the burden of RSV disease in Southern Europe so that baseline RSV hospitalization rates could be established and to develop appropriate RSV prevention guidelines before the implementation of palivizumab prophylaxis. High RSV hospitalization rates were observed during two respiratory seasons (13.4% and 13.1%, respectively). 13, 14 On the basis of these findings, the Spanish Neonatology Society (SEN) published recommendations before the 2000 to 2001 respiratory season for use of palivizumab in the prevention of RSV infection in high risk preterm infants. 15 The objective of the study described here was to determine RSV-related hospitalization rates during two RSV seasons (2000 to 2001 and 2001 to 2002) in a cohort of palivizumab prophylaxed preterm infants and to compare those hospitalization rates and risk factors for hospitalization with those of the previously studied non-palivizumab-prophylaxed infants. 13, 14

METHODS

Data for the nonprophylaxed cohort of infants were derived by combining the data from two previous studies. 13, 14 The same methodology was applied to the preterm infants and infants with CLD who were enrolled during the 2000 to 2001 and 2001 to 2002 seasons and who received palivizumab prophylaxis according to SEN guidelines. 15, 16 Palivizumab prophylaxis was “highly recommended” in children <2 years old with CLD requiring treatment in the 6 months before the start of RSV season and in those born at ≤28 weeks gestational age without CLD who were <12 months at the start of the RSV season. Palivizumab was also “recommended” in children born at 29 to 32 weeks gestational age, without CLD, who were <6 months old at the start of RSV season. The guidelines recommended that palivizumab prophylaxis be initiated in mid-October and be continued through mid-February.

Infants in both cohorts were drawn from neonatal Spanish units from all regions, most of which retained the medical staff responsible for the study from one year to the next. The number of participating centers in each season was respectively 14, 26, 27 and 21. Inclusion and exclusion criteria were comparable for both cohorts. 13, 14 Premature infants born at ≤32 weeks gestational age, with or without CLD were enrolled in all 4 seasons. During the initial visit informed consent was obtained from the parents or primary caregiver. Data from the neonatal period were recorded for the following items: date of birth; gestational age; gender; birth weight; occurrence of multiple births; number of days requiring mechanical ventilation and oxygen therapy; diagnosis of CLD (defined as requiring supplemental oxygen therapy at 36 weeks postconceptional age); and date of neonatal intensive care unit (NICU) discharge. Investigators also recorded any family history of allergy, number of school age siblings, day-care attendance, exposure to tobacco smoke in the home and the educational level of the parents/caregivers. Parents were instructed in hygienic measures that they should use to prevent RSV infection at NICU discharge and were reinstructed at monthly follow-up clinic visits. 15, 16

Data were collected during the monthly outpatient visits for medical checkups and (in the treated cohort only) palivizumab injections, information included the occurrence of respiratory infection and/or respiratory-related hospitalizations. Infants in both cohorts who were admitted to the hospital with lower respiratory tract symptoms were tested for RSV using approved enzyme-linked immunosorbent assay (73%) or immunofluorescence (27%) rapid antigen test methods. RSV disease severity was assessed by length of hospital stay, number of days in the intensive care unit, days of mechanical ventilation or death. Children with nosocomially acquired RSV infection were excluded from analysis. The overall incidence of RSV hospitalization was calculated by dividing the number of RSV-positive tests found in hospitalized patients by the number of infants in whom RSV testing was performed [1998 to 1999, 59 of 89 (66%); 1999 to 2000, 118 of 187 (63%); 2000 to 2001, 37 of 80 (46%); 2001 to 2002, 34 of 86 (40%)] and applying the percentage to the entire population of infants hospitalized with respiratory infections (1998 to 1999, 118; 1999 to 2000, 207; 2000 to 2001, 84; 2001 to 2002, 92), which determines the total number of RSV hospitalizations per year. The rate was then calculated by dividing this total by the study population for each year as described previously. 13, 14

Qualitative variables were expressed in absolute numbers and in percentages. Fisher’s exact test and the chi square test were used for nonparametric comparisons between groups. Continuous variables were expressed as mean ± sd or as median and interquartile range (IQR) (25th and 75th percentile of distribution) for nonnormally distributed data. Student’s t test or the Mann-Whitney U test was used for the comparison of two continuous variables. Statistical significance was set at P < 0.05. To quantify the influence of certain risk factors on the likelihood of RSV-related hospitalization (excluding palivizumab prophylaxis), all variables, categoric or continuous, in the univariate analysis that were significant at P < 0.10 were included in a multivariable analysis using logistic regression and with forward stepwise selection. The same test was also performed combining all patients from both cohorts to examine the effect of risk factors on prophylaxis in RSV-related hospitalization. This was done after adjusting for risk factors including birth weight, gestational age, CLD and days of oxygen and mechanical ventilation at birth. The odds ratios (OR) and 95% confidence intervals (CI) were calculated from the beta coefficients and standard errors of the regression model.

RESULTS

Demographics of the non-palivizumab and palivizumab-prophylaxed cohorts were compared (Table 1). Palivizumab-prophylaxed infants had a significantly lower median gestational age [29 (IQR 28 to 31) vs. 31 (IQR 29 to 32); P < 0.000], greater neonatal respiratory pathology evidenced by median length duration of mechanical ventilation [6 days (IQR 3 to 18) vs. 3 days (IQR 1 to 7); P < 0.001], greater number of nursery days with a supplemental oxygen requirement [median, 10 days (IQR 3 to 40) vs. 5 days (IQR 2 to 13); P < 0.001] and a higher incidence of CLD (11.3%vs. 4.8%; P < 0.001) than did nonprophylaxed infants.

T1-15
TABLE 1:
Demographics of nonprophylaxed and palivizumab-prophylaxed cohorts

RSV hospitalization rates in study cohorts

The rate of hospitalization for serious RSV illness was significantly different in infants receiving palivizumab prophylaxis compared with infants who had not received prophylaxis. The mean hospitalization rate for RSV illness in the palivizumab-treated cohort was 3.95% (3.9% in the 2000 to 2001 season and 4% in the 2001 to 2002 season). In contrast in the non-palivizumab-prophylaxed group, the mean RSV hospitalization rate was 13.25% (13.4% in the 1998 to 1999 season and 13.1% in the 1999 to 2000 season). RSV and non-RSV respiratory hospitalization rates in infants in both cohorts are shown in Figure 1. The significant difference in the RSV hospitalization rate was observed in infants receiving palivizumab prophylaxis, whether analyzed together or by individual season. Difference in RSV proven hospitalization rates were observed in all palivizumab-treated groups: 58.4% in infants ≤28 weeks gestational age [nonprophylaxed, 32 of 246 (13%), vs. prophylaxed, 40 of 739 (5.4%); P < 0.0001]; 74.7% in infants 29 to 32 weeks gestational age [nonprophylaxed, 129 of 1297 (9.9), vs. prophylaxed, 30 of 1170 (2.5%); P < 0.0000]; and 72% in infants with CLD [nonprophylaxed, 14 of 71 (19.7%), vs. prophylaxed, 12 of 217 (5.5%); P < 0.007].

F1-15
Fig. 1:
Other respiratory and RSV-positive hospitalizations before and after palivizumab prophylaxis.

A multivariate analysis performed combining all patients after correcting for risk factor differences observed in palivizumab-treated patient’s differences [smaller gestational age and birth weight, higher rate of CLD and more days in intermittent positive pressure ventilation (IPPV) or oxygen in neonatal period] clearly showed that risk for RSV-related hospitalization was greatest in patients not prophylaxed with palivizumab (OR 3.86; 95% CI 2.83 to 5.25;). In contrast lower gestational age (OR 0.91; 95% CI 0.83 to 1.01), birth weight in kilograms (OR 0.85; 95% CI 0.5 to 1.45), CLD rate (OR 1.5; 95% CI 0.9 to 2.3), IPPV days (OR 1.51; 95% CI 1.06 to 2.15) and oxygen days (OR 0.71; 95% CI 0.49 to 1.03) appeared to play lesser roles in predicting RSV-related hospitalization.

The median length of RSV-related hospital stay was shorter in the prophylaxed cohort [6 days (IQR 4 to 9) vs. 8 days (IQR 5 to 11); P < 0.01]. Nonprophylaxed and prophylaxed cohorts were comparable as assessed by percent of RSV-positive patients requiring intensive care unit admission [33 of 161 (20%) vs. 9 of 71 (13%), P not significant] or need for mechanical ventilation [13 of 161 (8%) vs. 8/71 (11%); P not significant]. There were 22 deaths in the nonprophylaxed cohort, one of which was related to RSV infection. In the palivizumab-prophylaxed cohort, 6 deaths occurred; none was the result of RSV infection, and none was thought to be related to palivizumab prophylaxis.

The palivizumab-prophylaxed cohort received a mean of 4.098 injections in the two seasons. Overall palivizumab protocol administration compliance was good in 91% of the patients. Similar rates of RSV-related hospitalization were found regardless of the number of doses administered [3 of 165 (1.6%), 1 dose; 7 of 175 (4%), 2 doses; 6 of 197 (3%), 3 doses; 16 of 271 (5.9%), 4 doses; and 39 of 1101 (3.5%), 5 doses]. No significant differences were found with respect to RSV hospitalization and the time elapsed since last palivizumab dose [<1 week, 8 of 71 (11.2%); between 1 and 2 weeks, 20 of 71 (28.1%); between 2 and 3 weeks, 9 of 71 (12.6%); between 3 and 4 weeks, 16 of 71 (22.5); between 4 and 5 weeks, 15 of 71 (21.1%)].

Risk factors for RSV hospitalization in palivizumab-prophylaxed infants

Univariate analysis performed on the palivizumab-prophylaxed cohort alone (excluding hospitalized but non-RSV-tested patients), demonstrated no statistical differences between patients hospitalized for RSV-proved (n = 71) and patients not hospitalized for RSV-related illness (n = 1838) with respect to: gender (boys 62%vs. girls 56%; P = 0.35); median days of mechanical ventilation at birth [6 days (IQR 3 to 12) vs. 6 days (IQR 3 to 18); P = 0.52]; CLD (17%vs. 11%; P = 0.17); multiple delivery (31%vs. 34%; P = 0.6); family history of allergy (11%vs. 17%; P = 0.3); tobacco exposure (52%vs. 40%; P = 0.07); day-care attendance (7%vs. 3%; P = 0.2); or median age starting palivizumab prophylaxis [106 days (IQR 62 to 148) vs. 108 days (IQR 56 to 194); P = 0.7]. RSV hospitalizations in the prophylaxed group were significantly associated with greater median number of days of oxygen therapy at birth [12 days (IQR 2 to 42) vs. 5 days (IQR 1 to 25); P = 0.01] and having school age siblings (41%vs. 29%; P = 0.04).

Multivariate analysis performed on the palivizumab-prophylaxed cohort demonstrated that the risk for RSV hospitalization decreased with greater gestational age (OR 0.86; 95% CI 0.77 to 0.96; P = 0.006) and in infants whose parents had completed primary education (OR 0.47; 95% CI 0.24 to 0.93; P = 0.02). Risk for RSV hospitalization was increased in infants <3 months chronologic age at the onset of the RSV season (OR 0.55; 95% CI 0.33 to 0.92; P = 0.02). A trend toward greater numbers RSV hospitalization was observed infants with school age siblings (OR 1.6; 95% CI 0.99 to 2.69; P = 0.05).

DISCUSSION

Premature infants are at high risk for hospitalization caused by severe RSV illness. 3–5 Immunoprophylaxis with palivizumab has been demonstrated to be both safe and effective in decreasing RSV hospitalization in a pivotal international single season trial. 12 The Spanish multicenter cohort study presented here is the first European multiseason study that clearly demonstrates the significant effect of palivizumab on RSV hospitalization in high risk preterm infants. Nonprophylaxed and palivizumab-prophylaxed infants were recruited during 4 years and followed from sites in comparable geographic areas and regional climates. Inclusion criteria and hospitalization policies were consistent throughout the four respiratory seasons studied.

Risk factors for RSV hospitalization identified in the palivizumab-prophylaxed cohort were similar to those described in nonprophylaxed infants. 15, 2 These risk factors were lower gestational age, chronologic age <3 months at the start of the RSV season and older siblings in school. 13, 14 An additional risk factor identified in the palivizumab-treated cohort was the level of primary education of the parents. This finding has been observed in a previous study by Hall. 3

The palivizumab-treated cohort demonstrated significantly lower RSV hospitalization rate than did the nontreated cohort. Those differences occurred despite the fact that the palivizumab-prophylaxed cohort had greater risk factors for RSV-related hospitalization 2, 4, 17 (lower gestational ages, more severe NICU respiratory courses and a greater incidence of CLD) than did the nonprophylaxed infants. These demographic differences may be explained by institution of national guidelines for palivizumab prophylaxis before the 2000 to 2001 seasons. The fact that smaller, more fragile infants were enrolled in greater proportion into the prophylaxed cohort makes the overall difference of 70% in the RSV-related hospitalization rate compared with the nonprophylaxed cohort even more remarkable. A multivariate analysis combining both cohorts for 4 years (after correcting for demographic differences between cohorts) demonstrated that not receiving palivizumab prophylaxis was the risk factor most associated with likelihood for RSV-related hospitalization. Nonprophylaxed patients were almost 4 times more likely (95% CI 2.83 to 5.25) to be hospitalized for RSV-related illness. Although the difference in the RSV hospitalization rates observed in preterm infants receiving palivizumab prophylaxis may be also influenced in part by varying RSV season severity and/or by extraprotective care of the more vulnerable babies in palivizumab-prophylaxed cohorts, this study demonstrates the efficacy of palivizumab prophylaxis and should encourage its implementation in development of guidelines for RSV prevention in this high risk population.

This study was supported by an unrestricted grant from Abbott Laboratories SA. We thank Andrés Rodrigo and Eduardo Ruf for their contribution to this study and Dr. Jessie Groothuis, Dr. Paul Pollack and David Morris, Ph.D. for review of the manuscript and valuable suggestions.

REFERENCES

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APPENDIX

Members of IRIS Study Group. Coordinators: X. Carbonell-Estrany, M.D., Ph.D., Hospital Clínic, Barcelona and J. Quero, M.D., Ph.D., Hospital La Paz, Madrid, Spain. Members: Mercedes Zapatero, M.D., Juana Guzmán, M.D., Hospital Reina Sofía, Córdoba; Adolfo Valls i Soler, M.D., Ángel Cotero, M.D., Hospital de Cruces, Baracaldo; Eduardo Doménech, M.D., Ricardo López, M.D., Hospital Clínico Universitario de Tenerife, Santa Cruz de Tenerife; Xavier Carbonell-Estrany, M.D., José Figueras-Aloy, M.D., Francesc Botet, M.D., Dolors Salvia, M.D., Jose Maria Pérez, M.D., Hospital Clínic, Barcelona; Jose Maria Fraga, M.D., Marta Gil, M.D., Maria Isabel Martínez-Soto, M.D., Hospital Xeral Galicia, Santiago de Compostela; Manuel García del Río, M.D., Tomás Sánchez, M.D., Pilar Valdés, M.D., Hospital Materno Infantil Carlos Haya, Málaga; Eduardo Narbona, M.D., Emilio Pérez-Bonilla, M.D., Hospital Clínico San Cecilio, Granada; Juana María Román, M.D., Juan Antonio Hervás, M.D., Hospital Son Dureta; Jesús Antelo, M.D., José Martínez, M.D., Hospital Xeral Cíes, Vigo; Eduardo Martínez, M.D., Juan Agüera, M.D., Hospital de Arrixaca, Murcia; Angel Marco-Tello, M.D., Angel Marco-Rivet, M.D., Hospital Miguel Servet, Zaragoza; Xavier Krauel, M.D., Ana Curcoy, M.D., Hospital Sant Joan de Deu, Barcelona; Luz García, M.D., Maria José Santos, M.D., Hospital Severo Ochoa, Leganés; José López-Sastre, M.D., Belén Fernández-Colomer, M.D., Hospital Central de Asturias, Oviedo; Vicente Roqués, M.D., Pilar Sáenz, M.D., Hospital La Fe, Valencia; José Quero, M.D., Sofía Salas, M.D., Hospital La Paz, Madrid; Salvador Salcedo, M.D., Ana Fina, M.D., Juan Vinzo, M.D., Hospital Vall D′Hebrón, Barcelona; Joaquín Ortiz, M.D., Hospital de Jerez, Cádiz; Bartolomé Jiménez, M.D., Jose Luis Serrano, M.D., Hospital General de Alicante, Alicante; Frederic Raspall, M.D., Xavier Demestre, M.D., Hospital de Barcelona, Barcelona; Antonio Pérez, M.D., Carmen Macías, M.D., Hospital Virgen del Rocío, Sevilla; Carmen Pedraz, M.D., A. Remesal, M.D., Hospital Clínico de Salamanca; Jose L. Fernández-Calvo, M.D., Hospital Clínico Universitario, Valladolid; Jon Kepa Arrate, M.D., Iñigo Echaniz, M.D., Hospital Civil de Basurto, Bilbao; Carlos Paredes, M.D., Hospital Clínico de Valencia; Ángel Vázquez, M.D., María Taboada, M.D., Hospital Juan Canalejo, La Coruña.

Keywords:

Respiratory syncytial virus infection; premature infants; respiratory tract infections; respiratory syncytial virus epidemiology in premature infants; respiratory syncytial virus prophylaxis; palivizumab

© 2003 Lippincott Williams & Wilkins, Inc.