Introduction
Respiratory tract infections, such as bronchiolitis or pneumonia, are the most common causes in developed countries of admission to hospital of infants and young children.Reference Kozak, Owings and Hall1, Reference Shay, Holman, Newman, Liu, Stout and Anderson2 Infections by the respiratory syncytial virus have been particularly well studied,Reference Bonnet, Schmaltz and Feltes3–Reference Simoes and Carbonell-Estrany6 and, in groups at risk, are known to be associated with increased morbidity and mortality.Reference Wang, Law and Boucher7–Reference Willson, Landrigan, Horn and Smout10 In children with congenital malformed hearts, such infection increases the length of stay in hospital, admissions for intensive care, mortality,Reference MacDonald, Hall, Suffin, Alexson, Harris and Manning11, Reference Navas, Wang, de Carvalho and Robinson12 and is associated with delays in elective cardiac surgery.Reference Khongphatthanayothin, Wong and Samara13, Reference Altman, Englund and Demmler14
Previous information about risk factors for these infections was generally attributed to the congenital cardiac disease itself. Other patients, particularly premature infants, have been studied in more detail, according to gestational age, social and family conditions. Patients with congenitally malformed hearts vary according to the effects of their lesion, producing cyanotic or acyanotic conditions, its haemodynamic significance, the need for surgical intervention or medications, while a subset of these children have other concomitant conditions, such as malnutrition, chromosomal, or genetic abnormalities that are associated with an increased susceptibility to infection of the respiratory tract.Reference Hilton, Fitzgerald and Cooper15
Over the past decade, strategies to decrease the impact of these infections were focussed on improving general management of the patient.Reference Moler, Khan, Meliones, Custer, Palmisano and Shope16, Reference Fixler17 Specific prophylactic measures, such as vaccinations and immunoprophylaxis, are now available to prevent many of the common infections of the respiratory tract.Reference Strutton and Stang18 The cost of prophylaxis has limited its use, specifically prophylaxis against the respiratory syncytial virus with palivizumab. In a pivotal third phase trial, palivizumab reduced hospitalization by 45% in children aged less than 24 months with haemodynamically significant congenital cardiac disease.Reference Feltes, Cabalka and Meissner19 As a result, guidelines for prophylaxis in North America,20 and Europe,Reference Tulloh and Feltes21 including the United Kingdom,Reference Tulloh, Marsh and Blackburn22 and Spain,23 have been established. All previous approaches, and recent controversies, about respiratory infection in young children with congenital cardiac disease were based on different methodological strategies, such as theoretical models, clinical trials, retrospective studies, hospital registries, and expert recommendations,Reference Rackham, Thorburn and Kerr24 but thus far, to the best of our knowledge, there have been no specific, large, prospective, epidemiological studies. The primary objective of our study, therefore, was to assess the incidence of infection of the respiratory tract requiring hospitalization in children under 24 months of age with haemodynamically significant congenital cardiac disease in Spain, and to describe its associated risk factors. Secondary objectives were to assess compliance with preventive measures used in this population, and to describe the source and clinical course of the respiratory events.
Materials and methods
Ours was an epidemiological, multicentric, prospective, observational study in children with haemodynamically significant congenital cardiac disease. The population studies included all patients less than 24 months of age at the time of inclusion during the season from October 2004 to April 2005 who had been followed up for at least one month. The study was sponsored by the Spanish Society of Pediatric Cardiology and Congenital Heart Diseases, and was conducted at 53 Spanish hospitals. These included 16 tertiary public centres, where paediatric cardiac surgery was available, and 37 collaborative hospitals involved in follow-up of the patients (see Appendix 1 for details). The protocol was reviewed and approved by a local ethics committee (Hospital Vall d’Hebrón, Barcelona), and written informed consent was obtained from parents or guardians before enrollment.
Patients meeting the criterions of eligibility were enrolled either at the outpatient clinic or the hospital ward, depending on where the initial contact occurred. Recommendations for prophylaxis against the respiratory syncytial virus,23 were followed for the participating children, who were regularly seen at the outpatient clinic once monthly. The main endpoint was the number of patients requiring hospitalization for acute respiratory infection at any time during the period if study. Acute respiratory infection was defined on the basis of the following grouped codes of the International Statistical Classification of Disease and Related Health Problems (ICD-10).25 Acute upper respiratory infections (J00–J06) and influenza (J10–J11); Pneumonia (J12–J18); Brochiolitis (J20–J21); and other acute lower respiratory infections (J22). All episodes of infection requiring hospitalization occurring before the follow-up visit were recorded based on review of the medical records. Follow-up ended at the date of completion of the study, the date of death, or the date of the last visit before withdrawal of the patient.
Episodes of respiratory infection occurring during hospitalization for other reasons, such as after surgery because of nosocomial infections were excluded. Children with known infection by the human immunodeficiency virus, and current or past participation in other investigational protocols of drugs or biological agents, were not eligible.
Variables
Information collected included social and demographic data, such as gender, date of birth, gestational age, current weight, child care attendance, breastfeeding, number of children in the house under 11 years of age, and exposure to tobacco smoke, clinical data such as age at diagnosis of the cardiac disease, whether the lesion was classified as cyanotic or acyanotic using similar criterions as in previous studies,Reference Feltes, Cabalka and Meissner19 surgical procedures and their risk,Reference Jenkins, Gauvreau, Newburger, Spray, Moller and Iezzoni26 [adaptedinSpanish,Reference Zavanella, Portela, Rueda and Medrano27] or catheterization, concomitant comorbidities, including chromosomal diseases, chronic respiratory diseases, and immunodeficiencies, and information about general and specific immunoprophylaxis against influenza, pneumococcus, chickenpox vaccines and respiratory syncytial virus using palivizumab according to the recommendations of the Spanish Paediatric Association for childhood immunization,23 provided by the parents or guardians at the time of entry and monthly thereafter when a change occurred. Information regarding hospital course and discharge were obtained by review of the medical records, and included length of stay in hospital, diagnosis at discharge, and severity, defined as death due to respiratory infection or the need for admission to an intensive care unit or mechanical ventilation or extracorporeal membrane oxygenation or occurrence of either pulmonary hypertensive crisis, pleural effusion, acute respiratory distress syndrome, or any other renal, neurological or gastrointestinal sequel. Microbiological data recorded included type of microorganism, such as bacteria, virus, or fungus, and the type of sampling and diagnostic tests used, such as spontaneous secretions, bronchial aspirate, or blood cultures, antigenemia, immunofluorescence, and serology, based on the standard practice at each hospital. Additional follow-up conditions were defined based on previously recorded data. These included borderline nutritional state when the weight was below the 10th centile (according to Spanish growth tables28) at any time during follow-up, new cardiac surgery or catheterization and its risk, complete vaccination, or complete immunoprophylaxis against the respiratory syncytial virus. A numeric definition is given in Appendix 2.
Analysis of data
Rate of hospitalization because of respiratory infection: Incidence was calculated by dividing the number of hospitalizations by the child-months of follow-up during the study period. Rates of hospitalization, with 95% confidence intervals, were calculated as the number of hospitalizations per 1000 patients with congenitally malformed hearts.
We used the Chi-square test or Student’s t test to assess differences between patients requiring hospital admission for respiratory infection and those not hospitalized for categorical or continuous variables, respectively. A logistic regression was used to identify independent risk factors for admission to hospital because of respiratory infection. Any risk factor that was statistically significant, with a p value less than 0.05 in the bivariate analysis, was considered for entry into the multivariate model. A forward stepwise approach was used. Results are expressed as odds ratios with 95% confidence intervals.
Results
Population
Enrollment: From October 2004 to April 2005, we found 791 patients with congenitally malformed hearts who were eligible for the study. Of these, 31 patients with less than one month follow-up were withdrawn. Reasons for withdrawal included the decision of the guardian in 2 instances, the decision of the investigator in 2 further cases, was unknown in 17 patients, and was due to death in 10 patients. Hence, a total of 760 patients participated in the study with a period of follow-up longer than one month.
Most patients were enrolled in October and November, 2004, and the highest number of patients was recruited in February. Mean time of follow-up, with standard deviation shown in parentheses, was 5 (1.6) months, and mean number of visits per patient was 4.5 (1.5). A total of 453 (57.3%) patients completed at least 5 follow-up visits. No differences were found when baseline characteristics were compared between patients lost to follow-up and those who completed the study.
During the study, 25 patients died, with respiratory infection being the main cause of death in 2 patients (one of them with trisomy 21), while 14 children died after cardiac surgery. Death was attributed to ‘other causes’ in 9 additional cases. The overall rate of death per 1,000 patients was 9.4 (95% confidence intervals from 6.3 to 12.5), and rate of mortality due to respiratory infection was 0.8 (0.1 to 1.7).
Demographics, assessment of clinical and risk factors
Among the 760 patients recruited, 57.4% were male, and 77.5% were under 12 months of age, Their mean age, with standard deviation, was 7.3 [6.1] months. Only 6% of children had attended child care, 47% had been breastfed, 45.2% lived with another child under 11 years of age at home, and 48% had a smoker in the house. Cardiac disease was most often diagnosed at birth (69.7%), and acyanotic disease was most common (55.8%). Of enrolled children, 71% had some risk factor for respiratory infection, including weight below the 3rd centile (53.7%, 408 patients), chromosomal diseases (13.8%, 105 patients), respiratory conditions (10.7%, 81 patients), or immunodeficiencies (1.1%, 8 patients).
Rates of hospitalization
Figure 1 shows the monthly admission to hospital, and rates of participation during the study period. We found that 79% of patients (10.4%, 95% confidence intervals from 8.2% to 12.6%) required admission for respiratory infections. The incidence in the 3,731 child-months of follow-up was 21.4 hospital admissions per 1,000 patients-month (95% CI: 16.7–26.1) during the season. Consecutive admissions were recorded in 19 patients, with 2 and 3 admissions were reported in 12 and 7 patients, respectively, accounting for a total of 105 admissions. No statistically significant differences in social and demographic characteristics and risk factors were found in patients with consecutive admissions.
Figure 1 Distribution of hospitalizations for acute respiratory infections by natural month for patients with congenitally malformed hearts aged less than 24 months in Spain from October 2004 to April 2005. n = number of patients in study.
Figure 2 shows the hospitalization incidence rate by age group. Rates were higher among infants under 6 months of age, 26.7 per 1,000 infants-month (95% CI 19.1, 34.2) and less in older ages groups: 18.7 (95% CI 10.6, 26,8) and 14.5 (95% CI 6.6, 22.4) per 1,000 patients-month among 6 to 12 and 12 to 24 month children, although differences were not statistically significant.
Figure 2 Incidence of hospitalization for acute respiratory infections per 1000 patients-months per age group in patients with congenitally malformed hearts aged less than 24 months. n = number patients-month (Acute respiratory infection hospitalization rate denominator).
Risk factors for hospitalization
Table 1 shows the characteristics at baseline and follow-up, stratified by hospitalization due to respiratory infection. In the bivariate analysis, the proportions of patients with weight below the 3rd centile at study baseline (69.6% versus 51.9%), siblings under 11 years (55.7% versus 43.9%), and risk factors for respiratory infection such as chromosomal diseases (26.6% versus 12.3%), respiratory disorders (24.1% versus 9.1%) and immunodeficiency (3.8% versus 0.7%) were significantly higher among patients requiring admission. Among follow-up variables, weight below the 10th centile, surgery or catheterization and/or surgery with cardiopulmonary bypass at any time during the study were significantly more common in hospitalized patients, 96.2% versus 79.7%, 40.5% versus 25.4% and 32.9% versus 18.1% respectively. No statistically significant differences were found for all other factors. We broke down congenital cardiac disease into cyanotic and acyantoic types, including 323 (42.5%) patients as cyanotic, and 424 (55.8%) as acyanotic, most of the latter with left-to-right shunt. We did not classify 13 (1.9%). Of the patients hospitalized, 36 (45.6%) were cyanotic as opposed to 43 (54.5%) who were acyanotic, this difference not being significant (p = 0.658). In the group of 19 patients that required multiple hospitalizations, 10 (52.6%) were cyanotic and 9 (47.4%) acyanotic. We found an augmentation in the proportion of associated conditions, that is risk factors, albeit without significant differences, in 6 (31.6%) having chromosomal or genetic disorder, 3 cases with deletion 22q11, 2 cases with trisomy 21, and 1 with another condition, in 6 (31.6%) with a chronic respiratory illness, and in 2 (10.5%) with immunodeficiency.
Table 1 Baseline characteristics in children less than 24 months with haemodynamically significant congenital cardiac disease in Spain by state of hospitalization.
*Cardiac transplantation, primary pulmonary arterial hypertension.
Main diagnosis
The median length of hospital admissions for respiratory infection was 7 days, with a mean of 9.7 and a range from 1 to 56 days. Hospital stay was shorter than 3 days in one-fifth of cases, but 18 admissions (17.1%) were defined as severe. The main reason for hospital admission according to severity is shown in Table 2. Overall, bronchiolitis was the most common main diagnosis, accounting for 49.5% of hospitalizations. The proportions of admissions for bronchiolitis and pneumonia were significantly higher among those with severe illness, 55.6 versus 48.3, and 38.9% versus 14.9%, respectively. Infection of the upper respiratory tract was significantly higher among the hospitalizations for less severe disease (0 versus 27.6% – p 0.02).
Table 2 Main cause of hospitalization for children aged less than 24 months with congenital cardiac disease according to severity.
*Severe respiratory infection (RI), definition is in Materials and methods.
Microbiology results are given in Table 3. Principal diagnostic tests were performed on spontaneous secretions (48.6%), bronchial aspirate (6.7%), or blood cultures (41.9%). Other specific antigen (32.4%), immunofluorescence (11.4%), and serological (9.5%) tests were used. Respiratory syncytial virus was investigated in 93% of patients using a rapid test (75%), direct fluorescent antigen test (10%), shell vial (8%), and culture (6%). A total of 37 pathogens were identified, with single infection being found in 31 patients and multiple infections in 6 patients. The most frequently identified pathogen was respiratory syncytial virus, in 25 patients (23.8%).
Table 3 Pathogens identified in 105 hospitalizations due to respiratory infection in children aged less than 24 months with congenitally malformed hearts.
*Other pathogens include staphylococcus (1), pseudomonas (1), other bacteria (4), and other viruses (3).
**The categories of multiple pathogen infection are not mutually exclusive.
Table 4 shows the state of vaccination and immunoprophylaxis according to the need for hospitalization. Influenza, pneumococcus, and chickenpox vaccines had been received by 24.5% (54% adjusted in more than 6 months), 73.8%, and 5.4% of patients respectively. In addition, 85.1% of patients had received complete immunoprophylaxis for respiratory syncytial virus with palivizumab. A significantly higher rate of hospitalization for respiratory infection was seen among children with incomplete as opposed to complete immunization against the respiratory syncytial virus, 24.1% and 13.8%, respectively.
Table 4 State of vaccination and immunoprophylaxis children aged less than 24 months in Spain with congenitally malformed hearts.
*Denominator for vaccination against influenza includes hospitalized and non hospitalized children below 6 months only, 33 and 337 respectively.
**Complete and incomplete respiratory syncitial virus immunoprophylaxis is defined in Appendix 2.
Patients with incomplete immunoprophylaxis accounted for 7.08% of hospitalizations proving to be due to respiratory syncytial virus, while the rate of hospitalizations was 2.32% among patients with complete immunoprophylaxis. This yields a 3.05 (95% CI: 2.14–4.35) relative risk of hospitalization in patients with incomplete immunoprophylaxis, and consequently a 67.2% reduction in the risk of hospitalization in those children with complete immunoprophylaxis. No statistically significant differences were found regarding the requirement of hospitalization and the state of vaccination against other pathogens.
Table 5 shows the independent risk factors associated with admission to hospital. Children with 22q11 deletion, weight below the 10th centile, previous respiratory disease, incomplete immunoprophylaxis, trisomy 21, cardiopulmonary bypass at any time during the study, and siblings less than 11 years old were more likely to require admission for respiratory infection, although estimates are not so precise.
Table 5 Risk factors for hospitalization due to respiratory infection in children aged less than 24 months with congenital cardiac malformations.
Discussion
Our study has quantified the incidence of acute respiratory infection requiring admission to hospital of Spanish patients with congenitally malformed hearts at 10.4%, or a monthly incidence of 21.4 hospital admissions per 1,000 patients-months of follow-up. Such data are possibly influenced by the design of our study, which excluded infections in other hospitalizations, the high rate of respiratory syncytial virus immunization, which, as shown, is a protective factor both in our patients and in premature infants in our setting,29 and the general measures for protection that were explained to all parents to prevent respiratory infections.
Seasonality, with a peak in the months of December–January, coincides with peaks of viral infections in the Northern hemisphere, specifically with infections by the respiratory syncytial virus in the southern regions of the United States in that same period.30 A progressive decrement in incidence of hospitalization by age (Fig. 2) confirm previous data from infections due to bronchiolitis and respiratory syncytial virus,Reference Boyce, Mellen, Mitcel, Wright and Griffin4, Reference Welliver8 with a maximum in patients less than 6 months, and a minimum in those older than 1 year. The fact that there is no significance in this difference probably is associated with the small number of children included in the range from 12 to 24 months.
Factors which increased susceptibility to respiratory infection and hospital admissions included 22q11 deletion, malnutrition, trisomy 21, and prior disease of the respiratory tract. Two-thirds of hospitalized patients were malnourished, being below the 3rd centile, while over nine-tenths showed a borderline nutritional state, being lower than the 10th centile at both baseline and follow-up. Malnutrition is multifactorial in children with congenitally malformed hearts.Reference Varan, Tokel and Yilmaz31 The predisposition of malnourished patients to respiratory infection in general has been widely reported.Reference Cashat-Cruz, Morales-Aguirre and Mendoza-Azpiri32 In cases of trisomy 21 or 22q11 deletion there are various degrees of immunosuppression or immune disorders, bronchial reactivity, abnormalities in cilia and the anatomy of the upper respiratory airways, neuromuscular disorders with hypotonicity, swallowing disorders, gastroesophageal reflux with potential microaspiration that may predispose to respiratory infection.Reference Deerojanawong, Chang, Eng, Robertson and Kemp33, Reference Hilton, Fitzgerald and Cooper34 A study,Reference Fjaerli, Farstad and Bratlid35 estimated a rate of hospitalization for bronchiolitis due to the respiratory syncytial virus of 153.8 per 1,000 patients in children aged less than 2 years with various risk factors, specifically trisomy 21 with and without congenital cardiac disease. This is a similar rate to that found in our study of 200 per 1,000. As in our study, one of the patients reported previously,Reference Fjaerli, Farstad and Bratlid35 who died because of respiratory infection, had trisomy 21.
Among the general risk factors associated with severe infection by the respiratory syncytial virus reported in prior literature reviews,Reference Simoes36 or in premature infants in Spain,Reference Figueras-Aloy, Carbonell-Estrany and Quero37 only the presence of siblings less than 11 years are supported by our study. Age under 6 months, absence of breastfeeding, exposure to tobacco smoke, family history of asthma, or low educational level of parents were not found to be significant. The low number of patients in our study attending nurseries does not allow for their comparative analysis.
The only clear cardiological risk factor is surgery with cardiopulmonary bypass during the period of study, possibly because of impaired immunity to these infections, antibodies being avoided, or because it is associated with a longer stay in hospital that increases the risk of infection. No differences were seen between cyanotic and non-cyanotic patients.
Despite the high number of microbiological tests, no pathogen was found in two-thirds of our patients. As regards the type of specific pathogen, bronchiolitis and infections due to the respiratory syncytial virus were expected to predominate because of the type of our study, having excluded infections while the patient was admitted for other reasons or nosocomial infection, and the season. The second leading pathogen was Streptococcus pneumoniae, the main germ reported in community-acquired pneumonia.Reference Michelow, Olsen and Lozano38 Concurrent infections represented one-sixth of cases in which a pathogen was identified, and were particularly common for infection by Haemophilus influenzae, this accounting for three-quarters of cases. The low number of other viruses detected may possibly be due to the low number of specific tests for such viruses.
Compliance with schemes of vaccination or immunoprophylaxis against pathogens responsible for infections of the respiratory tract, such as influenza, pneumococcus, or haemophilus influenzae type b, and chickenpox vaccines, or immunoprophylaxis for respiratory syncytial virus, was usually high, except for vaccination against influenza, recommended for infants older than 6 months, which had a compliance of only just over one-half. There was, however, no admission with a microbiological diagnosis of influenza virus, which does not agree with other data reported patients at risk,Reference O’Brien, Uyeki and Shay39, Reference Quach, Piche-Walker, Platt and Moore40 or as a cause of pneumonia.Reference Michelow, Olsen and Lozano38 By contrast, compliance with pneumococcal vaccination was very good, and both were administered free of charge by paediatricians at health centres on recommendation by the paediatric cardiologist. No significant differences were found between hospitalized and non-hospitalized children as regard these vaccinations.
Immunoprophylaxis with palivizumab is administered at hospital centres, and is theoretically recommended in all patients included in this study. Incomplete compliance with the recommendations 23 was found in only 113 patients (14.9%), suggesting a good compliance as compared to other reports.Reference Pignotti, Indolfi and Donzelli41 An analysis of this subgroup with incomplete prophylaxis as compared to the group receiving complete prophylaxis confirmed a marked decrease in both the overall risk for admission for respiratory tract infection, and the specific risk for admission due to documented infection. The rate of admission for respiratory syncytial virus in the group of patients with incomplete immunoprophylaxis, at 7%, is somewhat lower than reported for the placebo group in the study of the Cardiac Synagys Group,Reference Feltes, Cabalka and Meissner19 or for premature infants not given prophylaxis in Spain,Reference Pedraz, Carbonell-Strany, Figueras Aloy and Quero29 in which rates of 9.7% and 13.25% were found respectively, possibly due to administration of any dose could confer some degree of protection and due to methodological differences. Our study does not support other reports published in Switzerland,Reference Duppenthaler, Ammann, Gorgievski-Hrisoho, Pfammatter and Aebi42 and Sweden,Reference Eriksson, Bennet, Rotzen-Ostlund, von Sydow and Wirgart43 giving very low rates of hospitalization, ranging from 1.3% and 6.4%, in patients with congenital cardiac disease receiving no prophylaxis. Such divergence is due to methodological, rather than epidemiological, differences, because those studies were conducted in a single hospital center during the whole year, thus obviating seasonality, were based on retrospective review of hospital records, and did not use a clearly defined reference population. On the other hand, the rate of admission, at 2.32%, in the group with complete prophylaxis is lower than the rate of 5.3% seen in the group receiving palivizumab in the study performed by Feltes and colleagues,Reference Feltes, Cabalka and Meissner19 and closer to data found in premature infants who received palivizumab in Spain,Reference Pedraz, Carbonell-Strany, Figueras Aloy and Quero29 and the United States,Reference Romero44 in whom a rate of 3.95% was reported.
The mean stay of 9.5 days is similar to the 10.7 days reported elsewhere for patients infected by the respiratory syncytial virus.Reference Purcell and Fergie45 In one-fifth of cases, hospital stay is short, and the condition was not serious. This suggests that such admissions are for the purposes of observation, and are caused by a special concern for these patients when they experience infections that, while they may be initially mild, could potentially become serious or impair the underlying cardiac condition. There were few admissions for more severe conditions. Just over one-sixth of patients were admitted to a paediatric intensive care unit, just over one-twentieth required mechanical ventilation, and mortality was low, at 0.8% overall, and 2.8% among admitted patients. Other series,14 limited to infection by the respiratory syncytial virus reported one-third needing admission to intensive care, almost one-fifth needing mechanical ventilation, and mortality ranging from 2.5% to 3.4%, with mortality as high as one-third in historical series11. High protection against the virus may have possibly not only decreased the overall rate of admission, but also the severity and sequels. Readmissions occurred in one-quarter of patients, with no remarkable differences as regards risk factors.
Limitations
While the reference population is not exactly known, we think our study includes a wide sample representative of virtually all centers and potential patients aged less than 24 months with haemodynamically significant congenital cardiac disease in Spain. No information is available about eligible patients at screening not willing to participate in the study. In children withdrawn from the study, we did not find differences between patients in baseline variables, but the proportion lost to follow-up may therefore underestimate or overestimate the rate of hospitalization in children with congenital cardiac disease. There may be an information bias because details on the respiratory infection, microbiologic data, its cause, and its course were taken retrospectively from the discharge report and standard clinical practice. While the results are significant, some data include a low number of patients, and the ranges of risk estimators are very wide. Finally, the study is limited to a single season, and changes in the annual incidence and virulence of viral respiratory infections suggest the need for multiple years of study.
Acknowledgements
We thank Agata Carreño from Health Outcome Research -- Europe, Barcelona.
Sources of financial support:This study was sponsored by the Spanish Society of Paediatric Cardiology and Congenital Heart Disease, and supported by an unrestrictive grant from Abbott Laboratories SA, Spain.
Appendix 1: The CIVIC Study Group
Coordinator
Constancio Medrano, Hospital Juan Canalejo, A Coruna.
Scientific Committee
Jose Santos de Soto, President SECPCC. Hospital Virgen del Rocío. Sevilla.
Jaume Casaldaliga, Hospital Vall d’Hebron. Barcelona.
Luis García-Guereta, Hospital La Paz. Madrid.
Josefina Grueso, Treasurer SECPCC. Hospital Virgen del Rocío, Sevilla.
Pascual Malo, Direction SECPCC Hospital La Fe, Valencia.
Enrique Maroto, Hospital Gregorio Marañón, Madrid.
Pedro Suarez, Hospital Materno Infantil, Las Palmas de Gran Canaria.
Principal Investigators in Reference Hospitals
1. Fernando Ballesteros, Hospital Gregorio Marañón. Madrid.
2. Jaume Casaldaliga, Hospital Vall d’Hebron, Barcelona.
3. Victorio Cuenca, Hospital Carlos Haya. Málaga.
4. Fuensanta Escudero, Hospital Virgen de la Arrixaca. Murcia.
5. Lola Garcia de la Calzada, Hospital Miguel Servet. Zaragoza.
6. Luis Garcia-Guereta, Hospital La Paz. Madrid.
7. Josefina Grueso. Hospital Virgen del Rocio. Sevilla.
8. Beatriz Insa. Hospital La Fe. Valencia.
9. Maite Luis, Hospital de Cruces. Baracaldo-Bilbao.
10. Manuel Luque, Hospital Reina Sofia. Córdoba.
11. Constancio Medrano, Hospital Juan Canalejo. A Coruña.
12. Alberto Mendoza, Hospital 12 de Octubre. Madrid.
13. Fredy Prada, Hospital Sant Joan de Deu. Barcelona.
14. Ma del Mar Rodriguez, Hospital Virgen de las Nieves. Granada.
15. Pedro Suárez, Hospital Materno Infantil, Las Palmas de Gran Canaria.
16. Concepción Quero, Hospital Ramon y Cajal. Madrid.
Principal Investigator (Monitoring board, Data safety and Statistical team)
17. Magda Guilera, HOR-Europe, Barcelona.
Co-Investigators in Collaborative Hospitals
1. Francisco M. Anaya. Complejo Hospitalario de Ciudad Real.
2. Patricia Aparicio. Hospital Marques de Valdecilla, Santander.
3. Julio Ardura Fernandez. Hospital Clinico. Valladolid.
4. Sonia Arias, Complejo Hospitalario de Badajoz.
5. Ricardo del Alcazar Hospital Germans Trias, Badalona.
6. Ma del Mar Ballesteros. Complejo Hospitalario de Albacete.
7. Juan Carretero, Hospital Joan XXIII, Tarragona.
8. Susana Castro, Hospital Arquitecto Marcide Ferrol.
9. Gabriel Cebria, Hospital San Pedro de Alcantara, Caceres.
10. Fernando Centeno Malfaz. Hospital Rio Hortera, Valladolid.
11. Elena Coll Hospital de Granollers.
12. Rosa Collell Hospital Sant Joan, Reus.
13. Natalia Cutillas and Eduardo Carbona, Hospital San Cecilio. Granada.
14. Juan J. Díez Tomás. Hospital Central de Asturias, Oviedo.
15. Gabriel Erdozaín. Hospital de Barbastro
16. Juan F. Exposito, Hospital de Jaen.
17. Inmaculada Fernandez-Santamarina, Hospital Xeral-Cies, Vigo.
18. Fernando Garcia Alga and Ma Angeles de la Fuente Sánchez, Hospital Son Dureta, Palma de Mallorca.
19. Eugenio Garrido Borreguero, Hospital de Mostoles.
20. Miguel A. Granados Ruiz, Hospital Virgen de la Salud. Toledo.
21. Carmen Herrera del Rey. Hospital de Huelva.
22. Ma Soledad Jiménez Casso. Hospital General de Segovia.
23. Bernardo López-Abel, Hospital Cristal Piñor, Ourense.
24. Sabela Martinez, Complexo Hospitalario Universitario de Santiago.
25. Carmen Olivera Avezuela. Hospital Puerta del Mar. Cadiz.
26. Angeles Ortega. Hospital Torrecardenas, Almeria.
27. Alfonso Ortigado. Hospital de Guadalajara.
28. Beatriz Picazo Angelin, Hospital Costa del Sol, Marbella.
29. Angels Puigdevall. Hospital J Trueta, Girona.
30. Agustín Romay, Complexo Hospitalario de Pontevedra.
31. Carmen Ruiz-Berdejo Iznardi. Hospital de Jerez.
32. Yolanda Ruiz del Prado and Rosa María Garrido Uriarte. Hospital San Millan. Logroño.
33. Dolors Soriano Hospital de Terrassa.
34. Silvia Teodoro, Hospital Parc Taulí, Sabadell.
35. Ana Usano Carrasco. Hospital Virgen de la Luz. Cuenca.
36. Fernando Vera Cristobal, Hospital San Jorge, Huesca.
37. Mariano Vicente Cuevas, Hospital Punta de Europa, Algeciras.
Other Co-Investigators in Referente Hospitals
1. Marisa Antúnez, Hospital Materno Infantil, Las Palmas de Gran Canaria.
2. Felix Coserría Sanchez, Hospital Virgen del Rocio. Sevilla.
3. Ma Clara Escobar, Hospital Infantil Vall d’Hebron, Barcelona.
4. José M. Galdeano and Esteban Pastor Menchaca, Hospital de Cruces. Baracaldo-Bilbao.
5. Ana Lázaro and María Duplá. Hospital Miguel Servet. Zaragoza.
6. Amparo Moya Bonora, Ana Cano and Maria Maravall Llagaria Hospital La Fe. Valencia.
7. Macarena Taguas Castaño, Hospital Virgen del Rocio. Sevilla.
Nurses
Herminia Castro, Ma Carmen Leyva, Assumpta Mas, Paloma Millan del Bosch, Encarnación Montes, Maria Victoria Perez, Pilar Perez, María Pozuelo, Dolores Pallares, Guadalupe Reguera.
Monitoring board, Data safety and Statistical team
Magda Guilera, Agata Carreño. HOR-Europe, Barcelona
Acknowledgments for collaboration in the CIVIC Study
This study was sponsored by the Spanish Society of Paediatric Cardiology and Congenital Heart Disease (SECPCC), and supported by an unrestrictive grant from Abbott Laboratories SA, Spain.
Appendix 2: Numeric definition of immunoprophylaxis against respiratory syncytial virus with palivizumab
Complete:
• 5 or more doses
• Same number of doses as visits
• If a patient enrolled in November 2004 has received 4 or more doses
• If a patient enrolled in December 2004 has received 3 or more doses
• If a patient enrolled in January 2005 has received 2 or more doses
• If a patient enrolled in February 2005 has received 1 or more doses
• If a patient enrolled in March 2005 has received 0 or more doses
Non-complete:
• If the above criteria for complete immunoprophylaxis are not met.
