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The European Forum for Clinical Management: prophylaxis against the respiratory syncytial virus in infants and young children with congenital cardiac disease

Published online by Cambridge University Press:  03 May 2005

Robert M. R. Tulloh  and
Timothy F. Feltes
Robert M. R. Tulloh
Affiliation:
Department of Paediatric Cardiology, Bristol Royal Hospital for Children, Bristol, United Kingdom
Timothy F. Feltes
Affiliation:
Section of Pediatric Cardiology, Ohio State University and The Heart Center at Children's Hospital, Columbus, Ohio, United States of America
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Abstract

A recent, randomised, double-blind, placebo-controlled trial has demonstrated the effectiveness of palivizumab (Synagis®) for prophylaxis against infection by the respiratory syncytial virus in 1,287 young children with congenital cardiac disease. Guidelines for the use of palivizumab in these children considered to be at high risk were published by the American Academy of Pediatrics, followed by similar guidelines from the British Paediatric Cardiac Association, and recommendations from a number of other individual countries, including Canada, Germany, Spain, and France.

In May, 2004, further discussion was held between a group of 15 paediatric cardiologists at a European forum for clinical management held in Munich, Germany. The objective of this forum was to define optimal recommendations on prevention of infection by the respiratory syncytial virus in infants and young children with congenital cardiac disease, appropriate to the clinical needs and style of those practising in paediatrics in individual countries. Participants were invited because of their knowledge of the therapeutic area, and for their experience of using palivizumab for prophylaxis against the respiratory syncytial virus in children with congenitally malformed hearts. Measures to educate the carers of children with such congenital malformations on precautions against infection by the respiratory syncytial virus were discussed, along with the many different aspects of best practice for therapeutic prophylaxis with palivizumab. The most appropriate timing of prophylaxis, recommendations for which children are most likely to benefit from prophylaxis, and suggested protocols were among the issues covered. The recommendations resulting from the discussions are presented in this paper, as a step towards reaching consensus.

Keywords

Bronchiolitispalivizumabrecommendationsguidelines
Type
Original Article
Information
Cardiology in the Young , Volume 15 , Issue 3 , June 2005 , pp. 274 - 278
Copyright
© 2005 Cambridge University Press

Studies have shown that the respiratory syncytial virus is a leading cause of morbidity and hospitalisation in infants.1–4 Reports also suggest that subsequent utilisation and costs of healthcare are higher, and health-related quality of life is lower, in infants born prematurely with chronic lung disease hospitalised with respiratory syncytial virus compared with those not hospitalised with such an infection.5, 6 Furthermore, infection with the virus has additional implications for those undergoing surgery for correction of congenital cardiac malformations, both in terms of timing and negative outcome.7–10

A randomised, double-blind, placebo-controlled trial in 1,287 young children with haemodynamically significant congenital cardiac disease has established that palivizumab (Synagis®) is well tolerated and effective for the prophylaxis of serious diseases produced by the respiratory syncytial virus.11 The regime used was 15 milligrams per kilogram given intramuscularly for 5 months during the so-called season for infection by the virus. The efficacy of prophylaxis was demonstrated by a statistically significant reduction in the primary endpoint of hospitalisation for disease produced by the virus, along with similar reductions in total days hospitalisation and the need for supplemental treatment with oxygen.11

As a result of this trial, the American Food and Drug Administration, and the European Agency for the Evaluation of Medicinal Products, have licensed palivizumab for prophylaxis against the respiratory syncytial virus in children less than 24 months of age with haemodynamically significant congenital cardiac malformations. Recommendations reflecting the new evidence were published in 2003 by the American Academy of Pediatrics.12 These recommendations suggest that children of less than, or equal to, 2 years of age with such haemodynamically significant lesions, both cyanotic and acyanotic, would benefit from prophylaxis with palivizumab.

The British Paediatric Cardiac Association then published specialist recommendations appropriate to clinical practice in the United Kingdom.13 These recommendations suggest that children less than 1 year of age with haemodynamically significant congenital heart disease are most likely to benefit from prophylaxis (see Table 1 for definition of those congenital cardiac malformations considered to be haemodynamically significant). Children who are aged between 1 and 2 years with complex or palliated congenital cardiac disease may be considered suitable at the discretion of the paediatrician. This is in line with recommendations from the Joint Committee on Vaccination and Immunisation established in the United Kingdom at the request of the National Institute of Clinical Excellence. It is stated that certain children with congenital cardiac disease may receive prophylaxis on a case-by-case basis.14 The recommendations of the British Paediatric Cardiac Association, now renamed the British Congenital Cardiac Association, also highlight the fact that that there are some children admitted to the hospital during the season who may bring infection onto the ward. Because of this, it is suggested that children admitted for interventional procedures, for example, a 1-year old with persistent arterial duct undergoing coil occlusion, should be offered prophylaxis during the season, even though they may not themselves benefit. Normally, these children would not satisfy the indications for prophylaxis, but it is important to protect others with more complex disease who are resident on the ward, and who are thus vulnerable to nosocomial infection.13

Table 1. Haemodynamically significant congenital cardiac malformations, which may benefit from prophylaxis against infection by the respiratory syncytial virus, and conditions where benefit is not demonstrated.

Guidelines and recommendations on prophylaxis have also been put forward by a number of other countries, including Canada,15 Germany,16 Spain,17 and France.18

The European Forum for Clinical Management

In May, 2004, a group of 15 paediatric cardiologists from the United Kingdom, France, Germany, Australia, Italy, Austria, and The Netherlands, along with Tim Feltes from the United States of America, met in Munich, Germany, for a European forum on clinical management (Table 2). They discussed the use of palivizumab as prophylaxis against the respiratory syncytial virus in young children with congenitally malformed hearts, with the objective of defining optimal recommendations appropriate to the clinical needs and style of paediatrics in individual European countries. The committee spearheading the discussions was made up of Robert Tulloh, Damien Bonnet, Achim Schmaltz, Michael Marsh, Tim Feltes, and Jessie Groothuis. Those attending the forum had been assembled because of their comprehensive knowledge of the issues surrounding prophylaxis against the respiratory syncytial virus, and for their experience of using palivizumab for prophylaxis in children with congenitally malformed hearts.

Table 2. List of participants of the European Forum.

Existing guidelines and recommendations were discussed, along with the current views on prophylaxis for those with congenitally malformed hearts. On behalf of the forum, we hope that the issues outlined, and the opinions expressed, in the following sections of this paper will facilitate decision-making for paediatricians and paediatric cardiologists in the clinical management of children with congenital heart disease in their care.

Educational measures

The participants advised that parents, families, and carers of children with congenitally malformed hearts must be educated on the precautions they should take against infection by the respiratory syncytial virus. These precautions include frequent hand-washing, avoiding exposure of the child to crowds or other people with infections of the respiratory tract, tobacco smoke and, if possible, daycare during the season.12, 19 Stringent measures should also be taken by providers of healthcare to reduce the risk of nosocomial infection, which remains a common problem.20 Such measures include the use of clean masks, gowns and gloves, frequent hand-washing, early screening and identification of children infected by the respiratory syncytial virus, segregation or isolation of affected children, and exclusion of staff and visitors with infections of the respiratory tract.12

Prophylaxis with palivizumab

It was suggested that the timing of prophylaxis with palivizumab should be tailored to regional variations in the onset of the season at the discretion of the paediatrician or paediatric cardiologist. The usual regimen is five monthly intramuscular injections, each of 15 milligrams per kilogram, starting 2 weeks before the season is expected to commence. It was noted that palivizumab does not interfere with other paediatric vaccines, and therefore can be given concurrently.21 The participants agreed that prophylaxis is appropriate for children aged less than 2 years who have:

  • Haemodynamically significant congenital cardiac disease, cyanotic or acyanotic, be it uncorrected or partially corrected, or residual disease, or that which is scheduled for operation, catheterisation or hospitalisation
  • Residual pulmonary hypertension or chronic lung disease
  • Haemodynamically significant dilated or hypertrophic cardiomyopathy, defined as that which caused cyanosis or required cardiac medication.

They also agreed that the majority of candidates requiring prophylaxis are likely to be aged less than 1 year. This is the age at which the risk of severe infection is at its highest. Furthermore, therapeutic catheterisation, or surgery for congenital cardiac disease, is most often performed in the first year, or even 6 months, of life.

It was raised that a minority of children with other types of congenital heart disease aged between 1 and 2 years may also benefit from prophylaxis, for example, those undergoing staged surgical palliation for complex malformations, or those with ongoing pulmonary hypertension. Children aged from 1 to 2 years may require two injections per session because of their greater weight, in order to avoid administering an excessive volume of palivizumab into one site.

Children who should receive prophylaxis with palivizumab with caution

The committee outlined that caution should be used when children are under the following conditions:

  • Anticoagulant therapy, such as aspirin or warfarin
  • Acute or life-threatening cardiovascular or pulmonary instability
  • Haemodynamic instability or coagulopathy associated with severe infection.

Children who should not receive prophylaxis with palivizumab

It was decided that it is inappropriate to subject children to prophylaxis when they are acutely unwell. There is a significant risk that prophylaxis would be less effective, and there is a much higher chance of an adverse event such as bleeding or bruising. Furthermore, if there was a negative outcome from the unrelated illness, the cause might be incorrectly attributed to prophylaxis with palivizumab.

It was also deemed inappropriate to give prophylaxis to children who are older than 2 years, or who do not have haemodynamically significant cardiac disease, such as those with a small ventricular septal defect or an atrial septal defect. It was thought that the intervention and cost would be excessive and unjustifiable in these children, who may benefit little from prophylaxis. Further doses are also contra-indicated in children who have had a previous adverse reaction to palivizumab.

Additional complications that do not preclude prophylaxis with palivizumab

During the discussion, it was suggested that it would be helpful to provide paediatricians and paediatric cardiologists with a reference list of circumstances which, despite their complex nature, do not contra-indicate palivizumab prophylaxis. These include children with haemodynamically significant congenital heart disease who are less than 2 years old under the following conditions:

  • Previous treatment with palivizumab
  • History of past or current infection with the respiratory syncytial virus
  • Other vaccinations or normal immunisations, such as passive antibody
  • Food allergies
  • Kawasaki disease, with or without coronary arterial lesions after intravenous immunoglobulin
  • Immunocompromised state, such as those with organ transplantation or asplenia
  • Chromosomal or genetic mutation, such as 22q11.2 deletion.

Prophylaxis with palivizumab after cardiopulmonary bypass

It was proposed that prophylaxis with palivizumab should continue after cardiopulmonary bypass for as long as the child remains at risk from infection, either nosocomial or community acquired. Levels of palivizumab in the serum may be reduced by 58% following cardiopulmonary bypass, and therefore consideration should be given to providing postoperative prophylaxis at the earliest possible opportunity, as soon as the child is medically and haemodynamically stable.11 The rest of the timing, scheduling, and frequency of prophylaxis in the postoperative period should then be at the discretion of the attending paediatrician or paediatric cardiologist. Postoperative prophylaxis should be considered either for the remainder of the season, or into a second season. This would be appropriate for children who are less than 2 years of age with ongoing haemodynamically significant complications of cardiac disease, such as residual defects or pulmonary hypertension.

Areas of disagreement

As with all meetings of this type, unanimous consensus was not reached on all issues. It was recognised that provision of healthcare differs from country to country. For example, in some countries, palivizumab is extensively offered through private practice or insurance-based healthcare. In this situation, cost proves less of an issue, and the decision to give prophylaxis is often left to the individual parent or insurance scheme. It was argued that, in these countries, most parents would opt for prophylaxis up to 2 years of age in the appropriate circumstances. Indeed, it is important to state that it is not appropriate to receive prophylaxis in some situations, for example in those without haemodynamically significant congenital heart disease, in order to prevent excessive or injudicious administration.

Much discussion also centred on how long prophylaxis should be continued following surgical correction. In general, the feeling was that it should be discontinued after medication is no longer prescribed. In the United Kingdom, nonetheless, it is routine for medication to continue for 4 to 6 weeks postoperatively, in France for only 2 weeks, and in the United States of America for about 3 months. Hence, there is potential for confusion on this issue. The majority felt that it should be determined at the discretion of the administering physician, although the most cautious approach would be to give prophylaxis for the duration of the season.

Duppenthaler et al.22 recently challenged the cost effectiveness of the use of palivizumab in patients with congenitally malformed hearts by demonstrating a low incidence of hospitalisation due to the virus in children with haemodynamically significant congenital cardiac lesions in Switzerland. While methodological reasons might have resulted in an under-estimation of the extent of hospitalisation, the authors appropriately highlight the need for discretion in determining who might receive prophylaxis given the significant cost of the drug.23

Onuzo24 similarly questions the use of relative risk reduction to determine the effectiveness of Palivizumab to reduce hospitalisations and intensive care therapy in children with congenitally malformed hearts. In addition, he suggests that the cost to avoid hospitalisation could be excessive, having calculated this at 90,000 pounds sterling for each admission avoided. This is challenged both in reply,25 and also by Rackham et al.26 who have made a bold attempt at looking at the costs of avoiding admission. The recalculation takes account of savings in bed costs and transfers. This would then suggest that the cost of treating one child is just 800 pounds sterling, and the cost of avoiding admission is no more than 17,700 pounds. There are other hidden benefits, however, which have not been addressed, in terms of reduced morbidity and mortality of avoiding respiratory damage with bronchiolitis, which are as yet unmeasured.

Looking to the future

The European forum for clinical management consisted of a representative sample of paediatricians and paediatric cardiologists from across Europe, along with a representative from the United States of America. While the participants recognised that there are some regional variations in healthcare practice, provision and funding, the discussion led to many consensus views, which have been presented in the preceding sections of this paper. As already emphasised, we hope that these views will serve to aid paediatricians and paediatric cardiologists as a reference tool for the clinical management of children with congenitally malformed hearts.

It seems likely that, in the future, there will be further refinements in the administration and provision of prophylaxis against the respiratory syncytial virus. These may include new methods of prophylaxis, and further approval from governmental institutions to facilitate the process. It is generally agreed, however, that prevention of infection by the virus is of major benefit to children with haemodynamically significant cardiac disease, and that ongoing discussion is needed and should be encouraged.

Acknowledgements

We are grateful to Thomson ACUMED® for some editorial assistance in the development of this paper. Sources of financial support: This paper is based on a European forum for Clinical Management funded by an unrestricted educational grant from Abbott Laboratories.

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Figure 0

Table 2.