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Editor,—The letters from Drs Deshpande and Nicholl, in relation to the Impact-RSV study and the UK guidance for the use of palivizumab in the prevention of serious RSV infections, raise interesting questions that need to be addressed.
I believe Dr Deshpande “has got it wrong” in that he fails to realise that the primary objective of the IMpact study was to investigate whether palivizumab reduced RSV hospitalisations in high risk infants. It was never intended that this study would address the severity of RSV infections, the need for paediatric intensive care, the need for mechanical ventilation, or a reduction in death rate. It is unreasonable to suggest that because the study didn't show these then it is not valid. To show such benefits would require a totally different protocol, the numbers of patients being such that the study could never have been undertaken.
To reiterate the findings of the IMpact study, there was a 55% reduction in hospital admission rate for RSV proven disease—a significant result, however one wishes to interpret it. Those high risk patients admitted with RSV infection spent fewer days in hospital, had less need for oxygen treatment, and had lower respiratory infection clinical scores if they received palivizumab.
The study was designed in association with and with the approval of the licensing authorities to grant a marketing licence for the medication. It was not designed to provide economic data on the cost effectiveness of the product. Both Deshpande and Nicholl fail to realise that if they want this information then different studies are needed.
Does anyone know the lifelong cost of RSV disease in infancy? What is the relationship between RSV hospitalisation in the first year of life, recurrent wheezing in childhood, or indeed the possible development of chronic obstructive pulmonary disease in later adult life? To develop a relevant, long term, cost effectiveness plan, all these points need to be taken into consideration. In an attempt to help with this there are two ongoing studies that Deshpande, Nicholl, and others, may find helpful. One is taking place in four centres in the UK and the other is a follow up study from the IMpact trial. Both are attempting to identify the health service costs over a three year period following hospitalisation for RSV disease, and it is hoped the results will be available later on this year.
The UK guidance on the use of palivizumab does not advocate universal usage of the product, but makes recommendations on how infants may benefit. It is the role of clinicians in local hospitals to discuss with their managers, the local health authority, and the individual primary care group or trust, which specific patients they feel should receive palivizumab. These decisions may well differ between centres depending on budgets, the morbidity of their patients and interpretations of evidence both research and clinical.
RSV bronchiolitis remains the greatest annual epidemic disease to hit paediatric departments in Europe, the USA, and Australasia.1 The treatment of the symptoms is unsatisfactory in that the only proven benefit is oxygen. Each year, vast amounts of money are wasted on bronchodilators, steroids, ipratropium bromide, and antibiotics. Palivizumab, the first monoclonal antibody to be developed specifically for use in paediatrics, has been shown to be effective in reducing hospital admission in high risk infants. To dismiss it out of hand seems churlish. To rationalise its use in those whom it may most benefit seems clinically sensible. All new treatments need to be considered with caution. However, I believe that if clinicians take a back seat view whilst awaiting definitive confirmation of absolute cost effectiveness, we will continue to deny our most vulnerable patients the benefits of scientific advance.
Editor,—I am writing in reply to the recent correspondence regarding the use of palivizumab (Synagis),1-1 1-2 a monoclonal antibody licensed for the prophylaxis of respiratory syncytial virus (RSV) infection in premature infants. RSV is a disease that affects 50% to 70% of all infants within the first year of life, and causes significant morbidity and mortality, particularly in a number of well defined high risk groups.
The major trial demonstrating the safety and efficacy of palivizumab was the IMpact-RSV trial,1-3 a randomised, double blind, placebo controlled, multicentre trial that enrolled 1502 children with prematurity (⩽35 weeks gestation) or bronchopulmonary dysplasia (BPD). One hundred and twenty three of the children enrolled were from 11 UK centres. The primary end point of the IMpact-RSV study was hospitalisation due to confirmed RSV disease. The study was not powered to demonstrate a reduction in mortality, neither was it designed as a pharmaco-economic study. The average gestation of all the infants was 29 weeks and the placebo (n=500) and palivizumab (n=1002) groups were well matched for both demographic parameters and RSV risk factors. The study demonstrated a relative reduction in RSV related hospitalisation of 55% (10.6% placebo v4.8% palivizumab p=0.0004). A significant reduction in RSV hospitalisation was seen irrespective of gestational age, diagnoses of BPD, weight, or gender. Of all the children in both groups admitted with RSV infection, 27.7% were admitted to intensive treatment units (this figure was similar in both groups). There was however a significant reduction in the overall incidence of RSV related intensive treatment unit admission in the palivizumab group (3% placebo v 1.3 % palivizumab p=0.026).
The placebo RSV hospitalisation rate of 10.6% reported in the IMpact-RSV trial was lower than that seen in previous controlled trials which have reported rates of 13.5%,1-4 20%,1-522.4%,1-6 and 37%.1-7 Further reported rates of hospitalisation vary depending on the risk group studied, and data from the US demonstrate that it is possible to predict subgroups who have considerably higher hospitalisation rates.1-8
Further data from both Europe1-9 and the US1-10reported RSV readmission rates in large numbers of premature children receiving palivizumab prophylaxis over the 1998/9 RSV season (neither study had a placebo arm). Of the 565 European infants enrolled, 1.2% had confirmed RSV hospitalisation, whilst two US groups of 1839 and 7013 children had RSV hospitalisation rates of 2.3% and 1.5% respectively. Despite the lack of comparator arms, these data do suggest that the IMpact-RSV trial may have underestimated the true efficacy of palivizumab.
The generation of pharmaco-economic arguments directly from the IMpact-RSV data very much oversimplifies what is an extremely complex issue. Hospitalisation rates vary considerably between risk groups, and measuring the true economic cost of RSV hospitalisation requires long term follow up, both of hospital, community, and parental costs.
Despite its relatively high costs, modern neonatal care has led to dramatic improvements in the outlook of premature infants. Advances such as surfactant therapy and mechanical ventilation seem expensive on the face of it, but both controlled trials1-11 and clinical experience have shown the investment to be worthwhile.
Dr Deshpande refers to the guidance document reflecting the outcome of a consensus committee of a number of UK clinicians,1-1 and issued by ourselves. Many were aware of the guidelines published by the American Academy of Pediatrics regarding RSV prophylaxis and the use of palivizumab,1-12 and felt that whilst they were very useful, UK guidelines should be formulated at a local level, taking into account local risk groups and epidemiology. For these reasons, the UK guidance document deliberately avoids being too prescriptive and whilst describing the two major risk groups (premature infants, ⩽35 weeks gestation, and those with BPD), it emphasises that treatment priorities are likely to vary locally and that decisions regarding which preterm infants to treat will be individualised.
Abbott Laboratories are continuing to work with many in the paediatric community in order to help better define many of the issues. We strongly feel that palivizumab is an important breakthrough in the battle against RSV infection, a disease that continues to cause high levels of morbidity and significant mortality in high risk infants.
The editor comments:
In her letter, Dr Carnegie refers to a guidance document reflecting the outcome of a consensus committee of a number of UK clinicians and issued by Abbott Laboratories Ltd.
Earlier this year, we received as a submission for publication such a document, headed by the names of a number of distinguished paediatricians and neonatologists. I was puzzled because it was addressed from a public relations company. I contacted all those named to ask who the corresponding author was. I learned that they did not know the paper was to be submitted to a peer reviewed journal.
Consequently, I invited the PR company to withdraw the submission, which they did. The paper, itself, was marked as having been produced with the aid of an educational grant from Abbott Laboratories.
In general, Archives of Disease in Childhoodis reluctant to publish the results of consensus groups, unless the methods by which they arrived at their conclusions are totally transparent. This case illustrates one reason why we believe it is right to be cautious.