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Three Part Question

Clinical question:
Should infants diagnosed with cystic fibrosis [Patients] receive palivizumab prophylaxis [intervention] during their first RSV season to prevent bronchiolitis [outcome]?

Clinical Scenario

Scenario:
A 6 week old boy has been investigated for failure to thrive. After further work up with sweat chloride testing he was diagnosed with cystic fibrosis. He is currently being seen at a paediatric out-patients clinic for follow up. As it is the beginning of RSV season the medical student asks the consultant whether Palivizumab prophylaxis would be beneficial.

Search Strategy

Search date: November 2010; Secondary Search: Cochrane library (2010): One relevant systematic review
Primary Search: Pubmed: Search terms: Cystic Fibrosis AND Palivizumab via MESH database. This returned 7 results. Limit to English language reduced this to 6 results.

Search Outcome

5 relevant results as per the table:

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Robinson KA., Odelola OA, Saldanha I, Mckoy N 2010 USA	Infants with CF (n=186) randomized to receive palivizumab (n= 92) versus placebo (n= 94)	Cochrane systematic review of 1 RCT	Primary outcomes were need for hospitalization with indentified RSV infection and mortality.	Only one participant in both the placebo and Pavilizumab group were hospitalized due to RSV infection in the first 6 months. There was no significant difference between groups. Risk ratio was 1.02 (95% CI .006 to 16.09). No mortality in either group	Only one industry supported trial was eligible for inclusion. That trial had unpublished data which showed no significant difference for any endpoints between placebo and treatment. Further data requested from the trial was not received by the review
Giusti R. 2009 USA	83 CF center directors in USA and Canada identified 435 infants diagnosed with CF	Survey	Use of Palivizumab and prescription patterns	74 (16%) infants with CF had a documented RSV infection of which 13 had received palivizumab. 41% of CF center directors believed Palivizumab prophylaxis was standard of care	37% non responders rate in USA and 54% in Canada
Speer ME, Fernandes CJ, Boron M, Groothuis JR. 2008 USA	Infants from the Palivizumab Outcomes Registry from 2000 to 2004	Case Series	Prevalence of palivizumab use among CF patients	91 CF patients received palivizumab. None were hospitalized as a result of RSV LRTI	Hospitalization end point is rare
Giebels K, Marcotte JE, Podoba J, Rousseau C, Denis MH, Fauvel V, 2008 Canada	Children who were diagnosed with CF before the age of 18 months (n=75). Those diagnosed after 2001 (n=35) received palivizumab and those before 2001 (n=40) served as controls Retrospective cohort study Hospitalization for acute respiratory illness during the first RSV season that followed diagnosis of CF Palivizumab recipients had .8 ± 3.07 days in hospital for respiratory illness vs 1.73 ± 4.27 for controls. This difference did not reach statistical significance. Risk ratio between RSV prophylaxis and hospital day was .46 (95% CI 0.164, 1.31) Study limited by use of historical controls and not testing for RSV status in all patients	Retrospective cohort study	Hospitalization for acute respiratory illness during the first RSV season that followed diagnosis of CF	Palivizumab recipients had .8 ± 3.07 days in hospital for respiratory illness vs 1.73 ± 4.27 for controls. This difference did not reach statistical significance. Risk ratio between RSV prophylaxis and hospital day was .46 (95% CI 0.164, 1.31)	Study limited by use of historical controls and not testing for RSV status in all patients
McCormick J, Southern KW. 2007 UK	34 CF centres in the UK identified 143 infants with CF under the age of 1 year Survey Incidence of CF diagnosis, admittance with RSV infection and palivizumab use. 16 of the 143 were hospitalized with RSV illness. 14 infants received palivizumab with one of those infants hospitilized with RSV infection.	Survey	Incidence of CF diagnosis, admittance with RSV infection and palivizumab use.	16 of the 143 were hospitalized with RSV illness. 14 infants received palivizumab with one of those infants hospitilized with RSV infection. 34 of 42 centres responded to the survey. The 14 children who received palivizumab were from 3 centres	Only 34 of 42 centres responded to the survey. The 14 children who received palivizumab were from 3 centres

Comment(s)

Respiratory syncytial virus (RSV) is an important pathogen which is a cause of lower respiratory infection in all ages and can cause bronchiolitis in infancy. In the USA the majority of chidren will have been infected by the age of two and around half of those will have been infected twice1. RSV bronchiolitis is a cause of considerable morbidity among infants. In Spain the RSV hospitalization rate for children under six months of age was 37 per 1000 with an average hospital stay of 5.9 days2. Children with cystic fibrosis are at a greater risk of RSV infection which is characterized by prolonged hospitalization and significant morbidity including risk of mechanical ventilation and prolonged oxygen therapy3. Palivizumab is a humanized monoclonal antibody to RSV. It has been shown that treatment by monthly injection with palivizumab during RSV season can result in a significant decrease in the hospitalization rates of certain at risk groups such a premature infants and those with congenital heart disease1. However there is a lack of research into the efficacy of palivizumab in CF patients, with only one randomized control trial to date4. This trial was the only data included in a Cochrane review5 which showed no conclusive evidence to support the use of the treatment with CF patients. Data from the trial was obtained from the published abstract and a poster presented by the authors but the trial was never published in a peer reviewed journal. This data looked at 92 children randomized to palivizumab and 94 to placebo. One child from each group was hospitalized for RSV LRTI. The authors concluded that there is insufficient data to allow conclusions about the efficacy of palivizumab prophylaxis in CF children. The number of adverse events were similar in both groups but it was unclear how these were classified and as such the review stated it was not possible to comment on the safety of palivizumab use. Giusti6 and McCormick7 both completed surveys about the use of palivizumab in North America and the UK respectively. The UK study done in 2005-06 showed that only 3 of the 34 cystic fibrosis centres which responded were using Palivizumab. Interestingly despite American Academy of Pediatrics guidelines to the contrary8 43% of cystic fibrosis center directors polled in the USA in 2007 believed that the drug was standard of care in preventing RSV with CF patients6. Speer9 looked at the data from the Palivizumab Outcomes Registry to identify the 91 children with cystic fibrosis who had received palivizumab from 2000-2004. It was found that none of the infants who had received it had been hospitalized for RSV LRTI and concluded that further research was warranted. Giebels10 used historical controls to study the use of palivizumab in 75 children with cystic fibrosis. This study showed that palivizumab recipients spent 0.8 ± 3.1 days in hospital per patient for respiratory illness versus 1.73 ± 4.27 for controls. However, this difference did not reach statistical significance. As concluded by the Cochrane review5 and demonstrated by the Giebels10 study, a large sample size would be needed to demonstrate a significant difference in hospitalization rates between palivizumab and placebo. Other longer term end points could be looked at in relation to palivizumab use in the cystic fibrosis population. Newborn screening programs for CF leads to early diagnosis and results in improved nutritional status and fewer hospitalizations11 as well as better growth12. There has been a substantial rise in the number of CF newborn screening programmes in recent years13. With early diagnosis of CF clinicians will be faced more often with the question whether or not to treat with palivizumab for the patient’s first RSV season.

Clinical Bottom Line

Currently there is no convincing evidence that Palivizumab treatment in infants diagnosed with CF is an effective treatment in prevention of infection with RSV or that treatment decreases hospitalization. More research would be needed to see if this is an effective treatment especially given the very high cost involved which could be used on other interventions.

References

1. Robinson KA., Odelola OA, Saldanha I, Mckoy N Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database of Systematic Reviews 2010 Issue 2
2. Giusti R North American synagis prophylaxis survey. Pediatr Pulmonol Pediatr Pulmonol 2009;44:96-8.
3. Speer ME, Fernandes CJ, Boron M, Groothuis JR. Use of palivizumab for prevention of hospitalization as a result of respiratory syncytial virus in infants with cystic fibrosis. The Pediatric Infectious Disease Journal 2008;27(6):559–61.
4. Giebels K, Marcotte JE, Podoba J, Rousseau C, Denis MH, Fauvel V, Prophylaxis against respiratory syncytial virus in young children with cystic fibrosis. Pediatric Pulmonology 2008;43(2):169–7
5. McCormick J, Southern KW. A survey of palivizumab for infants with cystic fibrosis in the UK. Archives of disease in childhood 2007; 92(1):87–8.