Recommended changes in the prophylactic use of palivizumab for some premature babies at risk of respiratory syncytial virus in the 2009 Red Book continue to stir controversy, with at least one state chapter of the American Academy of Pediatrics, as well as Florida Medicaid deciding to stick with the 2006 Red Book recommendations.
The Red Book revision, which now recommends a maximum of three doses rather than five for babies born between 32 and 35 weeks' gestation, also has drawn fire from other health care professionals and consumers, who have sent more than 14,000 e-mails from a Web site created by MedImmune Inc., the company that manufactures palivizumab (Synagis). The site links visitors to a form letter suggesting that, if the 2009 revisions are adopted throughout the country, 60,000 preterm infants who previously could have received the drug will no longer get it.
The updated recommendation appeared in the 2009 Red Book (pp. 562-8) in August, and in the journal Pediatrics in September (2009 [doi:10.1542/peds.2009-2345]). The changes limit prophylaxis to those infants who either attend day care or have a sibling at home younger than 5 years, and who are born during or within 3 months of the RSV season. Prophylaxis would continue for only the first 90 days of life as RSV occurs within that time frame. Therefore, only infants born from October to January would receive three doses. Those born in September and February would receive two doses and those born in August and March would receive one dose (“AAP's Red Book Change in Synagis Dosing Questioned,” September 2009, p. 1).
The change reflects a balance between growing data suggesting that infants in this age group can be adequately protected from RSV hospitalization with fewer doses, and the cost of RSV prophylaxis, wrote Dr. Joseph A. Bocchini Jr., chair of the American Academy of Pediatrics Committee on Infectious Diseases, and his coauthors.
“Immunoprophylaxis with palivizumab is an effective, although costly, intervention,” wrote Dr. Bocchini, who is also the chair of pediatrics at Louisiana State University, Shreveport. “Optimal cost benefit … is achieved during the peak outbreak months in which most RSV hospitalization occurs.”
But at least one researcher whose study was used to help justify the new recommendations expressed concern about how his data were interpreted. Dr. Xavier Carbonell-Estrany, a neonatologist at the Hospital Clinic at the University of Barcelona, and his colleagues examined RSV rates in nonprophylaxed babies born at 32 weeks' gestation or younger during two consecutive RSV seasons. The Pediatrics article cited his study to show that RSV rates were highest in babies who were younger than 3 chronological months (Pediatr. Infect. Dis. J. 2001;20:874-9).
In an interview, Dr. Carbonell-Estrany, who also is the president-elect of the World Association of Perinatal Medicine, said that he “has no idea how our studies were used.”
There is no evidence-based medicine to support three injections, he said. “What happens with a poor 32 weeks' baby born on Aug. 15? He is going to get one dose only. Where is the rationale for this? Does it make any sense? It's a pity to link well-designed risk factors with proven causality, and then to mix this with expert opinion, which has the lowest level of evidence.”
The Red Book update represents an earnest effort to balance effectiveness and cost, said Dr. Thomas Rand, a pediatric infectious disease specialist in Boise, Idaho.
But the logistics surrounding its release made it too hard for Idaho pediatricians to swallow, at least for this year, he said in an interview.
Dr. Rand was one of a 17-member panel of Idaho AAP members who recommended that the state chapter stick with the 2006 AAP palivizumab dosing recommendations. He and his colleagues objected to the timing and process of the national recommendation, as well as its scientific underpinning.
“The timing when they came out [in August] was late with regard to when providers and clinics needed to order their palivizumab supplies. There was no preparation for the change—the idea was not first floated to get a feeling [for] what providers might think about it,” he said.
“Also, the basis of the change was data that have been in the public domain for a long time, with new interpretations that we have trouble buying into.”
Finally, he said, a year in which pediatricians are marshalling much of their energy into dealing with pandemic influenza A(H1N1) “is not the time to make a change that could lead to a population at increased vulnerability to respiratory infection.”
For all those reasons, Dr. Rand said, the committee recommended on Sept. 11 that Idaho pediatricians stick with the Red Book's 2006 dosing recommendations (www.idahoaap.org/pdfs/RSV_Consensus.pdf). The committee also promised to help state pediatricians deal with insurance companies that might balk at doctors who want to use five rather than the newly recommended three doses.
Next year might present a different picture, he said. “We do like the fact that [the recommendations] are simplified, and so it's easier to make risk distinctions that are not subjective, so once people have had a chance to digest and become accustomed to them, we will probably ultimately use them.”
However, Dr. Rand said, for this year Idaho Medicaid has decided to go with the new recommendations, setting up the potential for disparate payer situations. “This could be very difficult in a clinic when parents know that different babies are being dosed differently. These distinctions will be difficult to explain to parents.”
A similar situation may arise in Florida, where Medicaid has decided to stick with the 2006 Red Book guidelines, despite the fact that the Florida AAP chapter supports the new recommendation, said Dr. Mobeen H. Rathore, chief of pediatric infectious diseases at the University of Florida, Jacksonville.
He isn't sure how private payers will deal with the divergent situation, but said there could be confusion in the clinic. “Whenever there is disparity, there is some concern, but even if private payers only pay for what is recommended [three doses], children will be protected.”
Dr. Rathore said some Florida chapter members are concerned about the reduced dosage recommendations especially since the RSV season in South Florida is longer than it is anywhere else in the United States.
“For the Southern part of the state, it's about 7 months—a month longer than the rest of the state. Therefore, one would want to give palivizumab for 6 months in South Florida and not 5 months,” he said in an interview. “However, the new recommendations do allow for that.”
Florida Medicaid also cited the longer RSV season as the reason for sticking with the 2006 dosing schedule, said Tiffany Vause, press secretary for the state's Agency for Health Care Administration.
“The AAP guidelines recommend five doses in temperate regions of the United States,” she said in an interview. “Most clinicians recognize that Florida has a somewhat longer season. Therefore, we opted to leave the Florida Medicaid guidelines unchanged from the previous year.”
Dr. Myles B. Abbott, chair of the AAP's District IX (California), has gotten an earful from his constituents, courtesy of the Web site PreemieVoices.com.
Established by MedImmune, the company that makes palivizumab, the Web site gives readers the chance to electronically send a letter of concern to various recipients, including the AAP national executive committee, members of its Committee on Infectious Diseases, and the AAP chapter directors, said Salvatore Constantino, a company spokesman.
Dr. Abbott, a pediatrician in Berkeley, Calif., has been on the receiving end of many of those letters.
“I have gotten several hundred form letter e-mails and so have our other board members, suggesting that this policy is wrong and we should change it. The AAP has taken this very seriously, and members who have written to us about it have been contacted to discuss their thoughts,” he said.
So far, 408 individuals (doctors, nurses, advanced practice nurses, case managers, social workers, advocacy organization members, and consumers) have sent 14,200 e-mails using the tool, Mr. Constantino said. MedImmune employees are not allowed to access the Web site.
Dr. Doris A. Makari, senior director of medical affairs at MedImmune, said the company sticks by the Food and Drug Administration–approved dosing recommendations, which call for a maximum of five injections. She said the company has conducted its own literature review, and does not agree with the Red Book changes.
“We found no evidence to support the revised AAP recommendation to limit palivizumab to three doses, nor [to support] the recommendation to limit palivizumab to one, two, or three doses based on when an infant reaches 3 months' chronological age during the RSV season,” she said in an interview.
“The quality of evidence pertaining to this modification is classified as level III, which is based only on expert opinion,” she added, while “substantial level A-I clinical evidence supports monthly palivizumab dosing throughout the RSV season.”
The AAP recommendations have little or no supportive clinical evidence, yet they will undoubtedly affect which babies will receive palivizumab, Dr. Makari said.
“Ultimately, pediatricians may be confused by the recommendations and put in the unfortunate position of trying to decide whether to follow the AAP recommendations for 32-35 weeks' gestational age infants, which appear to be cost based, or the FDA-approved palivizumab package insert, which is based on the results of well-designed randomized clinical trials.”
The AAP and MedImmune have politely agreed to disagree, said Dr. Abbott. “I've met with the MedImmune people and I understand their reservations. At the same time, I have trusted our Red Book experts for a long time. They have always been conscientious professionals at the top of their field, making the best decisions possible with the available data.”
The beauty of recommendations, Dr. Abbott said is that they are simply that—recommendations.
“These are not laws. Physicians can review them and make their own decisions about therapy. We are just saying that this is the best knowledge we have and based on it, this is what is reasonable. But it is not the only way.”
And, he said, recommendations are flexible. The 2009 revisions replaced the 2006 recommendations, which updated those originally made in 2003. As the data evolve, so do the treatment guidelines.
“Every RSV season is different and this may not be decided in one season,” Dr. Abbott said.
“We will be looking at this very carefully to see if this recommendation holds water. Only time will tell if this was a great decision, a good one, or one with holes in it that need to be fixed. And if there are holes, believe me, we will fix them.”
Dr. Abbott had no financial disclosures to make with regard to the issue. Dr. Rand administered a one-time grant from MedImmune to the Idaho chapter of the AAP. Dr. Rathore has been a speaker for and has received research funding from MedImmune.
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