Respiratory syncytial virus prophylaxis: The risk-benefit of recommendations

In the next few months, essentially every community will have a notable, but unwelcome visitor, respiratory syncytial virus (RSV).

Each year, an estimated 2.1 million children younger than 5 years of age in the United States develop RSV infection requiring medical attention. Many of these infections are severe and costly. In those younger than 5 years of age, RSV causes one of every 334 hospitalizations, one of 38 emergency department visits, and one of 13 primary care visits yearly. Hospitalization rates are highest among infants, especially among young infants — 17 per 1,000 children 0-5 months of age and five per 1,000 children 6-12 months of age per year. Less recognized is the appreciable health care burden RSV causes in older children and in working and elderly adults. Immunity to RSV is incomplete, and repeated symptomatic infections occur throughout life.

Diminishing the burden from RSV remains a yearly challenge. Because no vaccine is yet available, the only prophylactic measure is passive immunization with palivizumab. Palivizumab is a humanized monoclonal IgG antibody directed against an epitope on RSV’s F protein, which is the immunodominant surface glycoprotein.

Monthly palivizumab injections in comparison to placebo have resulted in a significant relative risk reduction of 55% in the incidence of RSV hospitalizations among premature infants of <35 weeks gestational age with or without chronic lung disease of prematurity. Significantly fewer RSV hospitalizations, as well as the duration of hospital days and of supplemental oxygen administration, have also been demonstrated to occur with palivizumab prophylaxis among children with hemodynamically significant congenital heart disease.

Effective prophylaxis, therefore, is available, but the burden from RSV is extensive, even if focused only on those with severe enough disease to require hospitalization — and palivizumab is costly. Thus, the questions remain: Who among these “high-risk” children are most at risk? What is the risk and should it be defined clinically, economically or both?

Defining risk

The recent publication of the AAP's Modified Recommendations for Use of Palivizumab for Prevention of Respiratory Syncytial Virus Infections has highlighted the challenge in defining "at-risk" children.

These new recommendations emphasize the prime importance not only of gestational age but also of chronologic age. Young age and underlying conditions resulting in cardiopulmonary compromise have been well demonstrated to be associated with an increased likelihood of developing severe RSV disease. Concern and controversy, however, have arisen from the revised recommendations for the late-term premature infants, those with gestational ages of 32 weeks, 0 days through 34 weeks, 6 days. Since this group comprises approximately three-fourths of infants born prematurely each year, the modified guidelines further define among this group those at greatest risk for hospitalization by using age at the time of the RSV season and the probability of exposure to RSV infection.

The two major changes from the previous recommendations for infants of 32 through <35 weeks gestation to receive prophylaxis are:

1. Limiting eligibility to infants who are <3 months old at the start of the RSV season and who also have at least one of two additional risk factors for exposure to RSV (ie, attendance in a home that cares for any number of young children or at least one child younger than 5 years of age living permanently in the same household); and
2. Giving prophylaxis only until the infant reaches 3 months of age. Many infants, therefore, will receive only one or two doses of palivizumab.

Multiple studies indicate that the highest rates of hospitalization associated with RSV among both previously healthy infants and those with comorbid conditions occur during the first few months of life and also that young age is an independent risk factor for RSV hospitalization. Nevertheless, young age has been variably defined among studies, and the rates of hospitalization by each month of age are unclear.

Studies examining conditions likely to increase an infant’s exposure to RSV in congregate support the AAP conclusions regarding contact with other children. However, the environmental conditions reported to facilitate RSV's transmission to young children are numerous, including the number of siblings, children sharing a bedroom, residential crowding, daycare, and lower socioeconomic surroundings, and the reported risk among these studies varies widely. The type, intensity, and duration of contact are rarely considered. No single event or combination of environmental conditions has been consistently shown to be a reliable independent indicator of both exposure and a significantly elevated occurrence of severe RSV lower respiratory tract disease. In view of the complexity of these data, a stated and necessary goal of AAP's modified recommendations was to both “simplify the guidelines and optimize prophylaxis” for this largest group of premature infants.

The purpose of guidelines in general is to provide a succinct sum of experts' evaluation of a cornucopia of data, which few of us can feasibly or adequately review.

Another less recognized benefit of guidelines is the discussion and controversy they often generate that serve to emphasize the lacuna in currently available information. Certainly this is true concerning RSV prophylaxis. Information is lacking on the criteria, other than hospitalization, which are reliable independent outcome measures of the efficacy of RSV prophylaxis. Other potentially valuable, but less objective, outcomes include therapeutic and supportive measures required during and subsequent to the RSV illness and acute and long-term complications. Unknown also is the relative efficacy of prophylactic doses administered for each month of the RSV season, for example, months during the peak period of RSV activity versus the prior and subsequent months when RSV circulation is less. Furthermore, no standardized and validated tool exists for evaluating the severity of RSV lower respiratory tract infections among young children, which could be applied across different populations to assess the relative value and costs of prophylaxis.

Additional prophylactic products are needed, but the enormous time and cost of developing new agents is often prohibitive. Currently the only investigational product that has been extensively evaluated in large clinical trials is motavizumab.

Motavizumab is a recombinant humanized IgG monoclonal antibody derived from palivizumab that targets the same F protein epitope. In vitro, motavizumab has a 70-fold greater binding affinity for the F protein and has about a 20-fold greater neutralizing activity, which possibly could allow less costly dosing regimens and, in contrast to palivizumab, motavizumab significantly reduces the viral load in the upper as well as the lower respiratory tract. These properties suggest that less costly dosing regimens and prevention of the initial upper respiratory tract infection would be possible.

Motavizumab was compared to palivizumab in a randomized, double-blind study of 6,635 preterm infants with and without chronic lung disease. Infants receiving motavizumab had a 26% relative reduction in RSV hospitalizations compared with those receiving palivizumab. However, a recently convened FDA advisory panel reviewed these and other motavizumab data and voted not to approve the manufacturer’s (MedImmune) application for licensure. Part of the concern stemmed from the greater number of possible hypersensitivity cutaneous reactions observed among motavizumab than palivizumab recipients (0.7% versus 0.2%). The FDA has subsequently requested an additional clinical trial to assure that motavizumab has an acceptable risk/benefit association in these high-risk children.

Essential to recommendations for using palivizumab well and wisely is its cost analysis. Most cost estimations have not shown savings in healthcare dollars if palivizumab is offered to all at-risk infants for which it is currently licensed. Palivizumab costs approximately $6,000 per season per infant receiving five doses; in the study pivotal for licensure, the number needed to treat to prevent one hospitalization was estimated to be 17 or greater in some subgroups of infants. Studies assessing the costs of palivizumab prophylaxis have varied widely, suggesting that the factors that comprise a cost and quality-of-life analysis require better delineation. Furthermore, the incremental change in the economic burden that would result from each adjustment in the eligibility criteria for prophylaxis should be assessed.

To answer some of these questions, the CDC has recently formed a working group whose goal is to evaluate the currently available information necessary to make recommendations for the use of palivizumab among infants 32 to <35 weeks gestation. Their work is planned to be completed within the next few months, which potentially would allow recommendations from the Advisory Committee on Immunization Practices (ACIP) to be available by the end, but not the beginning, of this coming RSV season.

It is unlikely that additional new recommendations will absolve all the current controversy, nor should it. A continued dialogue may best help resolve our continual dilemma of balancing our roles as guardians of vulnerable infants and as stewards of dwindling resources.

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