Recurrent respiratory papillomatosis (RRP) remains a devastating disease for pediatric patients. Each time we diagnose a new case of RRP we are reminded of our limitations in battling a disease that has no known cure, that has an unpredictable course, and that carries a risk of morbidity. Answering probing questions from family members about disease transmission requires sensitivity, as the knowledge that it is a vertically transmitted disease often evokes much guilt in parents.
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October 2006The lack of a cure for this disease cannot be attributed to lack of research efforts. An infectious etiology for RRP was first proven in 1923 when Ullman injected homogenized papillomata from a child’s larynx into his own forearm and developed papillomatous lesions at the site three months later. Clearly, Dr. Ullman was operating prior to the creation of Institutional Review Boards! Numerous investigators have since sought to find a cure for this virally transmitted disease. Countless treatment modalities have been proposed based on promising preliminary results, only to find that the purported benefit was more likely a reflection of disease variability than efficacy of the drug. I recall the wisdom of Professor Bruce Benjamin, who told me during my fellowship that cures for RRP come and go like passing trends. His wisdom has prevailed.
Vaccines: A Great Leap Forward
The FDA approval of Gardasil in June of this year is the most exciting news for otolaryngologists who treat patients with RRP. This quadrivalent vaccine combines empty virus-like particles with the L1 major capsid protein of HPV-6, -11, -16, and 18 to induce a robust host-antibody response. The Phase II and Phase III trials have demonstrated remarkable safety and efficacy in preventing HPV-related cervical dysplasia and carcinoima in situ from the viral subtypes of interest. While the impetus for creating the vaccine has been to prevent anogenital HPV-related disease, the potential for preventing RRP, which is often considered an orphan disease, is clearly our windfall.
The cost of $360 for the three vaccines that are administered over a six-month period is trivial compared with the anticipated reduction in health care costs allocated to manage HPV-related disease. More than $100 million is spent annually to treat patients with RRP in the United States. This amount is small in comparison to the $1 billion allocated to treat HPV cervical dysplasia, cervical carcinoma, and anogenital warts. Americans unable to afford vaccine therapy can receive it through the Vaccines for Children Program, sponsored by the Centers for Disease Control and Prevention (CDC), or through an adult patient assistance program offered by Merck. The Bill and Melinda Gates Foundation announced in June its plan to give $27.7 million to fund research on how best to introduce the new vaccine to third world countries where HPV causes 25% of all cancers in women.
Use of the vaccine will not obviate the need for PAP smears, as other HPV viral subtypes not covered by the vaccine can still cause premalignant and malignant changes in the cervix.
It is not surprising that one of the biggest debates over the vaccine approval by the FDA was the age to initiate therapy. Convincing parents of pre-pubertal children that they should receive the vaccine might be difficult. Critics of early administration argue that explaining the vaccine’s purpose necessitates teaching recipients about sex and that such a discussion may encourage inappropriately young sexual activity. In support of early vaccination, however, is the finding that antibody levels to HPV-16 and -18 are two times higher in girls vaccinated between 10 and 14 years of age compared with women vaccinated between 20 and 25 years of age. The CDC’s Advisory Committee on Immunization Practices (ACIP) voted unanimously to urge all females between 11 and 26 years of age to be vaccinated and that girls as young as 9 receive the vaccine at the discretion of their physician. Hopefully Phase IV studies will confirm the long-term safety of the vaccine in children, unlike other vaccines, such as that for rotavirus, which was found to increase the risk of intussception.
Approval of Cervarix, the bivalent vaccine for HPV manufactured by GlaxoSmithKline, is expected in 2007. Because this vaccine does not confer direct resistance to HPV-6 and -11, it is incumbent upon us to push for use of the quadrivalent vaccine. We must convince pediatricians, family practitioners. and gynecologists of the importance of preventing HPV-6 and HPV-11-related disease. These viral subtypes are often termed low risk because of their low likelihood of inducing malignant disease. They are considered anything but low risk to us and to our patients with RRP.
Other Research Moves More Slowly
Research advancements for a vaccine to treat existent RRP are moving far more slowly. Pilot data from the HSPE7 vaccine, manufactured by Stressgen, showed a significant increase in the time interval between surgical interventions for patients receiving the vaccine. While I was concerned about the subjectivity of the outcome measure for patients that I enrolled in the study, I was thrilled to observe that two of my three severely affected patients entered remission in the year after the study was concluded-hinting at potentially promising long-term results. Nventa recently purchased the financially struggling Stressgen company and has announced plans to continue HSPE7 research.
Surgical therapy remains the mainstay for treatment of existent disease. Although we all have our personal preferences for instrumentation to remove papillomata, the equipment options do not vary the interval length between treatments. I believe that the use of the microdebrider will surpass the use of the CO2 and KTP lasers in the next decade. Having been an advocate for CO2 laser therapy for many years, I converted to microdebrider use several years ago as I find it better able to define the delicate plane between normal and abnormal tissue. Dr. Steven Zeitels continues his exploration of the pulsed dye laser (PDL) to eradicate papillomas by destroying their central feeding vessel. The PDL energy is delivered through a flexible cable and can be used in an office based setting under local anesthesia. It may carry a lower risk of causing web formation when treating lesions at the anterior commissure.
Early in the course of investigation are two topical agents that may eventually be useful for managing laryngeal papillomata. Ionic contraviral therapy (ICVT, Henderson Morley, UK) is an antiviral agent with excellent efficacy in treating plantar warts. It reportedly alters the host cell to create a hostile environment rather than affecting the virus itself. Carrageenan is an extract of red algae and is used as a thickener in many foods, cosmetic products, and even vaginal gels. This agent inhibits binding of HPV to the target cells and may prove useful as a lubricant gel.
RRP Resources
No editorial comment would be complete without commenting on the accomplishments of the RRP Task Force. Headed by Craig Derkay, MD (Eastern Virginia Medical School), the RRP Task Force is credited for widespread dissemination of knowledge regarding RRP. Initiated in 1994 following a survey of members of ASPO, the ABEA, and the AAO-HNS regarding the treatment of RRP, the task force has made great strides in establishing a nationwide registry for juvenile onset RRP, in analyzing the demographics of patients with RRP, in assessing various treatment modalities and in fostering the continued research of treatment. The annual AAO-HNSF instructional course offered by Craig Derkay and Brian Wiatrak, MD (University of Alabama) is a must for physicians treating patients with RRP who wish to know the current and future trends in disease management.
Patients with RRP should be made aware of the RRP Foundation directed by Bill Stern (www.rrpf.org ). This nonprofit organization, established in 1992, serves as an outstanding information resource for patients, families, and practitioners, and promotes public awareness of this devastating disease.
In summary, the future looks promising for the management of RRP. Although a cure is not imminent, we may be on the cusp of preventing this disease with vaccine therapy. We can all hope for the day when discussions of the management of laryngeal papillomas become of historic interest only.
©2006 The Triological Society