Pediatric recurrent respiratory papillomatosis (RRP) can be devastating for patients and their families. The disease is caused by two strains of the human papilloma virus, HPV-6 and HPV-11, and affects approximately 4 in 100,000 children. The disease course is highly variable, with some children requiring only one or two surgeries and others requiring a hundred. Research and new tools are helping to improve patient care, though many questions remain unanswered and the rarity of the disease makes finding some answers difficult.
HPV Type Influences Disease Course
Several recent studies show that HPV-11 is more frequently associated with aggressive RRP than is HPV-6, though both strains are associated with genital warts or condylomas in adults. In a 10-year prospective study of 73 pediatric RRP patients, Brian J. Wiatrak, MD, Chief of Pediatric Otolaryngology at The Children’s Hospital of Alabama in Birmingham, and colleagues found that patients infected with HPV-11 had a higher severity score at presentation, required more frequent surgeries, and more frequently required medical adjuvant therapies to control disease compared with patients infected with HPV-6.
HPV-16, which is known to cause cervical cancer in women, is infrequently found to infect the airway. When it does however, the likelihood that RRP will progress to cancer increases, said Dr. Wiatrak, and patients should be followed more closely.
Given these differences in disease course, Dr. Wiatrak regularly tests new patients to determine which HPV type they are infected with. If it is HPV-11, you know ahead of time that you are going to be dealing with a more aggressive subtype and you can adjust your clinical plan accordingly, he said. When treating such patients he is likely to electively schedule more frequent debridements to stay ahead of the disease as it can get out of control rather quickly. Additionally, he is more likely to start adjuvant medical treatments with this type of infection.
One problem with typing, however, is that the currently available commercial tests do not distinguish between HPV-6 and -11. Rather, the results come back in the form of low risk or high risk with respect to cancer, not RRP. As both HPV-11 and HPV-6 fall in the low-risk category for cancer, the tests are not particularly useful for RRP prognosis. Roche Laboratories plans to come out with a more specific test in the next few years, which will discriminate between -11 and -6, but until then such tests are really available only in research facilities. So general clinicians cannot find out what specific type they are dealing with unless they have a research lab they are associated with-and then only the commercially available tests are covered by insurance, said Dr. Wiatrak.
Host Factors Influence Susceptibility
In addition to viral subtype, host variables play a big role in who gets the disease and how it manifests itself. A key indication that host factors are important is the low rate of disease relative to the number of children exposed to the virus. Only seven of 1000 children born to women with condylomas develop RRP, although mother-to-child transmission during fetal development or delivery is the major route of infection.
Moreover, not all children infected with HPV-6 or -11 develop RRP. Researchers at the University of Mississippi Medical Center examined tonsillectomy specimens from 50 children undergoing tonsillectomy for hypertrophy or recurrent tonsillitis. Although none of the children showed evidence of RRP, one child did have HPV-11 infection. In an earlier survey of healthy children, researchers at the University of Iowa found that 9% of healthy children under the age of seven had evidence of oral HPV infection.
Given these patterns of disease, scientists are looking for host factors that make individuals susceptible to RRP. Already, several studies have shown that specific alleles of the major histocompatibility complex (MHC) are disproportionately represented in the RRP patient population relative to the population as a whole. However, because most people with those MHC alleles and HPV exposure do not develop RRP, the MHC factors cannot be the whole story.
Farrel J. Buchinsky, MD, PhD, a pediatric otolaryngologist at Allegheny General Hospital in Pittsburgh, and colleagues have launched a large multicenter genetic study to scan the genome for gene variants associated with RRP. Thus far, the team has enrolled 177 patients in the study, along with one or both parents. The idea behind the study is that any allele that increases susceptibility to RRP should be transmitted more frequently to the affected offspring than would occur by random chance. The researchers have performed a preliminary low-resolution genome scan-using just 6000 single nucleotide polymorphisms to mark the variation across the genome-on the first 60 patients, but found no hits. We now want to do the same thing, but instead of looking at 6000 spots, looking at 300,000 across the genome in a larger sample of patients, said Dr. Buchinsky. The problem is that it is extremely expensive and we are going to need additional funding before we can do it.
In the meantime, they are using a candidate-gene approach, looking to see if genes that have been previously implicated in RRP or an HPV-related condition, are segregating disproportionately between parents and children. Preliminary analysis showed no correlation between the EVER1 gene, which is responsible for susceptibility to epidermodysplasia verruciformis 1, a skin disease caused by HPV. The team is now looking more closely at EVER1 and EVER2, another gene involved in the same disease, and at the TAP-1 gene. The TAP-1 protein is required for efficient antigen presentation on immune cells and is known to interact with HPV E7 protein. The E7-TAP-1 interaction appears to decrease the amount of TAP-1 in the cell. Thus, researchers have hypothesized that certain TAP-1 alleles may help HPV evade immune detection in some individuals.
The group also plans to look for genetic factors that influence the aggressiveness of the disease course. If you are one of these people who had one or two operations and then it went into remission, who would care? Dr. Buchinsky said. That is not nice, but it is not a big deal. On the other hand, if you are one of these people who undergoes 100 operations that is a huge deal. So we also want to look at whether there is any genetic influence over the type of course that one runs.
In the long run, Dr. Buchinsky hopes that identifying the susceptibility genes will help reveal the biology that underlies RRP, and lead to improved treatments. But that won’t happen quickly and in the meantime surgery remains the mainstay of therapy.
The Standard of Care-Surgery
Until recently most otolaryngologists used the carbon dioxide laser to remove papillomas from the larynx of children. A recent survey of American Society of Pediatric Otolaryngology (ASPO) members found that more than half are now using the laryngeal microdebrider as their surgical tool of choice.
It is as effective as laser for removing papillomas but safer because you don’t have any collateral thermal damage to the tissues nearby, said Craig S. Derkay, MD, Professor of Otolaryngology and Pediatrics at Eastern Virginia Medical School in Norfolk and Chair of the RRP Task Force, which is sponsored by ASPO. Additionally, the use of the microdebrider does not require specialized nursing, as do laser-based procedures, but it still allows for a delicate dissection of the papillomas.
Recently some physicians have started to use the 585-nm pulsed dye laser for the treatment of adult RRP patients. This laser has the advantage that it can be used with local anesthetic in the physician’s office, which saves the patient another trip to the operating room. There may be a role for the laser in the treatment of older children in the future, but it is not suitable for use in younger children, said Dr. Wiatrak.
Adjuvant Therapy for Severe Cases
For patients who have aggressive disease, adjuvant medical therapies may help increase the time between surgeries. The two most common adjuvant therapies used, according to the survey of ASPO members, are interferon and cidofovir. However, only interferon has been tested in randomized placebo-controlled trials.
In two randomized controlled trials, both of which were reported in 1988, systemic interferon therapy significantly reduced the severity of the disease, compared with controls. Following discontinuation of the drug, disease severity rapidly returned to baseline levels. As expected with interferon therapy, side effects included nausea, fatigue, headaches, and intermittent fever.
Unlike interferon, cidofovir has not undergone rigorous efficacy trials or even extensive safety testing. The US Food and Drug Administration approved cidofovir for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients in 1996, prior to the development of effective anti-HIV therapies at a time when activists were demanding rapid approval of any agents that might work. Cidofovir has not been approved for other indications.
Numerous case series show that as many as two-thirds of pediatric RRP patients derive some benefit from the drug, which is injected into the surgical bed after removal of the papilloma. Typically, one-third of the patients show a dramatic improvement, with some having clinical resolution of their disease. Another third will show some limited improvement. The remaining patients show no improvement on therapy.
Despite these positive results, experts express responsible skepticism because the drug has not been evaluated in a randomized placebo-controlled trial. Without that type of study, it is impossible to know what portion of a patient’s improvement is due to the drug and what is due to a change in the natural history of the disease.
Concern about the off-label use of cidofovir in RRP has increased following recent reports of a few patients treated with cidofovir whose disease progressed to cancer.
What we really need is a multicenter [randomized] study to look at the effectiveness, safety, and toxicity of cidofovir, said Dr. Derkay, but the company that makes it is perfectly happy to have ear, nose, and throat doctors use it off-label. It is not currently approved for the use of respiratory papilloma disease but they are not interested in putting the money into seeking FDA approval for it as a papilloma drug or accepting the liability for it if it turns out to be cancer-producing. So we are caught in a Catch-22. We have a drug that looks like it is a pretty good drug, but that is based on anecdotes and small patient series, and the safety data are actually a little scary-and we don’t have a company willing to bankroll the proper study that needs to be done.
Because of these safety concerns and the lack of demonstrated efficacy, the RRP Task Force has published a recommendation regarding the use of the drug. The committee agreed that the drug should be considered for use only in patients who require four or more surgeries per year or in whom the warts are starting to progress down the aerodigestive tract. In that case, the benefits of the drug may outweigh the risks. The drug, however, is not recommended for use in newly diagnosed patients for whom the natural history and aggressiveness of their disease is not yet apparent. Additionally, given that the drug has not been approved for use in RRP and there are safety concerns, physicians should go through an informed consent process with the parents of pediatric patients prior to administering the drug.
Andrew F. Inglis Jr., MD, Associate Professor in the Division of Pediatric Otolaryngology at Children’s Hospital & Medical Center at the University of Washington in Seattle, is an outspoken critic of the use of cidofovir in RRP. In an editorial he wrote for The Annals of Otology, Rhinology, and Laryngology last year, Dr. Inglis pointed out that the doses used in RRP treatment lead to systemic drug levels that induced tumors and kidney toxicity in rats during short-term toxicity testing. Twenty percent of the rats in the study developed cancers, despite the fact that the toxicity tests were not the long-term studies typically used to look for cancer formation in animal models. The impact of RRP on some patients is so truly devastating that they would gladly assume the still-theoretical risk of cidofovir-induced human malignancy. On the other hand, the physician should be aware of the results of the animal studies with this drug, and put them in the proper perspective for the patient, he concluded.
In the absence of a randomized controlled trial, several groups are trying to follow patients treated with cidofovir to determine whether benign warts are converting to precancerous or cancerous lesions at a higher-than-expected rate. For example, Richard J. Smith, MD, Professor and Vice Head of the Department of Otolaryngology at the University of Iowa, and colleagues are collecting pathology samples, treatment data, and HPV type on RRP patients treated in the university health care system. No data are yet available however.
Novel Adjuvant Agents
In addition to cidofovir and interferon, two other agents look promising in the treatment of RRP: celecoxib, which is a cyclooxygenase (COX)-2 inhibitor, and a novel immune modulatory agent called HspE7. Preliminary data suggest that both agents reduce the severity of disease. Unfortunately, pivotal studies for each drug have been delayed because of a lack of funding.
Researchers at Long Island Jewish Medical Center in New Hyde Park, N.Y., have designed a multicenter randomized placebo-controlled trial to determine whether the use of celecoxib can reduce the frequency of surgery in adult RRP patients. While awaiting NIH funding for the multicenter study, the group is enrolling patients onto the protocol at Long Island Jewish Medical Center itself.
HspE7 is used as a therapeutic vaccine. The drug is a fusion protein linking together a heat shock protein, which should stimulate the immune system, and the HPV-16 E7 protein. (Although the E7 proteins from HPV-16, -11, and -6 are not identical, scientists hypothesize that they are similar enough to induce an anti-HPV immune response in RRP-affected individuals.) In an open-label multicenter trial, Dr. Derkay and colleagues treated 27 pediatric RRP patients with HspE7. Following an initial surgery to remove the papillomas, each patient received three subcutaneous injections of the fusion protein over three months. The primary endpoint of the trial was to determine whether treatment increased the interval between surgeries after the three-month treatment period as compared with the four surgeries prior to HspE7 treatment. The mean increase in duration between surgeries for all patients was 93% following therapy, suggesting that the agent was active in RRP.
While setting up for a prospective randomized controlled trial, the company that initially produced HspE7 and supported the open-label trial ran out of funds. Fortunately, the company was recently purchased and the new owners, Nventa, are working to start trials where the former company left off, although no launch date for the larger trial has been announced.
As demonstrated by the HspE7 and celecoxib trial delays, one of the biggest challenges facing RRP researchers is obtaining funding for work on a rare disease. It is an orphan disease, said Dr. Wiatrak. It is extremely difficult to get funding for large trials. Additionally, because the disease is rare, recruiting an adequate number of patients demands that studies be run at multiple institutions, which increases the cost of a trial. The problem with papillomas is that you can’t do a study, a good prospective trial, at one institution. There are just not enough patients. There may not be enough patients in the entire country. We have looked at the possibility of doing international studies to have enough patients to accrue into the study to have worthwhile data, he said.
The Big Hope: HPV Vaccine
Experts agree that the most important weapon in the fight against RRP is likely to be the newly approved vaccine that protects against HPV infection. (For more about HPV vaccines, see the editorial on page 3.) Dr. Derkay compares the potential impact of this vaccine to the dramatic drop in acute epiglottitis following the introduction of the haemophilus influenzae type B (HiB) vaccine. When I was a resident in the 1980s, one of the most common ENT emergencies was epiglottitis resulting in acute airway distress, with one or two cases each week in big medical centers, said Dr. Derkay. The introduction of vaccine virtually wiped it out. Residents in my program have not seen a case of this.
However, the vaccine approach is not without challenges. Both the Merck vaccine, Gardasil, which has been approved by the FDA, and the GlaxoSmithKline vaccine, which is still in clinical trials, appear to block HPV infection. Yet only Gardasil is intended to protect against the HPV types that cause RRP. Gardasil is a quadrivalent vaccine designed to protect against infection of HPV-16 and -18, which are associated with cervical cancer, as well as against HPV-6 and -11. By contrast, the GlaxoSmithKline vaccine protects only against the cancer-associated types.
Therefore, in addition to the challenges that come with any vaccine, such as making sure the people who need it get it, otolaryngologists have another task in front of them: making sure that the most widely used vaccine is the right one.
Otolaryngologists should be very vocal about the use of the HPV vaccine and cast as wide a net as possible in terms of who should be vaccinated, and in terms of including -6 and -11 in the vaccine, said Dr. Wiatrak. I think if the society speaks as one voice maybe we will be heard, and the vaccine that will be used widely will be the one that protects against all four viral types.
©2006 The Triological Society