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glossary2Key Glossary Terms

Recurrent Respiratory Papillomatosis (RRP)
Wart-like growths in the airway passages caused by the human papilloma virus; these growths usually form on the vocal folds, causing a voice disorder

Human Papilloma Virus (HPV)
The virus that causes recurrent respiratory papillomatosis; HPV also causes genital warts

Wart-like growth caused by the human papilloma virus (HPV)
How is recurrent respiratory papillomatosis treated?
Currently, there is no known cure for RRP. However, treatment can successfully address the condition’s effects on voice and/or breathing. More importantly, new treatment strategies are under investigation, holding promise that improved therapies will be available in the future.
Since the disease varies from patient to patient, treatment strategies are designed on a case-to-case basis.
Surgical Management – Aimed at Reducing Bulk of Viral Growths
Microsurgical excision under general anesthesia is the accepted method of controlling RRP. Although surgery is necessary to prevent airway blockage and may improve voice quality, it does not stop the growths from returning. In fact, some otolaryngologists have speculated that surgery might in some instances exacerbate regrowth by activating latent virus in adjacent normal tissue.
Surgical treatment: There are a number of surgical techniques in use by RRP surgeons.
A CO2 laser is considered especially efficacious for glottic and supraglottic papillomas.
A microdebrider and “cold steel” are surgical instruments commonly used in removal of papillomas.
Pulse dye laser therapy is being evaluated as treatment for RRP. Pulse dye laser therapy eliminates the blood supply to the papillomas, causing them to “die off.” Long-term follow-up of patients receiving this treatment is necessary to determine whether recurrence is a problem, as it is with other surgical techniques.
Other new technologies that are becoming available, with limited data as to long-term success, include flash pump dye and argon plasma coagulation.
Key InformationKey Information
Surgical Skill Is Key: Regardless of surgical approach, the surgeon must be highly skilled in using the surgical tools of choice.

Preservation of Normal Tissue Is Critical: There is a danger in being “too aggressive” in removing papilloma from the vocal folds, since excessive scarring and damage to normal tissue may result.

Task Force Guidelines on RRP state, “Since there is currently no therapeutic regimen that reliably eradicates the human papilloma virus or HPV, when there is a question about whether papilloma in an area needs to be removed, it is prudent to accept some residual papilloma rather than risk damage to normal tissue and producing excessive scarring.” Scarring results in a permanent voice disorder.
Limitations of Surgical Removal
Even with the removal of all clinically evident papillomas, latent virus may remain in adjacent tissue which may explain why RRP recurs. Therefore, the aim of therapy in cases of extensive RRP should be to:
Reduce the papilloma burden
Decrease the spread of disease
Create a safe and patent airway
Improve voice quality
Increase the time interval between surgical procedures
Removal of Papillomas in Stages
When both sides of the vocal folds have papillomas that need to be removed, surgery is usually performed in two stages. This prevents the contact of two raw surfaces of the vocal folds in the front region (anterior commissure), where the vocal folds normally meet in the middle and vibrate during sound production.
Surgery typically involves the partial removal of the papillomas (usually only one side and as much of the other side as possible, sparing the anterior commissure). The second surgery follows a month (or more) later for the complete removal of the growths on the other side.
Medical Treatment: The goal of current anti-papilloma medical therapies is to reduce or eliminate the need for future surgeries. A variety of medical therapies for RRP exist. Medical therapies can be classified according to the drug’s mechanism of action.
Hormonal: Alters the tissue environment, making it unfavorable to RRP growth
Immunotherapeutic: Boosts the body’s immune system to fight against the viral infection
Anti-viral: Counters the viral infection
Anti-tumor: Eliminates the cells that are rapidly growing and forming the viral tumors
Currently, no single treatment has been found to be generally effective in controlling RRP. The following therapies have proven to be effective in treating RRP. Patients should consult with their physician as to best drug treatment and possible side effects of drug treatment.
Hormonal: e.g., Indole-3-carbinol/Diindolylmethane (I3C/DIM)
What it is: I3C is a phytochemical that is found in cruciferous vegetables (i.e., cabbage, broccoli, cauliflower, etc.); DIM is the major active by-product of I3C when it is broken down by stomach acid.
Mechanism of action: I3C induces an estrogen metabolite balance, which discourages papilloma virus growth, since RRP is considered by physician-scientists to be hormonally sensitive.
Clinical observations: Preliminary results show that severity of RRP is reduced in about half to two-thirds of patients treated.
How given: I3C is given by mouth once or twice a day.
Side effects: I3C has not been found to have any side effects or toxicity.

Modulation of Immune System: e.g., Interferon alpha (IFN-a)
What it is: Interferon is a substance produced by the body as part of the inflammatory response to tissue injury or infection. It is one of the “cytokines.” There are several types of interferon produced by the body, each with its own specific properties. One type is interferon alpha, or IFN-a.
Mechanism of action: The exact mechanism by which interferon alpha affects RRP is not well understood. It is believed that IFN-a modulates the patient’s immune response, which then results in inhibition of the virus causing RRP.
Clinical observations: IFN-a has been used to treat selected cases of aggressive RRP for about two decades and has demonstrated some effectiveness in ameliorating RRP by slowing down the recurrence rate.
How given: IFN is given as an injection into the muscle weekly or more often.
Side effects: The most common side effects are flu-like symptoms, especially low-grade fevers, mild lethargy, fatigue, and headache. Long-term use of IFN has been linked to neurologic disorders and reduced growth rate in children. Occasionally, patients may experience an elevated liver function, which would require at least a temporary discontinuation of the therapy.
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IFN is only effective on RRP when it is continued. Often, after IFN is stopped, RRP returns and may be even more aggressive.

Anti-Viral Drug: e.g., Cidofovir
What it is: Cidofovir is a fairly new drug exhibiting a broad spectrum of anti-viral activity.
Mechanism of action: It is absorbed by papilloma cells, which then convert it into an agent that kills the cells that have HPV. Cells that do not have HPV should not absorb it.
Clinical observations: The first pilot study to treat RRP with Cidofovir was done in Belgium involving severe adult RRP patients in 1995. The results were very encouraging. Another pilot study that used Cidofovir to treat 10 pediatric patients with severe RRP resulted in a dramatic reduction in disease severity for most of the patients. Many doctors now use Cidofovir on a case-by-case basis to treat RRP.
How given: Cidofovir is usually injected directly into the RRP lesions (or location of the lesions after removal), which should avoid most of the toxicity (kidney damage) associated with this drug.
Side effects: The only side effect that has been commonly associated with Cidofovir has been some irritation to the laryngeal tissue. However, since the drug is still relatively new, extended patient follow-up will be necessary to determine if any longer term side effects are associated with Cidofovir.
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Cancer-link in Laboratory Animals
Long-term follow-up is crucial since this drug has been linked to cancer in laboratory animals.
Treatments That Target Tumor Cells: e.g., Photodynamic Therapy (PDT)
What it is: Photodynamic therapy is based on the targeted killing of cells through the activation of a photosensitizing dye. Activation results in chemical alteration of said dye converting it to a form that can kills cells which contain the activated dye.
The dye is given into the bloodstream and preferentially taken up by cells that are actively dividing, such as tumor cells (including papilloma cells).
Cells are then killed when the dye is activated by applying a light of a particular wavelength.
Killing of cells can be targeted to the papillomas (or any tumor) by directing the photoactivating light source to the papillomas on the vocal folds (the usual location of respiratory papillomatosis).
Mechanism of action: In some patients treated with photodynamic therapy, the growth rate of the papillomas has slowed, but elimination of HPV has not occurred.
Clinical observations: Photodynamic therapy has been tested in experimental trials for more than a decade. Results have varied.
Results using a dye called Photofrin (a porphyrin derivative) were not particularly encouraging.
A new agent, m-tetra(hydroxyphenyl)-chlorin (or m-THPC) has shown more encouraging early results, especially for laryngeal papillomas.
How given: The photosensitizing dyes are injected into the bloodstream and then absorbed by the cells of the body.
Side effects: Photosensitivity is the major side effect.
Photofrin has a long “washout” period for the dye, thus leaving patients extremely photosensitive for up to two months.
The new photodynamic therapy agent, m-THPC, has a quicker washout period; photosensitivity is only a problem for two to three weeks.
Unknown Mechanism: Mumps Vaccine
Clinical observations: The mumps vaccine appears to be responsible for improvement in a number of RRP patients. The reason for why it may be effective against HPV is not understood at this time.
How given: It is administered via intralesional injections.
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To date, the mumps vaccine has only been used in an uncontrolled setting and has not been formally reviewed regarding its effect on RRP.
What are other considerations in the management of patients with RRP?
Awareness of Course of Disease Important
A frank and open discussion between the physician and the patient and his/her family regarding the nature of the disease and the proposed treatment approach is important for the long-term management of this chronic disease. Surgical risks and outcomes, including the risk of vocal fold scarring, airway edema (swelling), etc., should be discussed in detail.
Helpful Role of Speech Therapy
Speech therapy may be helpful in some cases. Vocal function exercises (i.e., gentle stretching) may reduce stiffness. Establishing a balanced use of respiration, phonation (e.g., loudness and pitch), and resonation may be appropriate. (For more information, see Voice Therapy.)
Avoiding Factors That Worsen Symptoms of RRP
Certain factors can worsen the symptoms of RRP.
Swelling and inflammation in areas with papillomas can exacerbate voice complaints or breathing difficulty. Common culprits are:
backflow of stomach fluids to the voice box (as occurs in reflux laryngitis) (For more information, see Reflux Laryngitis.)
other agents such as tobacco smoke, drying agents, or other mucosal irritants
Any agent that results in a decrease in the body’s ability to fight infection – even if transient – can worsen RRP, since RRP is caused by a viral infection. A common culprit is:
medications containing steroids, which tend to compromise immune function and may allow more aggressive growth of the papillom
What if I do not have treatment for RRP?
Ignoring RRP symptoms and refusing treatment could result in airway blockage, which can lead to breathing difficulties.
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Any and all airway problems require immediate attention.
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Patient education material presented here does not substitute for medical consultation or examination, nor is this material intended to provide advice on the medical treatment appropriate to any specific circumstances.
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