Recurrent Respiratory Papillomatosis
Recurrent Respiratory Papillomatosis
National Organization for Rare Disorders, Inc.
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Recurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the development of small, wart-like growths (papillomas) in the respiratory tract. The respiratory tract is the system of organs within the body that allows individuals to breathe. The respiratory tract includes the nose, mouth, throat (pharynx), voice box (larynx), windpipe (trachea), various airway passages (bronchi), and lungs. Papillomas can develop anywhere along the respiratory tract, but most often affect the larynx and the vocal cords (laryngeal papillomatosis). Less often, the disorder affects the area within the mouth (oral cavity), trachea and bronchi. Only in rare cases do these growths spread to affect the lungs. Papillomas are noncancerous (benign), but in extremely rare cases can undergo cancerous (malignant) transformation. Although benign, papillomas can cause severe, even life-threatening airway obstruction and respiratory complications. In RRP, papillomas have a tendency grow back after they have been removed. RRP can affect children or adults and is caused by infection with human papillomavirus (HPV), although exposure to the virus alone is insufficient to cause the disease.
RRP is generally broken down into two subtypes – the juvenile-onset form and the adult-onset form. Juvenile cases develop before the age of 12 and are generally more aggressive and recurring. Children tend to need surgical treatment more often than adults. The disorder tends to improve in late childhood. Although aggressive disease is more common in children, adults can still potentially develop an aggressive form of the disorder.
The specific symptoms, course of the disease, and severity of RRP can vary greatly from one person to another. In some cases, the disease may resolve without treatment (spontaneous remissions) or it may remain stable requiring only periodic intervention (e.g. only a few surgeries during their lifetime). In other cases, the disease may be aggressive requiring frequent medical intervention and potentially more than 100 surgeries during a person's lifetime.
The most common presenting symptom of RRP is hoarseness. Hoarseness may become progressively worse and the voice of an affected individual may be weak or sound low in pitch or strained. The severity of voice problems can vary from one person to another due, in part, to the size and specific locations of papillomas. Affected individuals may develop labored, noisy breathing (stridor) due to obstruction of the airway. Initially, stridor may occur when breathing in (inspiratory stridor), but eventually occurs both when breathing in and out (biphasic stridor). Some individuals may exhibit difficulty speaking (dysphonia) or lose their voice entirely (aphonia). Affected infants may also have a weak cry, episodes of choking and fail to grow and gain weight at the expected rate (failure to thrive).
Additional symptoms that can develop include a chronic cough, difficulty swallowing (dysphagia), shortness of breath or difficulty breathing (dyspnea), the sensation of a foreign body in the throat, and choking episodes.
Left untreated, papillomas can eventually compromise the airways, resulting in life-threatening breathing difficulties (acute respiratory distress). If RRP spreads to the lungs, affected individuals can potentially experience recurrent pneumonia, chronic lung disease (bronchiectasis) and, ultimately, progressive pulmonary failure. In extremely rare cases (i.e. less than 1% of cases), papillomas can become cancerous (malignant transformation) developing into squamous cell carcinoma.
Recurrent respiratory papillomatosis is caused by the human papillomavirus (HPV). This virus is common in human beings with some studies estimating as many as 75%-80% of men and women will be affected by HPV at some point during their lives. HPV is passed through genital contact, most often during sex. Most individuals who are infected with HPV never develop any symptoms. There are more than 150 different subtypes of HPV and approximately 40 of these subtypes can affect the genital tract. Two specific subtypes, HPV 6 and HPV 11, account for more than 90% of cases of RRP. These two subtypes are the same HPV subtypes most often identified in genital warts (anogenital condyloma). HPV subtypes 16 and 18 account for most of the remaining cases. Together, these four subtypes are responsible for about 70% of cases of cervical cancer.
In children, the most likely cause of the transmission of HPV is passage from an affected mother to the child during labor as the child passes through the birth canal. However, this may not account for all cases of juvenile onset RPP and other mechanisms for HPV infection may exist. Some cases appear to have developed before birth (in utero).
Most children born to women with HPV do not develop RRP. In addition, many individuals with HPV in the tissues of the respiratory tract never develop papillomas. This suggests that additional factors, such as immunologic or genetic ones, are necessary for the development of RRP in individuals with HPV. Other factors such as timing, length and volume of exposure to the HPV may play a role.
Certain risk factors have been identified for the development of RRP. Risk factors are variables that are associated with an increased risk of disease or infection. Three risk factors for juvenile-onset recurrent respiratory papillomatosis are firstborn child, vaginal delivery, and the mother being under 20 years of age. If the mother has active genital warts, the risk of passing on HPV is approximately 1 in 250-400. These risk factors do not apply to adult-onset recurrent respiratory papillomatosis.
In adults, the mode of transmission is less clear. Some cases may represent infection during infancy as described above, but that remains latent until being triggered for unknown reasons in adulthood. Some circumstantial evidence suggests that RRP can develop after HPV is transmitted through oral sexual contact.
Adult-onset recurrent respiratory papillomatosis may be worsened by tobacco exposure, gastroesophageal reflux, or radiation therapy.
The juvenile form of recurrent respiratory papillomatosis affects males and females in equal numbers. The adult form affects males slightly more often than females. In the United States, the incidence of RRP is estimated to be approximately 2 per 100,000 adults and 4 per 100,000 children. There are approximately 1,000 new pediatric cases in the United States each year. In children, the disorder is most often diagnosed between the ages of 2-4. In adults, the disorder occurs most often in the third or fourth decade.
A variety of conditions can produce signs and symptoms that are similar to those seen in RRP. Such conditions include asthma, allergies, chronic bronchitis, croup, vocal nodules, and gastroesophageal reflux. Comparisons may be useful for a differential diagnosis.
A diagnosis of recurrent respiratory papillomatosis is based upon identification of characteristic symptoms (e.g. papillomas), a detailed patient history, a thorough clinical evaluation and specialized tests such as indirect or direct laryngoscopy. These procedures are performed by physicians who take care of disorders of the ear, nose and throat (otorhinolaryngologists or ENTs). Unfortunately, there is generally about one year delay in diagnosis from the onset of symptoms till a diagnosis of juvenile onset recurrent respiratory papillomatosis is made.
Clinical Testing and Workup
An indirect laryngoscopy involves holding a small mirror in the back of the throat. An ENT physician will reflect light off the mirror to illuminate the throat and detect the presence of papillomas. With advances in technology, this type of procedure is much less common than in the past.
Direct laryngoscopy involves inserting a thin, flexible lighted tube (endoscope) into the throat. The endoscope often has a tiny fiberoptic camera attached to the end and allows a physician to see deeper into the throat. In some cases, a rigid tube may be used under anesthesia in an operating room. Direct laryngoscopy also allows physicians to remove a small sample of tissue to study under a microscope (biopsy). A biopsy can confirm the diagnosis of RRP. A direct laryngoscope can also be used to remove the growths once a diagnosis of RRP is confirmed.
Chest x-rays can be used in cases where RRP is suspected of having spread to the lungs. A computed tomography (CT) scan of the chest, in which a computer and x-rays are used to create a film showing cross-sectional images of the lungs, can reveal the presence of papillomas. Pulmonary function tests may rarely be used to estimate the degree of airway obstruction.
In some cases, physicians may run tests to determine the specific subtype of HPV present (HPV typing). Preliminary research suggests that HPV subtyping can help predict the aggressive of RRP in an individual. For example, HPV-11 appears to be associated with more severe disease, usually requires more surgical intervention and is more likely to require a tracheostomy.
There is no cure for RPP. Treatment is directed toward removing papillomas, decreasing the spread of disease, creating safe and patent airway, preserving nearby anatomical structures, improving voice quality if necessary and increasing the time between surgical procedures. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, ear-nose-throat specialists that focus on children (pediatric otorhinolaryngologists), anesthesiologists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan a child's treatment.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as frequency of disease recurrences; specific location and spread of the disease; papilloma size; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
None of the various treatment options for RRP have proven consistently effective. Additionally, most treatment recommendations are based on case reports or small case series. Large scale clinical trials for treating RRP are required to determine the best therapeutic options, which ultimately may vary from one person to another.
The mainstay of treatment is surgical removal of papillomas. However, these growths often return necessitating more surgery. The recurrence of papillomas is unpredictable. Some individuals may require surgery every few weeks while others may only require surgery twice a year or only a few times during their life. Surgical techniques used to treat individuals with RRP include "cold" excision, microdebridement, various pulsed dye lasers, cryotherapy, or carbon dioxide laser. Cold excision, sometimes referred to as the "cold steel," is the use of normal, unheated surgical equipment to remove papillomas. Cold excision may be beneficial for the initial removal (debulking) of papillomas and for papillomas located in certain areas. Microdebridement is an increasing popular procedure in which suction is applied to affected tissue which is then cut away (debrided) by miniature shavers. Pulsed dye lasers use various light frequencies focused into a single beam to destroy the blood vessels that supply the papillomas. Cryotherapy is the use of extreme cold to freeze and destroy papillomas. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the papilloma. CO2 laser ablation generates a laser beam by passing electricity through a mixture of several different gases including carbon dioxide. The laser is used to directly destroy papillomas.
In severe cases where tumor growth is aggressive, an affected individual may need a tracheostomy to keep the breathing airways open. A tracheostomy involves surgically inserting a tube into the windpipe (trachea). A tracheostomy is used only as a method of last resort because the procedure may allow for spread of the disease further into the respiratory tract.
After surgery, some individuals may receive certain medications designed to slow the regrowth of papillomas and increase the time between surgeries (adjuvant therapy). Medications that have been used include antivirals such as acyclovir, ribavirin or cidofovir (see below), interferon, and indole 3-carbinol (I3-C). Interferon is a drug that is a synthetic form of certain proteins produced by the immune system. I3-C is an anticancer compound that is found in cruciferous vegetables such as cabbage, cauliflower, and broccoli. Adjuvant therapy is usually recommended based upon specific indications: undergoing more than four surgeries in one year, rapid regrowth of papillomas causing airway compromise, or spread of the disease down the throat and into the lungs.
Some physicians recommend that affected individuals take medications for gastroesophageal reflux (GERD) as this condition has been known to worsen RRP.
A newer antiviral medication that has been used to treat individuals with recurrent respiratory papillomatosis is cidofovir. This drug is an adjuvant therapy that is injected directly into the lesions (intralesional) or inhaled. Initial studies of cidofovir have demonstrated that the drug is active against RRP and led to a partial response in some patients or complete remission in others. In some cases, cidofovir increased the time between surgeries. However, cidofovir has been associated with several side effects including toxicity to the kidneys (nephrotoxicity) and a potential for malignant transformation of the papillomas. The exact role and specific cases where cidofovir will be most beneficial has not been established. More research is necessary to determine the long-term safety and effectiveness of cidofovir for the treatment of RRP.
Additional drugs are being studied as potential adjuvant therapies for individuals with RRP. Such drugs include the monoclonal antibody bevacizumab and celecoxib. Monoclonal antibodies are manmade (synthetic) versions of an immune system protein. Bevacizumab, especially when combined with use of a pulse dye laser, prevents tumors from growing new blood vessels, which are required to feed the tumor nutrients. Celecoxib may work through its affect on estrogen pathways important to papilloma growth. More research is necessary to determine the long-term safety and effectiveness of such therapies for individuals with RRP.
Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light has been used to treat some individuals with RRP, especially those with large papillomas. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A special wavelength of light is used to activate the drug which binds with oxygen creating a chemical that destroys the affected cells.
Two HPV vaccines (Gardasil and Cervarix) have been developed and approved by the Food and Drug Administration (FDA) to protect women from cervical cancer, which is also associated with HPV infection with the same subtypes that cause RRP. Gardasil is a vaccine against HPV types 6, 11, 16 and 18 (remember, RRP is caused by types 6 and 11), while Cervarix is a vaccine against only HPV types 16 and 18. Researchers hope that the use of the Gardasil vaccine in boys and girls before they are exposed to the virus will lessen the spread of HPV in the general population. Theoretically, this would also lower the incidence of RRP. Unfortunately, this type of vaccine does not make existing infections go away. The exact role of HPV vaccines in regard to RRP has not yet been established.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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