Recurrent Respiratory Papillomatosis 

Updated: Dec 14, 2020
Author: Eloise M Harman, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 



Recurrent respiratory papillomatosis (RRP) is a disease caused by the human papillomavirus (HPV). See Human Papillomavirus and Medscape’s HPV and Cervical Cancer Resource Center for more information on HPV. Warty growths in the upper airway may cause significant airway obstruction or voice change.[1] RRP has a bimodal age distribution and manifests most commonly in children younger than 5 years (juvenile-onset RRP [JORRP]) or in persons in the fourth decade of life (adult-onset RRP [AORRP]).

Respiratory papillomatosis is shown in the image below.

A 48-year-old woman presents with inspiratory stri A 48-year-old woman presents with inspiratory stridor, dyspnea, and hoarseness. On direct laryngoscopy, extensive respiratory papillomatosis were diagnosed as the cause of her symptoms. Courtesy of Sat Sharma, MD, and L. Garber, MD.

JORRP is more common and more severe than AORRP. JORRP is caused by exposure to HPV during the peripartum period. The mode of infection in adults is still not known, but sexual transmission is likely.

Treatment usually involves repeated debulking of the warty growths by angiolytic laser or microdebridement coupled with intralesional cidofovir therapy in patients with moderate or severe disease. Interferon treatment appears to slow the rate of growth without curing the disease. Although some antiviral agents (eg, cidofovir) also may slow the rate of regrowth of lesions, they are not curative. Eventually, some patients may enter remission. In 3-5% of patients, respiratory papillomas may undergo malignant degeneration to squamous cell carcinoma, and the prognosis for patients with these cancers is quite poor. See Squamous Cell Carcinoma for more information on this topic.


Human papillomavirus (HPV), the virus associated with cutaneous warts, genital condyloma, and cervical cancer, causes recurrent respiratory papillomatosis (RRP). While more than 20 types of HPV can cause genital warts, only two of these, HPV-6 and HPV-11, cause the vast majority of cases of RRP. The disease associated with HPV-11 is more severe; thus, in children with HPV-11–associated disease, as many as 70% may require tracheostomy, compared with less than 20% of children infected with HPV-6 (see Human Papillomavirus).

The cause of JORRP is peripartum transmission of the virus from an infected mother. Vaginal delivery is a risk factor, but cesarean delivery is not completely protective.[2] The classic triad for increased risk of JORRP includes being firstborn, vaginal delivery, and having a mother younger than 20 years.[3, 4] Lower socioeconomic status is also a risk factor. Suspect sexual abuse in children older than 5 years who acquire RRP. The mode of transmission of the virus in adults with RRP is unknown, but sexual transmission is probable as risk factors in adults include more lifetime sexual partners and increased frequency of oral sex as compared with controls.[5]

Papillomas may develop anywhere in the respiratory tract, from the nose to the lung; however, >95% of cases involve the larynx. The sites of respiratory system involvement have been described more completely for JORRP; 52% of children have only laryngeal involvement. The trachea is the next most commonly involved site. However, 31.8% of children had papillomas in areas outside of the trachea and larynx (eg, oropharynx, nasopharynx, mouth, bronchi, lung parenchyma).


Human papillomavirus (HPV) causes recurrent respiratory papillomatosis (RRP). HPV-6 and HPV-11 are the most common types associated with RRP, but, rarely, affected tissues contain HPV-16 and HPV-18. HPV is the most common sexually transmitted disease in the United States; as many as 75% of women have genital HPV at some time in their lives. Thirty to 60% of mothers of children affected with JORRP have genital HPV, compared with 5% of mothers of unaffected children. A study using questionnaires of affected children or their parents (identified through the RRP Foundation) verified that the 3 risk factors for JORRP are (1) firstborn child, (2) vaginal delivery, and (3) mother younger than 20 years. The risk factors for JORRP do not apply to adult-onset cases. This suggests that adult disease does not represent reactivation of latent disease. The mode of transmission of HPV in AORRP is not known. Sexual transmission is likely.


United States data

Prior to the introduction of a quadrivalent vaccine for prevention of genital HPV in 2006, the estimated incidence of recurrent respiratory papillomatosis (RRP)in the United States was 4 per 100,000 in juvenile‐onset RRP (JORRP) and 2 per 100,000 in adult–onset RRP (AORRP).[6] RRP is declining in incidence; however it remains the most common benign laryngeal neoplasm in children.[7, 8] Roughly 15,000 surgical procedures for the condition are performed each year, at an estimated cost of $100 million.[9]

International data

A study by Donne et al estimated the prevalence of patients with recurrent respiratory papillomatosis in the United Kingdom to be 1.42 per 100,000.[10]

Australia introduced a nationwide immunization effort in 2007 which provided the HPV vaccine to at least half of all females aged 12-26.[11] The Australian National Immunisation Program began providing immunizations to all students aged 12-13 years (girls in 2007 and boys in 2013) through a school-based initiative. As a result, the incidence of HPV in women 18 to 24 dropped from 22.7% in 2005 to 1.1% in 2015.[12] The incidence of JORRP declined to 0.022 per 100,000 in 2016.[11]

Race-, sex-, and age-related demographics.

The National Registry for Juvenile-Onset Recurrent Respiratory Papillomatosis,[13] a registry including 603 children from around the United States, reports that 63% of the children were white, 28.4% were black, 0.8% were Asian, 0.8% were Native American, and 7% were unknown. Ethnicity was reported for 367 (60.9%) of the patients; 57 (15.5%) were identified as Hispanic and 310 (84.5%) as white or black non-Hispanic.[13]

JORRP affects males and females in equal numbers, whereas AORRP is more common in males.

The mean age at diagnosis of JORRP is 3.1 years.[13] The adult form usually manifests in the third or fourth decade of life but may rarely manifest in patients older than 60 years.[14]


Children with recurrent respiratory papillomatosis (RRP) frequently experience remission after several years, which may be related to puberty. By this time, the patient may have undergone more than 20 surgical procedures. Younger patients with HPV-11 etiology experience a worse clinical course. Disease in adults tends to be milder; however, older patients with an HPV-6 etiology experience a worse clinical course.[15]

Because the disease is uncommon and requires direct laryngoscopy for diagnosis, children usually have symptoms for a year before a physician makes the diagnosis. The morbidity of this disease has been studied more completely for JORRP, in which the average number of surgical procedures required is 4.4 per child per year and the average number of procedures per child's lifetime is more than 20.[16] This exacts a tremendous financial cost and severely affects quality of life, including the ability to attend school and work. Ten to 15% of children with JORRP ultimately require tracheostomy, usually when younger than 2 years. Many eventually tolerate decannulation.

The need for tracheostomy in adults appears to be less common than in children, but repeated surgical procedures are the rule, and procedures may be required as often as every few weeks.

Malignant degeneration of papillomatous lesions to squamous cell carcinoma occurs in 3-5% of patients with RRP. The prognosis for squamous cell carcinoma in the context of RRP is grave. Cure is uncommon.


Complications of this disease include airway obstruction and malignant transformation.

With regard to tracheostomy, older literature suggests that in RRP patients, it may promote distal airway spread (ie, distal to the larynx) of papillomas. A more recent review suggests that patients who require tracheostomy tend to present at a younger age with more severe disease that already involves the more distal airway. Distal spread after a tracheostomy most commonly involves the tracheostomy site. After laser and antiviral treatment over a period of years, the tracheostomy often can be removed successfully; therefore, tracheostomy is a reasonable option if required due to significant airway obstruction.[17]  The need for tracheostomy probably is a marker of more severe disease rather than an independent cause of distal spread.

Malignant degeneration of papillomatous lesions to squamous cell carcinoma occurs in 3-5% of patients with RRP. Distal airway spread of papillomas often is a forewarning of malignant degeneration. The site of malignancy in JORRP usually is the bronchial or pulmonary parenchyma, whereas the larynx is the usual site in AORRP. Malignant degeneration is more common with disease caused by HPV-11 and HPV-16. Cigarette smoking, bleomycin therapy, and radiation treatment of involved areas also increase the risk of malignant degeneration in RRP.

Patient Education

Recurrent respiratory papillomatosis (RRP) usually is a pediatric disease. The main problem is recurrent airway obstruction. Teach parents to recognize potential warning signs, including a weak cry, hoarseness, stridor, wheezing, cyanosis, and decreased exercise tolerance. Airway obstruction may recur as soon as 2-4 weeks after laser procedures, and recognizing its development before critical, life-threatening obstruction occurs is important.

RRP can be devastating to individuals and families. Children with JORRP may require repeated surgery and can be ill for a long time. The RRP Foundation may provide group support for individuals and families.

For patient education resources, see the patient education article Bronchoscopy.



History and Physical Examination


Recurrent respiratory papillomatosis (RRP)is a rare disease, and adult patients may have symptoms for months or longer before the disease is recognized. Because the larynx is the most frequently affected site for both juvenile‐onset recurrent respiratory papillomatosis (JO‐RRP) and adult–onset recurrent respiratory papillomatosis (AO‐RRP), symptoms of upper airway obstruction predominate. Upper airway obstruction may be life threatening and may be the presenting symptom. Hoarseness is the most common presenting symptom. Other symptoms include the following:

  • Voice change

  • Choking episodes

  • Foreign body sensation in the throat

  • Cough

  • Dyspnea

  • Inspiratory wheeze

  • Stridor

Physical examination

Physical examination findings often are nonspecific. Voice change may be noted. Inspiratory wheezing, stridor, or both may develop over the trachea or the upper thorax.

Patients with JORRP commonly present with a weak cry, episodes of choking, hoarseness, or failure to thrive. Patients with AORRP present with hoarseness, choking spells, voice change, dyspnea, or a foreign body sensation in the throat.



Diagnostic Considerations

Due to its nonspecific clinical manifestations, recurrent respiratory papillomatosis (RRP) is easily mistaken for asthma, acute laryngitis, upper respiratory infection, or bronchitis.[18]

Other conditions to consider in the diagnosis of RRP include the following:

  • Benign lung, laryngeal, or tracheal tumors

  • Laryngeal infection

  • Malignant laryngeal or tracheal tumors

  • Squamous cell lung cancer

Differential Diagnoses



Laboratory Studies

Once the physician diagnoses recurrent respiratory papillomatosis (RRP) via laryngoscopy or bronchoscopy, typing of the virus may be helpful for determining prognosis. This may be accomplished by polymerase chain reaction on fresh tissue. As noted, HPV-11 is associated with more severe disease and, possibly, with a greater risk of malignant transformation.

Imaging Studies

Chest radiographs rarely may reveal an intratracheal density in recurrent respiratory papillomatosis. This may be observed best on the lateral view. In the uncommon instance of distal bronchial involvement, chest radiographs may reveal segmental or lobar atelectasis or postobstructive pneumonia. Nodules or cystic lesions on chest radiographs provide evidence of pulmonary parenchymal involvement.

CT scans of the upper airway may be helpful in revealing the tumorlike papillomatous growths on the larynx or in the trachea.

Other Tests

Pulmonary function studies may be helpful in suggesting the presence of upper airway obstruction in the workup of recurrent respiratory papillomatosis. The flow-volume loop may show the characteristic flattening of the inspiratory limb, suggesting variable extrathoracic upper airway obstruction or flattening of both the inspiratory and expiratory limbs if the upper airway obstruction is fixed.


Laryngoscopy or bronchoscopy findings provide confirmation of the diagnosis of recurrent respiratory papillomatosis (RRP). Confirmation in patients presenting with hoarseness or voice change requires visualization of the vocal cords. Because laryngeal involvement occurs in more than 95% of patients, direct laryngoscopy reveals the characteristic warty growths. Rarely, the trachea is involved without laryngeal lesions, and bronchoscopy may be required for diagnosis. These procedures reveal the characteristic cauliflowerlike warty growths.

A 48-year-old woman presents with inspiratory stri A 48-year-old woman presents with inspiratory stridor, dyspnea, and hoarseness. On direct laryngoscopy, extensive respiratory papillomatosis were diagnosed as the cause of her symptoms. Courtesy of Sat Sharma, MD, and L. Garber, MD.
This adult patient was seen for hoarseness, with a history of several prior procedures for recurrent respiratory papillomatosis. A papillomatous lesion is seen along the left true vocal fold with associated reactive edema. On pathologic analysis, moderate squamous dysplasia was seen within the papilloma. Video courtesy of Vijay R Ramakrishnan, MD.

Obtaining a biopsy specimen of visualized lesions is essential for histologic confirmation of respiratory papillomatosis. Biopsy is necessary both for viral typing and for histologic examination to rule out malignant transformation. Atypical histologic features often are noted, sometimes making the diagnosis of malignant transformation difficult.

Histologic Findings

Under low power, the recurrent respiratory papillomatosis lesion has a papillary appearance. This results from the exophytic growth of keratinized squamous epithelium overlying a fibrovascular core. Koilocytes, vacuolated cells with clear cytoplasmic inclusions, are noted and are indicative of viral infection. Metaplasia and dysplasia occur in varying degrees.


A staging system for recurrent respiratory papillomatosis was published in 1998 and assigns a numerical score based on clinical and anatomic parameters.[19] The clinical parameters include of urgency of intervention, voice quality, and the presence and severity of stridor and respiratory distress. The anatomic score is based on the number of sites of disease and whether the lesion is surface, raised, or bulky. Elements of the staging system have been found to help predict the frequency of needed surgical intervention.[20]



Approach Considerations

There is no curative therapy for recurrent respiratory papillomatosis (RRP). The goals of therapy are to relieve airway obstruction, improve voice quality, and facilitate remission. The primary treatment involves repeated surgical debulking, usually by means of microdebridement, angiolytic laser, cryotherapy, or carbon dioxide laser. This may be followed by an injection of cidofovir into the resection site in patients with moderate-to-severe disease. Compared with microdebridement and laser procedures, surgical resection may be associated with a higher risk of complications (eg, tracheal stenosis). Tracheostomy may be needed if significant airway obstruction occurs. Six months of subcutaneous interferon therapy may be beneficial but there is controversial evidence regarding clinical efficacy.[21]

Medical Care


Because recurrent respiratory papillomatosis (RRP) is rare, large-scale trials of medical therapies have not been possible; however, several agents are available that appear to increase the intervals between need for resection. The use of intralesional cidofovir in moderate-to-severe disease has been a major advance in the management of RRP. It is indicated if surgical debulking is required 6 or more times per year or every 2-3 months, and its administration must be guided by knowledge of safe dosing limits.[22]

With the increased use of intralesional cidofovir and because of its adverse effects, treatment with interferon is now used infrequently as second-line therapy for patients with refractory severe disease.

Bevacizumab, a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor in vitro and in vivo, by preventing receptor activation. Based on the evidence that vascular endothelial growth factor is an important factor in the development of RRP, there have been reports of promising results achieved with bevacizumab.[23] This adjuvant therapy could increase the time interval between surgical procedures, with a simultaneous reduction in number of procedures required per year; improvements in voice quality may also be achieved.


A quadrivalent vaccine for prevention of genital human papillomavirus (HPV) infection was approved in 2006. This vaccine protects against HPV types 6, 11, 16, and 18 and has promise for decreasing the incidence of RRP.[24, 25] (See Epidemiology.)

Vaccine therapy for those already affected with HPV has been reported in the literature. A study by Hočevar-Boltežar and colleagues pointed out that vaccination with the quadrivalent HPV vaccine can favorably influence the course of RRP in patients with rapid growth of papillomas by significantly prolonging intervals between surgical procedures and reducing of the number of procedures needed in the majority of patients observed.[26]

Chirila et al concluded that the quadrivalent HPV vaccine was effective to diminish the recurrence rate of RRP in 85% of patients, although that study was retrospective and lacked a control group.[27]

Another retrospective chart review also assessed the effect of quadrivalent vaccine on the disease course of RRP. Analysis was conducted on 20 patients receiving the vaccine; intersurgical interval (ISI) before and after vaccination and the number of remissions (both partial and complete) were described. Complete or partial remission was achieved in 65% of patients; an ISI increase of 4.2 months was noted in males (95% CI: 1.6-6.7, P = 0.0048) while a nonsignificant ISI increase of 1.2 months was noted in females (95% CI: 3.1-5.4, P = 0.51).[28]

In a small retrospective observational study of the impact of the quadrivalent HPV vaccine on the immune status of patients with recurrent respiratory papillomatosis, Pian et al found that mean antibody reactivity against the associated HPV type rose from 1125 median fluorescence intensity (MFI) pre-vaccination to 4690 MFI post-vaccination (P <  0.001). In addition, the mean number of surgical interventions in a specific time frame after vaccination decreased with approximately a factor of 3.3.[29]

Although promising, these isolated positive experiences need to be validated by multicenter trials that might be able to ascertain the true benefits of vaccination as a treatment of RRP.

Surgical Care

Multiple resections are typical. Microdebridement of laryngeal lesions is often preferred to laser therapy in the treatment of recurrent respiratory papillomatosis (RRP). With anesthesia induction, take extreme care to maintain the already-compromised airway. The surgical team should be prepared for the possibility that emergency tracheostomy may be required. A survey of anesthesiologists regarding anesthesia techniques for patients undergoing laser procedures for RRP indicated the following preferences:

  • Laser-safe endotracheal tube (46%)

  • Jet ventilation (26%)

  • Apneic technique (16%)

  • Spontaneous ventilation (12%)

  • Preferred anesthetic agents - Halothane and propofol

Physicians may combine surgery with an injection of the surgical bed with medication that may slow regrowth. Cidofovir is effective in a significant proportion of patients and has replaced intralesional interferon.

The carbon dioxide laser previously was the preferred method for resection of papillomas because it affords good hemostasis and minimizes potential thermal injury of surrounding healthy tissues. The use of microdebridement using angled oscillating blades that incorporate suction and irrigation or the use of pulsed dye laser is now the preferred resection method at many centers. These offer the advantage of shorter operative times, potential for outpatient surgery, decreased risk to personnel, and avoidance of the risk of airway burns. These methods may also decrease recurrence rates. Repeat evaluation of the airway in newly diagnosed RRP may be required as frequently as every 2-4 weeks.

Photodynamic therapy, in small trials, has been shown to slow the rate of papilloma growth. Hematoporphyrins are taken up selectively by neoplastic cells and are used as photosensitizing agents for subsequent laser therapy. Dihematoporphyrin ether (DHE) usually is administered 2-3 days before surgery. Delivery of argon laser light to the affected area via laryngoscope or bronchoscope activates the drug.

The virus may be aerosolized during surgical procedures; therefore, staff should take particular care to wear goggles and a particulate barrier facemask or shield during procedures.


In 2006, a vaccine was released that protects against human papillomavirus (HPV) types 6, 11 (associated with venereal warts), 16, and 18 (associated with cervical cancer). Administration to girls before they become sexually active is expected to be highly effective in preventing HPV infection and resultant venereal warts and would be expected to lead to a future reduction in JORRP incidence.[24]

Two additional strategies have been proposed to have more direct effects on JORRP incidence[30] :

  • Vaccination of neonates born to women with clinically diagnosed genital warts

  • Vaccination of pregnant women infected with HPV 6/11, to boost maternal titers of neutralizing antibody and increase maternal transfer of antibody to the newborn.

The role of cesarean delivery in the prevention of JORRP is controversial because the disease is quite uncommon, despite the frequency of genital HPV infection. Consider cesarean delivery in a young woman with visible condylomata who is giving birth to her first child.[2]



Medication Summary

No drug can cure recurrent respiratory papillomatosis (RRP). Vaccine therapy with a quadrivalent HPV vaccine has demonstrated promising results in several studies, as well as in the nationwide initiative in Australia. Several drugs appear to slow the growth of papillomas and increase the interval between necessary surgical debulking procedures. Intralesional cidofovir is frequently effective; however, because optimal dosing and long-term effects are not known, it should probably be reserved for persons with moderate-to-severe disease.[18] Dietary supplementation with oral indole-3-carbinol is often effective. Because of its adverse effects, treatment with interferon is now used infrequently as second-line therapy for patients with refractory severe disease. Control of gastroesophageal reflux is beneficial in children with RRP.

Dietary Supplements

Class Summary

Certain types of vegetable extracts appear to improve symptoms.

Indole 3-carbinol (I3-C)

I3-C or its derivative, diindolylmethane (Indolplex), may be the active substance in cruciferous vegetables. I3-C changes the ratio of estradiol metabolites to the 2-hydroxyl derivative; this slows papilloma growth. Anecdotal experience demonstrates improvement in the disease with consumption of cabbage juice or a diet high in cruciferous vegetables (eg, cabbage, cauliflower, broccoli, Brussels sprouts). In clinical trials, one third of patients had a complete response and one third had a partial response to I3-C.

Antiviral Agents

Class Summary

Nucleoside analogs are phosphorylated initially by viral thymidine kinase to eventually form a nucleoside triphosphate and inhibit viral replication.

Cidofovir (Forvade, Vistide)

Currently approved for treatment of CMV retinitis in AIDS. First member of a group of antivirals known as acyclic phosphonate nucleotide analogs. In infected cells, nucleotide analogs such as cidofovir inhibit viral DNA polymerase, which is responsible for replication of new viral RNA and DNA. Because HPV is the causal agent for RRP, eradication of the virus offers the potential for cure. Small trials have reported that intralesional use is beneficial. In a prospective trial of 16 RRP patients, 77% of the 13 patients available for follow-up experienced remission of disease after an average of 3.5 injections.

Acyclovir (Zovirax)

Inhibits viral DNA synthesis. A synthetic deoxyguanosine analog and the prototype antiviral agent that is activated by viral thymidine kinase. In small numbers of patients, acyclovir started on the day of surgical resection appeared to slow the rate of regrowth of papillomas. Combined treatment with interferon may decrease the rebound regrowth sometimes noted with interferon discontinuation.


Class Summary

Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa, beta, and gamma interferons may be administered topically, systemically, and intralesionally.

Interferon alfa-2a (Roferon A)

Exerts antiviral effects by inhibiting translation of viral proteins. In the absence of an effective antiviral agent, use of drugs that augment host defense is a reasonable approach. Seventy-five to 80% of patients respond to interferon, with a complete response in approximately 30%. Does not eradicate the virus, and relapse may occur after discontinuation of treatment. Usually is administered for at least 6 mo in patients who require more than 3-4 surgical procedures each year. Case reports suggest that combined treatment with acyclovir or retinoic acid may be beneficial in patients with recurrent disease during interferon treatment.

Vaccines, Inactivated, Viral

Human papillomavirus vaccine, quadrivalent (Gardasil (DSC), Hpv vaccine, quadrivalent)

Protects against diseases/precancerous conditions caused by human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52, and 58.