Quote this article as:
D Novakovic & AT Cheng (July 2023). Prevention of Recurrent Respiratory Papillomatosis. www.HPVWorld.com, 237

Background
Recurrent Respiratory Papillomatosis (RRP) is a rare HPV-related disease manifesting as recidivistic exophytic papillomatous growths in the larynx and respiratory tract, impacting voice and airway function (Figure 1). It often has a protracted course requiring multiple treatments and frequent hospital visits over many years and can result in mortality if left untreated. It can severely impact the quality of life of patients and carers with a significant economic burden in some countries^1,2.

Infection with HPV 6 or 11 is known to be the causative factor in most cases of both juvenile and adult-onset forms of this disease. Only a small proportion of people who are infected with these HPV subtypes will go on to develop RRP, and there is increasing evidence for altered/defective innate immunity in affected people³.



Prevention of primary RRP
Vertical transmission is thought to be the primary mechanism for Juvenile onset RRP (JoRRP), most seen in firstborn children, delivered vaginally to young, unvaccinated mothers². The implementation of a national HPV vaccination program in 2007 with high uptake has translated to a decrease in the incidence of Juvenile onset RRP (JoRRP) in Australia between 2012 – 2016, with no new cases occurring in previously vaccinated mothers⁴. More recently, there is evidence of a similar decline in JoRRP case-patients and incidence in the United States from 2004 – 2013, spanning the initial recommendation for HPV vaccination in this country in 2006². These results, suggesting interruption of vertical transmission via HPV vaccination, are promising; however, this strategy for primary prevention is limited by variable vaccination rates around the world⁵. A reduction in the burden of adult-onset disease has not yet been demonstrated, possibly due to challenges with measurement and monitoring along with delayed disease presentation after initial HPV infection in adults.

Prevention of recurrent RRP after treatment
Treatment of RRP has classically focused on surgical debulking and minimising healthy mucosal trauma to address symptoms of dysphonia or dyspnoea; however, multiple recurrences are typical, leading to the exploration of adjuvant treatments to prevent or reduce the frequency of recurrent lesions.

There is increasing evidence that adjuvant HPV vaccination of patients with existing disease, including RRP, related to vaccine-preventable subtypes may assist with secondary disease prevention. Multiple studies, including a meta-analysis, report clinical improvement in disease activity, especially in patients who were previously HPV seronegative⁷. However, the mechanism by which this occurs is yet to be elucidated.

Research into therapeutic vaccines which stimulate cellular immunity via a T-cell response to HPV has also begun. Studies of 2 different therapeutic vaccines (encoding HPV E2 and E6/E7 genes, respectively) have suggested a clinical benefit in patients with RRP, opening the pathway for proper clinical trials³.

Biological adjuvant treatments are another potential pathway to reduce disease burden and recurrence. Vascular endothelial growth factor (VEGF) expression is increased in RRP samples. Bevacizumab (a VEGF receptor blocker) has shown efficacy when given intralesionally in refractory cases. Guidelines have now been developed for its use systemically in treating more severe cases, especially with diffuse disease and pulmonary involvement⁸.

The PD-1 pathway has recently been implicated in the pathogenesis of RRP⁹, opening the potential for immunotherapy as a treatment in severe disease.



References

1. Harrison A, Montgomery J, Macgregor FB. Economic impact of recurrent respiratory papillomas in a UK adult population. J Laryngol Otol. 2016;130(7):645-9. Available from: https://www.cambridge.org/core/journals/journal-of-laryngology-and-otology/article/abs/economic-impact-of-recurrent-respiratory-papillomas-in-a-uk-adult-population/FFE44C2787BBBA4C5C5276E1695061DB

2. Meites E, Stone L, Amiling R, Singh V, Unger ER, Derkay CS, et al. Significant Declines in Juvenile-onset Recurrent Respiratory Papillomatosis Following Human Papillomavirus (HPV) Vaccine Introduction in the United States. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021;73(5):885-90. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380742/pdf/nihms-1712540.pdf

3. Bai K, Allen C. How Enhancing Immunity to Low-Risk HPV Could Cure Recurrent Respiratory Papillomatosis. Laryngoscope. 2021;131(9):2041-7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363585/pdf/nihms-1728311.pdf

4. Novakovic D, Cheng ATL, Zurynski Y, Booy R, Walker PJ, Berkowitz R, et al. A Prospective Study of the Incidence of Juvenile-Onset Recurrent Respiratory Papillomatosis After Implementation of a National HPV Vaccination Program. The Journal of infectious diseases. 2018;217(2):208-12. Available from: https://pubmed.ncbi.nlm.nih.gov/29136168/

5. Benedict JJ, Derkay CS. Recurrent respiratory papillomatosis: A 2020 perspective. Laryngoscope Investig Otolaryngol. 2021;6(2):340-5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035938/pdf/LIO2-6-340.pdf

6. Rosenberg T, Philipsen BB, Mehlum CS, Dyrvig AK, Wehberg S, Chirilă M, et al. Therapeutic Use of the Human Papillomavirus Vaccine on Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-Analysis. The Journal of infectious diseases. 2019;219(7):1016-25. Available from: https://doi.org/10.1093/infdis/jiy616

7. Dion GR, Teng S, Boyd LR, Northam A, Mason-Apps C, Vieira D, et al. Adjuvant Human Papillomavirus Vaccination for Secondary Prevention: A Systematic Review. JAMA Otolaryngol Head Neck Surg. 2017;143(6):614-22. Available from: https://jamanetwork.com/journals/jamaotolaryngology/article-abstract/2613366

8. Sidell DR, Balakrishnan K, Best SR, Zur K, Buckingham J, De Alarcon A, et al. Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement. Laryngoscope. 2021;131(6):E1941-e9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034687/pdf/nihms-1796353.pdf

9. Ahn J, Bishop JA, Roden RBS, Allen CT, Best SRA. The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis. Laryngoscope. 2018;128(1):E27-e32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771441/pdf/nihms929120.pdf



This article is included in the HPW Special Issue Prevention of HPV-related diseases in Australia

Scientific coordinators:
Suzanne Garland, Dorothy Machalek, Cristyn Davies, Xavier Bosch

HPW editors:
Marisa Mena, Patricia Guijarro, Paula Peremiquel

On behalf of the editorial team, we would like to thank all the authors who contributed to this special issue of HPW



OTHER ARTICLES IN THIS HPW SPECIAL ISSUE:

D Machalek, C Davies. Australia’s HPV Vaccination Program: 15 years of success

I Frazer, S Garland. HPV eradication: targets for the century

D Machalek, K Sharma, J Kaldor. Tracking the impact of HPV vaccination on infection prevalence to measure vaccination program success

E Chow, J McCloskey. HPV vaccination is highly effective at preventing genital warts

O McNally, R McBain, KL Talia. Prevention of vulvar, vaginal precancer and cancer

R Hillman, M Poynten. Prevention of anal cancer

C Davies, SR Skinner. School-based vaccination is key to reducing HPV-related diseases

C Vujovich-Dunn, C Vajdic, R Guy. Enhancing Australian monitoring and evaluation systems to support equitable HPV vaccination

J Brotherton, M Saville, D Wrede. Prevention of cervical precancer and cancer

M Smith, L Whop, J Brotherton. Cervical cancer elimination: true success requires equity