key: cord-0797676-k55yb46z
authors: Benedict, Jacob J.; Derkay, Craig S.
title: Recurrent respiratory papillomatosis: A 2020 perspective
date: 2021-03-13
journal: Laryngoscope Investig Otolaryngol
DOI: 10.1002/lio2.545
sha: 2b8f80e3da04bf8b68d6f9de5d8d341aa53a030f
doc_id: 797676
cord_uid: k55yb46z

OBJECTIVE: Despite recent advancement recurrent respiratory papillomatosis (RRP) remains a rare but challenging benign airway neoplasm. In recent years there has been significant shifts in incidence of this disease due to changes in vaccination and prevention for human papilloma virus (HPV) and its related pathology. This review will highlight the epidemiology, prevention and treatment of RRP. METHODS: The PubMed database was searched using relevant MeSH terms including “recurrent respiratory papillomatosis.” The titles and abstracts were reviewed to assess relevance and unrelated articles were excluded. A full‐text review for select articles was performed, the data and discussions were interpreted and synthesized to create a concise update on the management of RRP. RESULTS: With the increasing utilization of the 9‐valent and quadrivalent HPV vaccine in Australia, we have seen a significant decrease in the incidence of RRP. Preliminary data in the US shows a similar trend of decreased incidence after implementation of vaccination. Single dose Gardasil in developing countries has shown sustained immunization for at least 7 years. Preliminary clinical trials and retrospective studies have shown the HPV vaccine may have benefit as a treatment method in addition to prevention for HPV related diseases. Bevacizumab (Avastin), a VEGF monoclonal antibody, has shown promise as a systemic treatment for RRP. The Corona Virus Disease 2019 (COVID‐19) pandemic has affected perioperative management of RRP. CONCLUSION: RRP continues to decline in incidence since the implementation of HPV vaccination. Advancement in the medical management including Bevacizumab show promise as an additional option for the management of RRP.

morbidity and mortality of cervical cancer and genital warts, the incidence of RRP is rapidly changing but has previously been estimated to be 4.3 per 100 000 children and 1.8 per 100 000 adults. 1 The initial 2 year direct cost of treating RRP can be as high as $76 000 and the annual cost of all RRP patients has been estimated to be between $40-123 million, which highlights the importance of prevention. 10, 11 The most substantial improvements to our understanding of RRP have been made in prevention and adjuvant therapies which will be highlighted in this review.

Since the identification of the infectious etiology of RRP, extensive research has been performed on HPV. The two primary HPV subtypes in RRP are HPV 6 and 11, but high-risk subtypes 16, 18, 31, 33 and 39 have all been identified. 12, 13 HPV is a ubiquitous virus with 75% to 80% of non-vaccinated adults having immunologic evidence of primary infection. HPV most commonly affects the skin, genitourinary tract, anus, and oropharynx. We do not understand why 90% of these patients go on to clear the disease and some individuals are affected by sequela of the infection, though it has been postulated to be due to complex immunologic interactions. 14, 15 RRP has a variable course and predicting the timing and severity of recurrence has remained a challenge. RRP is generally classified as adult onset RRP (AORRP) and juvenile onset RRP (JORRP) due to the bimodal distribution of presentation and its relative natural history.

JORRP is generally more aggressive form with higher recurrence rates while AORRP is thought to be more indolent, although adults can have aggressive variation of the disease. The variability in disease severity and recurrence highlights the challenge of simple surgical excision as single modality treatment. JORRP is thought to be obtained via vertical transmission of HPV during delivery via infected genital tract although exact mechanism is not clear. AORRP is thought to be obtained via sexual transmission. 16 Early onset appears to be a risk factor for disease severity in JORRP, with age of onset <5 years of age being an independent risk factor. 14,17 Laryngo-pharyngeal reflux (LPR) has also been identified as a risk factor, although no study has yet identified any reduction in disease recurrence or severity with treatment of LPR. 18, 19 Previously HPV subtypes, especially HPV 11, was thought to be an independent risk factor but recent data does not definitively correlate subtype with disease severity. 14, 20 The larynx is the most common site of RRP, specifically the membranous vocal fold. 19 Recurrence rate also appears to be linked to primary location with higher rates of recurrence near the primary site of infection.

HPV vaccination has had a profound effect on the incidence of RRP.

Initial HPV vaccine development began with the discovery of the ability to isolate virus-like particles (VLP) which could stimulate a similar humoral response to L1 viral proteins. 21 The initial quadrivalent vaccine (Gardasil, Merck) developed from the HPV L1 viral capsid was FDA approved in June of 2006 and included both high risk strains 16 and 18 and low risk 6 and 11. An additional vaccine Cervarix, manufactured by GlaxoSmithKline, included L1 protein of HPV 16 and 18, and was approved in 2007 in Australia and Europe. Cervarix was eventually approved in the US in 2009. Gardasil has since been approved for females and males from ages 9 to 26 years of age with initial dosing recommended at 11 to 12 years of age. A 9-valent HPV vaccine was developed (Gardasil-9, Merck) which included additional strains 31, 33, 45, 52, and 58. 22 As more data surrounding HPV and its sequelae including oropharyngeal carcinoma the age range has been expanded to ages 9 to 45 and labeling now includes prevention of head and neck cancers caused by HPV. 23, 24 The original Advisory Committee on Immunization Practices (ACiP) recommendation of a 3 dose protocol for all individuals has been scaled down to 2 doses given 6-months apart when initiated at 9 to 14 years of age and is also supported by the World Health Organization and the European Union Many studies have shown that anti-vaccine messages and content receive more attention and views than pro-vaccination messages. 29, 30 Social media "influencers," users that are more influential within their social media network, have been shown to have the most substantial effect on consumer behavior and views. 31 Focusing HPV vaccination as an anti-cancer vaccine using social media and "influencers" may be an effective way to reach more Americans. 32 Additional resources, including both audiovisual and printable information pamphlets, have shown some improvement in vaccine acceptance as well. 33 Insurance status and proximity to metropolitan statistical area (MSA) appear to have an effect on vaccination rates. It is hoped that improved national access to vaccinations may help solve this disparity.

the developing world may have the most profound effect on RRP eradication due to a higher incidence of JO RRP in low resource nations. 34 Despite the higher incidence of disease burden, many low income and middle-income countries have not introduced the HPV vaccine as part of their national routine vaccination schedule. 35 This may be in part be due to cost and supply availability. The exact mechanism for a therapeutic effect of the HPV-9 vaccine as a therapeutic is unknown but is postulated to be due to a vaccine-mediated humoral response inhibiting latent HPV infection near or within the surgical site decreasing the risk and rate of recurrence. 42 Additionally, there is evidence that patients with RRP have a more robust immunologic response to HPV vaccination compared to their response to their indolent HPV infection which may explain the vaccines' efficacy as a treatment option. 43 In addition to the currently available Gradasil-9 vaccine there has been significant breakthroughs in HPV DNA vaccines. Gardasil-9 targets the L-1 protein of the viral capsid to create neutralizing antibodies while the novel DNA vaccines target E6 and E7 oncoproteins. 44 E6 and E7 have been shown to have high expression in HPV related tumors and associated diseases increasing potential therapeutic efficacy. 45 The potential benefit of DNA vaccines for treatment of HPV related disease stems from the ability to create more robust T cell immunologic response. The novel vaccine INO-3016 has shown both in vitro and in vivo immunologic response and clinically significant reduction in frequency of operative intervention. 44, 45 Additionally there are two ongoing trials for HPV-DNA vaccines, Inovio trial INO-3107 (NCT04398433) and an NIH funded trial being performed by Clint Allen et al. 46 These DNA vaccines may be a better option for future therapeutic vaccination treatment. 47 It is worth noting that all of these experimental trials have been completed in the adult population which represents a different patient population and disease severity from pediatric cohort.

In addition to primary prevention with vaccination, the last few years 57 Best et al. surveyed the RRP task force and identified 8 patients who were treated with 5-10 mg/kg every 2 to 4 weeks, all displaying at least partial response. A standardized treatment protocol is currently in development with patients often requiring repeated cycles every 2 to 3 months with endoscopy to reevaluate the lesions. 55 The current best practice recommendation is to collaborate with your oncology service to perform IV infusion after hospital approval for off-label use. Pretreatment labs should include evaluation of kidney function and echocardiogram as side effects can include bleeding, hypertension, thrombus formation, electrolyte abnormalities and renal injury. Patients should then undergo direct laryngoscopy and debridement in the operating room followed by IV bevacizumab 10 mg/kg for 1.5 hours. 54 

The COVID-19 pandemic has had a profound effect on public health, economics and social interaction worldwide. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified to be transmitted via large and small droplet aerosols, leading to challenges with containment and isolation. 62 

Over the last several years, we have seen significant advancement in our ability to prevent and treat RRP. Current data suggests that there will be significant decrease in the incidence of RRP due to the increas- pandemic has added additional challenges to caring for RRP patients but with appropriate precautions and PPE quality care can still be performed.

The authors have no financial disclosures or conflict of interest. 

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How to cite this article: Benedict JJ, Derkay CS. Recurrent respiratory papillomatosis: A 2020 perspective