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REVIEW

CURRENT
OPINION Recurrent respiratory papillomatosis: update 2018
Craig S. Derkay a,b,c and Andrew E. Bluher a,d

Purpose of review
Recurrent respiratory papillomatosis (RRP) is the most common as well as the costliest benign airway
neoplasm in the United States [Ivancic et al. (2018). Laryngoscope Investig Otolaryngol 3:22; Derkay
(1995). Arch Otolaryngol Head Neck Surg 121:1386]. In addition, it is potentially deadly, with risk of
airway obstruction as well as a 3–7% risk of malignant conversion [Schraff et al. (2004). Arch
Otolaryngol Head Neck Surg 130:1039]. This review highlights exciting advancements over the past
1–2 years in scientific understanding of the pathophysiology, epidemiology, natural history, prevention,
and treatment of this difficult disease.
Recent findings
Recent studies have yielded the following findings: The primary quality of life reduction that patients
perceive is voice-related; the membranous vocal folds are the most frequently involved anatomic subsite in
adult-onset RRP; there may be a correlation between laryngopharyngeal reflux, herpes simplex virus type 2,
and adult-onset RRP; there has been a decline in RRP incidence in Australia following the implementation of
a national vaccination program; addition of educational audiovisual aids assists in vaccine acceptance
rates; preventive vaccination can be used as treatment for pediatric as well as adult RRP patients with
demonstrable effects on antibody titers and reoperation rates; calreticulin-linked DNA vaccines show
promise in reducing the growth rate of human papilloma virus (HPV)11 E6/E7-expressing tumors in mice;
injection of bevacizumab is associated with no adverse tissue affects; systemic bevacizumab is effective as
a treatment for severe uncontrolled disease; pegylated interferon treatment is effective in select severe
pediatric RRP disease; and finally, increased rates of programed death 1 T-lymphocyte infiltration and
programed death-ligand 1 expression are seen on both papilloma and infiltrating immune cells.
Summary
RRP is declining in incidence but remains a challenging disease to treat with great costs to patients,
families, and the healthcare system. As the disease continues to be better understood, new frontiers are
opening in treatment, particularly for severe or poorly controlled disease. Until the disease can be
eradicated, it remains a vital area of research to help prevent new cases and treat afflicted patients.
Keywords
bevacizumab, programed death 1, pegylated interferon, recurrent respiratory papillomatosis, vaccination

INTRODUCTION quality of life burden of RRP as a disease, as well

Recurrent respiratory papillomatosis (RRP) remains
a challenging disease afflicting children and adults
alike, resulting in an estimated $120 million dollars
per year in United States healthcare-related costs,
with annual costs per patient approaching $60 thou-
sand dollars [1]. In addition, it is associated with
higher rates of depression and lower voice-related
quality of life [2]. Although the prevalence of RRP
has thankfully declined since the introduction of
the human papilloma virus (HPV) vaccine 12 years
ago, RRP remains the most common benign laryn-
geal neoplasm in children, and is unique in its high
rate of multisite recurrence, its high burden on
patient quality of life and its high associated health-
care costs. This review summarizes recent advances
in our understanding of the natural history and
as basic science advancements in prevention and
treatment, giving hope for a future with lower prev-
alence of RRP and improved treatment options.
a
Department of Otolaryngology – Head and Neck Surgery, bPediatric
Otolaryngology, Eastern Virginia Medical School, cChildren’s Hospital of
the King’s Daughters and dEastern Virginia Medical School, Sentara
Norfolk General Hospital, Norfolk, Virginia, USA
Correspondence to Craig S. Derkay, MD, Professor and Vice-Chairman,
Department of Otolaryngology – Head and Neck Surgery; Director,
Pediatric Otolaryngology, Eastern Virginia Medical School, Children’s
Hospital of the King’s Daughters, 601 Children’s Lane, 2nd Floor,
Norfolk, VA 23507, USA. Tel: +1 757 668 9853;
fax: +1 757 668 9838; e-mail: craig.derkay@chkd.org
Curr Opin Otolaryngol Head Neck Surg 2018, 26:000–000
DOI:10.1097/MOO.0000000000000490

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Pediatric otolaryngology
KEY POINTS
 There has been a decline in RRP incidence in Australia
following the implementation of a national vaccination
program [Novakovic et al. (2018). J Infect Dis
217:208].
 Quadrivalent vaccination can be used as treatment for
pediatric as well as adult RRP patients with
demonstrable effects on antibody titers and reoperation
rates [Sullivan et al. (2017). Int J Pediatr
Otorhinolaryngol 93:103; Makiyama et al. (2017). J
Voice 31:104; Kin Cho Goon et al. (2017).
Laryngoscope Investig Otolaryngol 2:184; Dion et al.
(2017). JAMA Otolaryngol Head Neck Surg
143:614].
 Systemic bevacizumab treatment is effective as a
treatment for severe uncontrolled disease [Zur and Fox
(2017). Laryngoscope 127:1538; Best et al. (2017).
Laryngoscope 127:2225; Bedoya et al. (2017). Am J
Case Rep 18:842].
 Calreticulin-linked DNA vaccines show promise in the
treatment of HPV-related neoplasms based on animal
study data [Ahn et al. (2017). Laryngoscope
127:2713].
 The PD-1 pathway may contribute to localized
immunosuppression in RRP, and is a promising target
for future therapeutic trials [Ahn et al. (2018).
Laryngoscope 128:E27].
NATURAL HISTORY
RRP is a heterogeneous disease, caused by two pri-
mary strains of HPV (HPV 6 and HPV 11), and
presenting in two predominant age groups (juve-
nile-onset occurring before the age of 12, and adult-
onset occurring between the ages of 20 and 40) [3]. It
has previously been shown that HPV 11 is the more
aggressive viral strain of the two, and that younger
age of presentation is associated with a more detri-
mental course [4].
Recent work has brought us closer to an under-
standing of the natural history of adult-onset RRP.
&
Benedict et al. [5 ] described a cohort of 83 previ-
ously untreated patients with adult-onset RRP, and
noted that the membranous vocal folds is most
frequently involved. They also noted a significant
association between proton pump inhibitor usage
and involvement of subglottic and posterior glottic
regions, prompting further questions on the poten-
tial interplay between laryngopharyngeal reflux, its
medical therapies, and RRP. This is the first study of
its kind to demonstrate the sites of involvement in
adults with RRP prior to their treatment.
Formánek et al. [6] further explored the associa-
tion between laryngopharyngeal reflux and RRP,
2 www.co-otolaryngology.com
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examining biopsied tissue from 20 RRP-afflicted
individuals as well as 20 controls for evidence of
pepsin within the tissue, as well as the presence of
herpes simplex virus type 2 (HSV-2). They found
that 40% of RRP patients had pepsin within biopsied
tissue and 45% had HSV-2, while controls had nei-
ther. This suggests that inflammatory and immuno-
suppressive effects of laryngo-pharyngeal reflux
(LPR) and HSV may trigger or exacerbate papilloma-
tous growth. Further study is indicated regarding
whether treatment of these concomitant conditions
could assist in adult RRP management.
PREVENTIVE VACCINATION
Perhaps the most exciting result of the past 2 years
has been the publication of a 5-year report in
Australia following the implementation of a system-
atic HPV vaccination program. The quadrivalent
vaccine was introduced in 2007 with more than
80% uptake in girls and more than 75% uptake in
boys of at least two doses. This report showed a
decline in RRP annual incidence from 0.16 to 0.02
per 100 000 children. Only 15 incident cases were
noted nation-wide; none of the mothers of these
children were vaccinated, 13/15 were born vagi-
nally, 3/15 were born to mothers with active warts,
and 9/15 were first-born. This study constitutes the
first demonstration that the HPV vaccine may hold
promise in the eradication of RRP [7]. Ongoing
surveillance studies in the United States and Canada
are attempting to document similar declines despite
lower levels of population uptake.
Vaccination holds a great deal of promise for a
vast reduction in RRP incidence; however, it is lim-
ited by suboptimal rates of acceptance among pro-
viders and patient families in countries such as the
United States. According to the 2016 National
Immunization Survey, while 91% of teens aged
13–17 years old report having received one or more
doses of the hepatitis B vaccine and 82% received
the meningococcal conjugate vaccine, only 60%
received a single dose of the HPV vaccine [8]. This
is despite enormous potential benefit in preventing
not only RRP but all HPV-related disease (cervical
cancer, anogenital cancer, oropharyngeal cancer,
and anogenital warts). There is continued debate
regarding how to improve vaccination acceptance
rates. Nwanodi et al. [9] found that adding audiovi-
sual aids as well as a patient health education hand-
out raised both HPV-specific knowledge and raised
vaccination acceptance rates. Despite low vaccine
acceptance rates in the United States, Markowitz
et al. [10] noted a greater-than-expected reduction
in HPV-related diseases in the United States 10 years
out from the introduction of the quadrivalent HPV
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vaccine. This excellent review offers insight into
future reductions with improved uptake of the
nine-valent vaccine.
VACCINATION AS TREATMENT
In addition to its enormous potential benefits in
the prevention of RRP, the nine-valent HPV vaccine
may have a role in juvenile-onset RRP treatment. A
recent case report highlights the potential benefit
of vaccination for the already-HPV-afflicted RRP
patient. A 2-year old child with RRP was treated
with three doses of nine valent HPV vaccine, and
subsequently experienced an increase in average
intersurgical interval from 46 to 340 days [11].
The potential for use of the vaccine as treatment
may extend well beyond childhood. In a proof-of-
concept effort, Makiyama et al. [12] demonstrated a
significant increase in antibody titers in adult male
RRP patients aged 32–74 postvaccination with
quadrivalent HPV L1 vaccine (Gardasil, Merck &
Co. Whitehouse Station, NJ, USA). Meanwhile,
Kin Cho Goon et al. [13] report a cohort of 12 adult
RRP patients aged 27–78 years who experienced a
more than seven-fold decrease in their incidence
rates of papillomatosis requiring surgical interven-
tion after receiving vaccination with Gardasil.
A systematic review of the use of adjuvant HPV
vaccination for secondary prevention found 9/12
studies reported decreased disease recurrence,
decreased disease burden or increased intersurgical
interval in those with active disease. Of note,
there was great variability in serologic and HPV
DNA collection, outcome measures, and under-
powering that limited critical analysis of benefit
for those already seropositive without disease, but
findings do suggest a role in those with active
disease [14].
Although the quadrivalent HPV L1 vaccine
shows promise in helping to control recurrent dis-
ease, DNA vaccines are under investigation for their
greater potential therapeutic benefit. Preventive
vaccines are composed primarily of inactivated viral
proteins; in contrast, DNA vaccines contain the
DNA blueprints to synthesize these proteins. DNA
vaccines are harnessed by recipient cells to repeat-
edly transcribe these proteins, subsequently pro-
moting a greater immune response than simply
presenting those antigens during an isolated injec-
tion. In addition, DNA vaccines are customizable
such that antigenic proteins can be linked to other
proteins such as calreticulin that may further
enhance immune responses. Ahn et al. [15] report
specific HPV11 CD-8 positive T-cell responses as well
as slowed tumor growth rate in mice inoculated with
a HPV11 E6E7 expressing tumor cell line, after DNA
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Recurrent respiratory papillomatosis Derkay and Bluher
vaccine administration encoding the HPV11 E6 and
E7 genes linked to calreticulin.
FRONTIERS IN MEDICAL TREATMENT
Until vaccination rates reach levels high enough to
promote herd immunity, RRP will still demand fur-
ther advances in treatment [16]. Although surgical
treatment continues to be vital in both the diagnosis
as well as control of the disease, major strides are
being made in the basic sciences that may pave the
way to further medical therapies. These advances
range from novel DNA vaccine development as
described above, to the description of differential
ligand expression in the papillomatous mileu, to the
investigational use of therapies previously used to
treat viral hepatitis or ocular neoplastic disease. For
instance, pegylated interferon, used in the treat-
ment and cure of hepatitis C viral infection, was
recently used in the treatment of a child with severe
RRP with good response [17].
Bevacizumab (Avastin, Genetech, San Francisco,
CA, USA) is another focus of intense study. A mAb to
vascular endothelial growth factor (VEGF) which pre-
vents its interaction with the VEGF receptor, bevaci-
zumab was developed with the aim of reducing
neoplastic angiogenesis, and was first approved for
use in the United States in 2004 as a combination
therapy for metastatic colon cancer. It has since been
approved for use in the treatment of a variety of neo-
plasms. Local intralesional injection has been used in
RRP with some success in the past. No detrimental
vocal fold changes were observed on pathologic
review of injected porcine laryngeal specimens [18].
Systemic bevacizumab is now on the rise as a
treatment for RRP, with some dramatic successes
reported in particularly severe cases refractory to other
medical treatments [19]. Best et al. [20] found eight
patients nationwide with severe disease who were
treated with 5–10 mg/kg every 2–4 weeks, with all
displaying at least a partial response. Minimal com-
plications included proteinuria in one patient, and
hemoptysis in another. All patients have required
continued treatment, with relapse noted when treat-
ment intervals were extended too long; however,
remission was achieved in select patients with inter-
vals decreased to 6 weeks [21]. A protocol for uniform
treatment of severely affected patients with systemic
bevacizumab is currently in development at the Child-
ren’s Hospital of Philadelphia and Johns Hopkins [19].
Current best practice recommendations for sys-
temic bevacizumab administration in the treatment
of RRP include partnership with oncology services to
do thorough off-label consent and arrange for infu-
sions with hospital approval. The main monitored
side effects are hypertension, thrombus, electrolyte
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Pediatric otolaryngology
imbalances and renal damage; thus it is recom-
mended to screen for these sequelae and obtain
baseline studies including a cardiac echocardio-
gram. The patient’s disease should first be debrided
in the operating room, followed immediately by
Avastin 10 mg/kg intravenous (IV) infusion for
1.5 h. The next procedure and infusion is performed
in approximately 3 weeks to examine and debride as
needed. As a response is observed, intervals for
debridement and infusion intervals can be liberal-
ized to 2–3 months. Those without tracheal disease
can be followed in clinic for flexible laryngoscopic
monitoring [19,20].
An additional exciting line of research concerns
programed death 1 (PD-1) pathway inhibitors. The
T-lymphocyte coinhibitory receptor and its ligand
programed death-ligand 1 (PD-L1) are thought to
contribute to a locally immunosuppressed environ-
ment that allows for immune system evasion and
resultant papillomatous growth. Ahn et al. [22]
reported increased rates of PD-1 T-lymphocyte infil-
tration and PD-L1 expression on both papilloma and
infiltrating immune cells. Targeting the PD-1 pathway
thus represents a promising strategy for treating RRP.
A prospective clinical trial for treatment of adult RRP
with an anti-PD-L1 antibody called avelumab (Baven-
cio, Merck & Co. Whitehouse Station, NJ, USA) is
currently underway at the National Institutes of
Health [23]. A nonrandomized phase II trial for treat-
ment of adults with tracheal, bronchial, pulmonary,
or severe laryngeal RRP with the anti-PD-1 mAb
pembrolizumab (Keytruda, Merck & Co. Whitehouse
Station, NJ, USA) is currently undergoing FDA
review [24].
CONCLUSION
The past 2 years have seen breakthroughs in our
understanding of RRP pathophysiology, epidemiol-
ogy, natural history, prevention, and treatment. It
appears that the incidence of RRP may be decreasing
with the rising rates of HPV vaccination, with
encouraging data from the Australian vaccination
program. Improved educational materials may assist
in improving vaccination acceptance rates. Until
the disease is eradicated, it will remain a difficult
disease for patients and practitioners alike. Thera-
peutic use of quadrivalent vaccines, novel DNA
vaccines, pegylated interferon, PD-1 pathway inhib-
itors, and systemic VEGF inhibitors show promise in
controlling the most refractory cases. For further
reading, we would recommend the excellent review
&
by Ivancic et al. [25 ].
Acknowledgements
None.
4 www.co-otolaryngology.com
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Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
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death-ligand 1 (PD-L1) pathways in the proliferation of RRP serves as the basis for
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Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Recurrent respiratory papillomatosis Derkay and Bluher
clinical studies utilizing anti-PD-1 and PD-L1 therapies to treat severely affected
individuals.
23. Hinrichs CS; Avelumab for people with recurrent respiratory papillomatosis.
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This is an excellent review article on the current and possible future management of
recurrent respiratory papillomatosis (RRP) in children and adults reviewing ad-
juvant medical therapies and therapeutic use of HPV vaccines.
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