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Eur Arch Otorhinolaryngol

DOI 10.1007/s00405-013-2755-y

LARYNGOLOGY

Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine


in patients with recurrent respiratory papillomatosis
Magdalena Chirila Sorana D. Bolboaca

Received: 7 July 2013 / Accepted: 2 October 2013


 Springer-Verlag Berlin Heidelberg 2013

Abstract The aim of the study was to assess the clinical


efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in
patients with recurrent respiratory papillomatosis (RRP).
This was a prospective study of patients with RRP treated
from January 2009 to July 2012 at the Ear, Nose and Throat
Department of the Emergency County Hospital of ClujNapoca, Romania. Demographic characteristics, onset of
RRP, HPV typing, use and number of cidofovir injections,
number of surgeries for RRP per year, and use of human
papillomavirus vaccine (types 6, 11, 16, 18) (recombinant,
adsorbed)/Silgard were considered from all the patients
included in the study. Charts were reviewed for follow-up
after diagnosis, after cidofovir, and after Silgard; all the
statistical tests were applied at a significance level of 5 %.
The recurrences were observed within 27.53 11.24 days
after intralesional cidofovir injection. Thirteen patients with
recurrence after cidofovir agreed and received Silgard
vaccine. 85 % [54.4499.41] of patients had no recurrences
during 1-year follow-up. The recurrence of papillomas was
observed in two patients (15 %, 95 % CI [0.5945.56]), one
with adult-onset RRP and one with juvenile-onset RRP. Both
recurrences appeared after the first Silgard dose; one month
after the third vaccine dose each patient underwent a new
M. Chirila (&)
ENT Department, Iuliu Hat ieganu University of Medicine
and Pharmacy, 13 Emil Isac, 400023 Cluj-Napoca, Romania
e-mail: chirila_magda@yahoo.com
M. Chirila
ENT Department of the Emergency County Hospital,
Cluj-Napoca, Romania
S. D. Bolboaca
Medical Informatics and Biostatistic Department,
Iuliu Hat ieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania

surgery for remaining papillomas with no recurrences at


1-year follow-up visit. Silgard vaccination had a good
effect and proved to be efficient in the treatment of our
patients with RRR without appearance of recurrence in 85 %
of the patients during 1-year follow-up.
Keywords Recurrent respiratory papillomatosis
(RRP)  Silgard  Recurrence

Introduction
The human papillomavirus (HPV) infection is the most
common of all sexually transmitted infections, with up to
three-quarters of the general population infected at some
time in their lives [1]. It has been found that the human
papillomavirus causes recurrent respiratory papillomatosis
[2]. HPV-6 and -11 cause benign lesions in the airway and
on the skin, and they are classified as low-risk HPVs, as
compared to the high-risk HPVs, 16 and 18, which cause
the majority of cervical cancers [3].
Infection with either HPV-6 or HPV-11 can result in
local proliferation of epithelial cells anywhere along the
respiratory tract [4], which can progress to airway
obstruction [5] and more infrequently, malignant transformation [6]. The RRP (recurrent respiratory papillomatosis)
has an estimated incidence of 1.8/100,000 in adults and of
4.3/100,000 in children [7, 8]. The most commonly affected areas are the true vocal cords where the squamous
epithelium of the vocal cords gets into contact with the
respiratory epithelium of the larynx. Exolaryngeal sites can
become involved, including the trachea and bronchial
segments, the lungs, the oropharynx, the oral, and nasal
cavity [9]. Variable courses of the disease have been
observed in practice, from no recurrence after the first

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Eur Arch Otorhinolaryngol

presentation to severe disease with frequent recurrences of


papillomas, which require surgical removal every
34 weeks [3].
Clark and MacKenzie [10] reviewed different medical,
surgical, and immunological procedures used for the
treatment of laryngeal papillomatosis. One of the mainstays
of adjuvant therapies was the administration of intralesional Cidofovir (Vistide) [1113].
Recurrent respiratory papillomatosis is an ideal disease
to target with therapeutic vaccination [5]. There are two
main vaccine candidates: a bivalent vaccine targeted at
HPV types 16 and 18 and a quadrivalent vaccine targeted at
both of the oncogenic HPV types 16 and 18, as well as
HPV types 6 and 11 [1]. A single report about the HPV
vaccine being used for RRP was first published in 2008, by
F}
orster et al. [14]. They attempted to influence positively
the aggressive course of the disease in a 2-year-old boy by
immunization with the quadrivalent HPV vaccine Gardasil. After the third immunization, the disease became
stable with no further surgery for 10 months [14].
The aim of this pilot study was to assess the clinical
efficiency of human papillomavirus vaccine (types 6, 11,
16, 18) (recombinant, adsorbed)/Silgard in patients with
RRP.
Materials and methods
A prospective, non-randomized study was conducted
between January 2009 and July 2012 on subject which
addressed for treatment at Ear, Nose and Throat (ENT)
Department of the Emergency County Hospital of ClujNapoca, Romania. Both adult-onset and juvenile-onset
RRP cases were included in the study. The criteria for the
type of RRP were as follows: juvenile-onset recurrent
respiratory papillomatosis (JoRRP): RRP diagnosed before
the 17th birthday; adult-onset recurrent respiratory papillomatosis (AoRRP): RRP diagnosed on or after the 17th
birthday.
All the patients included in the study accepted both the
participation and the follow-up schedule: at 30 days,
60 days, 6 months, and 1 year after the first Cidofovir
injection as well as the first dose of Silgard. They also
signed an informed consent form, which contained a
comprehensive description of the procedure, the expected
outcomes, and the possible side effects. For patients
younger than 18 years old, the informed consent form was
signed by their parents. No penalties were applied for
discontinued participation in the study. Patients who
underwent more than three surgeries per year for RRP
(considering that the disease has a variable course from no
recurrence after the first presentation to severe disease with
frequent recurrences of papillomas) were included in the

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group receiving quadrivalent HPV (types 6/11/16/18)


vaccine, if they agreed the vaccination. Note that the HPV
vaccination has been withdrawn from the National Health
program in Romania and the patients who agreed with the
vaccination had bought their vaccine.
Demographic characteristics, such as sex and age, were
collected from all of the patients included in the study. The
onset of RRP (adult-onset and juvenile-onset RRP), the
HPV typing (detected by PCR), the use and number of
Cidofovir injections, the number of surgeries for RRP per
year, and the use of Silgard (Merck Sharp & Dohme,
Netherlands) were also collected and taken into consideration. Videolaryngoscopy was performed and recorded
before each Silgard injection as well as at the last clinical
outpatient visit (1-year follow-up). The charts were
reviewed for follow-up after diagnosis (date of diagnosis of
RRP until the last clinical outpatient visit), follow-up after
cidofovir (first dose of cidofovir until the last clinical
outpatient visit), follow-up after Silgard (first dose of Silgard until the last clinical outpatient visit), and malignancy
of the upper airway. The patients laboratory charts (before
and after the first injection of cidofovir) included the following: number of neutrocytes (1.87.7 9 109g/l), serum
level of creatinine (0110 mmol/l), eGFR (ml/min/
1.73 m2), and proteinuria (\20 mg/l).
The following therapeutical protocol had been applied to
the patients included in the study:

Intralesional adminstration of Cidofovir. Cidofovir was


injected (max 5 mg/kg, maximum dose of 187.5 mg) at
the base of the papillomas. In the same session, before
Cidofovir injection, a CO2 laser vaporization was
performed. The number of intralesional administrations
depended on the symptoms and on visible recurrence,
but no more than three injections were administered.
The cidofovir injections were made based upon the
recurrence, as noted in the clinic. At the beginning of
2011, the producer of cidofovir informed released
information about severe side effects, such as nephrotoxicity, neutropenia, and oncogenicity following the
off-label use of cidofovir, mostly after intraocular
application, but there was no information about incidents after the drugs use in respiratory papillomatosis
[15]. The European laryngological society (ELS)
decided to initiate an international multicenter-study
about this issue; promising results were reported at the
ninth congress of the ELS in Helsinki [12]. The final
results published in European archives of otorhinolaryngology and head and neck found no clinical evidence
for neither nephrotoxic nor neutropenic or oncogenic
side effects after the use of intralesional cidofovir in
patients with RRP; laboratory values should be monitored with caution before and after Cidofovir [13].

Eur Arch Otorhinolaryngol

Silgard vaccination. The vaccine was administered


after finishing cidofovir but only in the patients
undergoing more than three surgeries per year and
agreed with the procedure. Silgard was administered
on day 1, month 2, and month 6, given as a 0.5 ml
intramuscular injection. All the subjects were observed
for at least 30 min after each vaccination for any
immediate reaction. Their temperatures were recorded
orally for 5 days following each injection. All the
adverse experiences were recorded daily for 14 days
following each vaccination. The follow-up visits were
done at 30 days, 60 days, 6 months, and 1 year after
the first dose of vaccine. In their review, Barr and
Tamms [16] noted that the vaccination was generally
well tolerated. The proportions of subjects with serious
adverse experiences were comparable between the
vaccine and placebo groups, for both injection site
adverse events (pain, swelling, erythema, and pruritus)
and systemic events (fever, nausea, and dizziness).

The study was approved by the Ethics Committee of


Iuliu Hat ieganu University of Medicine and Pharmacy,
Cluj-Napoca, Romania.

Table 1 Characteristics of the investigated patients


Variable

Results
Thirty-one patients, 11 female and 20 male patients, met
the inclusion criteria and were investigated for recurrent
respiratory papillomatosis. The main characteristics of the
investigated patients are presented in Table 1. Only 17
patients were new cases (4 with JoRRP, 12 with AoRRP,
and one with sinonasal papillomas). For all the thirty-one
patients included in the study the HPV typing was performed. Fourteen patients had previous RRP histories: all
of them were diagnosed with laryngeal papillomatosis in

Statistics (p value)

Sex n (%)
Female (F) vs.
male (M)

11 (35.48) vs. 20 (64.52)

3.379 (0.0007)a

Age, m stdev (min, max)


All

30.74 11.09 (4, 57)

F vs. M

27.45 12.82 (4, 43) vs.


32.55 9.89 (14, 57)

-1.235 (0.227)b

AoRRP
(n = 18,
58.06 %)

5 (27.78) F and 13 (72.22)


M

-1.055 (0.2891)a

JoRRP
(n = 12,
38.71 %)

6 (50.00) F and 6 (50.00) M

1.342 (0.1802)a

Sinonasal
papillomas
(n = 1,
3.23 %)

0 (0.00) F and 1 (100.00) M

-0.754 (0.4533)a

Pathology, n (%)

Follow-up days after diagnosis, median [interquartile range] and (min,


max)

Statistical analysis
Quantitative variables are presented as means and standard
deviations whenever the data were normally distributed;
otherwise, medians and ranges are reported. Qualitative
variables are presented as absolute and/or relative frequencies associated with 95 % confidence intervals (provided in square brackets as []), confidence intervals being
calculated using a formula similar to the algorithm presented by Jantschi and Bolboaca [17]. The Z-test was
applied to test the differences between proportions. The
Chi-square test was applied to investigate the independence
on 2 9 2 contingency table. The Statistica software (StatSoft, Tulsa, OK, USA), version 8.0, was used for the statistical analysis; all the tests were applied at a significance
level of 5 %.

Value

All

1,095 [7301,460] (365,


8,760)

F vs. M

1,095 [1,091,460] (730,


6,570) vs. 1,095
[7301,551] (365, 8,760)

85.5 (0.3172)c

HPV type, n (%)


All: 6 vs. 11

27 (87) vs. 4 (13)

F: 6 vs. 11

11 (100) vs. 16 (0)

M: 6 vs. 11

16 (80) vs. 4 (20)

-2.251 (\0.0001)a
n.a.
-6.708 (\0.0001)a

No. of surgeries, n (%)

1: F vs. M

5 (45.45) vs. 3 (15.00)

1.854 (0.0643)a

2: F vs. M
3: F vs. M

0 (0.00) vs. 2 (10.00)


3 (27.27) vs. 6 (30.00)

-1.084 (0.2801)a
-0.610 (0.8729)a

4: F vs. M

0 (0.00) vs. 3 (15.00)

-1.352 (0.1770)a

5: F vs. M

2 (18.18) vs. 4 (20.00)

-0.123 (0.9045)a

6: F vs. M

1 (9.09) vs. 0 (0.00)

1.371 (0.1707)a

7: F vs. M

0 (0.00) vs. 1 (5.00)

-0.754 (0.4533)a

11: F vs. M

0 (0.00) vs. 1 (5.00)

-0.754 (0.4533)a

Z-test for proportions

t test for two independent samples assuming equal variances

MannWhitney test

our department, between 1992 and 2009. The onset of RRP


(JoRRP or AoRRP) was established, based on whether
RRP was diagnosed before or after the 17th birthday. The
patients underwent multiple laryngeal papillomas surgeries
(Table 1).
Twenty-nine patients were diagnosed with laryngeal
recurrent papillomatosis. One patient had small laryngeal
lesions associated with a huge tracheal bouquet of
papillomas (Fig. 1). Another patient was previously

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Table 3 Time of recurrence (expressed in days) after cidofovir
Variable

Mean stdev
(min, max)

-1.194 (0.242)a

Sex
Female

28.75 11.15 (21, 45)

Male

27.15 11.69 (14, 54)


0.405 (0.689)a

HPV
6 (15, 55.56 %)

28.00 11.92 (14, 54)

11 (2, 50.00 %)

24.00 1.41 (23, 25)

AoRRP
JoRRP

25.13 4.85 (21, 35)


29.67 14.87 (14, 54)

-1.920 (0.065)a
2.631 (0.070)b

No. CIDO injections

Fig. 1 Laryngeal and tracheal papillomatosis

Statistics (p value)

1 (n = 7)

28.29 10.05 (21, 48)

2 (n = 7)

25.86 13.06 (14, 54)

3 (n = 3)

29.67 13.32 (21, 45)

Stdev standard deviation, Min minimum, Max maximum

Fig. 2 Papillomas at the level of the right inferior turbinate and


adjacent meatus
Table 2 Age at diagnosis (years old)
RRP type

Min

Max

Mean stdev

AORRP, n = 18 (25, 18, 22, 26, 27,


20, 23, 21, 19, 33, 23, 34, 21, 27, 29,
27, 43, 39)

18

43

26.50 6.91

JORRP, n = 12 (2, 12, 13, 16, 14, 15,


5, 14, 16, 11, 4, 2)

16

10.38 5.42

RRP recurrent respiratory papillomatosis, AORRP adult-onset recurrent respiratory papillomatosis, JORRP juvenile-onset recurrent
respiratory papillomatosis, n number of patients, Min minimum, Max
maximum, Stdev standard deviation

diagnosed with inverted sinonasal papilloma. He underwent right endoscopic medial maxillectomy with no
recurrence of inverted papilloma; after 1 year, he presented
with papillomas located at the level of the right inferior
turbinate and adjacent meatus (Fig. 2). His mother had died
of cervix squamous cell carcinoma, and he has a sister with

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Independent samples t test assuming equal variances

ANOVA test

the same disease. After HPV typing (type 11), he accepted


the quadrivalent HPV vaccine. One year after the Silgard
vaccination, there was no sign of recurrence.
The type of RRP proved not to be related to sex (Chisquare statistics = 1.531, p value = 0.2159). Infection
with HPV type 11 was exclusively found in the male
patients: three cases with AoRRP and one case with sinonasal papillomas. In Table 2, the ages at the time of RRP
diagnosis are presented.
All the patients received cidofovir injections (a minimum of one and a maximum of three injections) with two
exceptions: the patient with sinonasal inverted papilloma,
and a 12-year-old girl whose parents refused intralesional
cidofovir administration. One patient had proteinuria
before being administered cidofovir (30 mg/l) and after
cidofovir injection (100 mg/l). No patient developed clinical nephrotoxicity after receiving intralesional cidofovir
injections. None of the patients developed malignancies
between the first and the last follow-up visits after
receiving the first intralesional cidofovir injection.
In 58.62 % (17 patients out of 29 who received cidofovir: 95 % CI [38.0575.74]), the recurrences after cidofovir were observed at one of the follow-up visits (4
female patients, 36 % [972] and 13 male patients, 65 %
[4085]). One female patient had AoRRP and three female
patients had JoRRP; seven male patients had AoRRP and
six male patients had JoRRP. Neither sex nor type of RRP
proved to be correlated with recurrence [Chi-square statistics with Yates correction = 1.336 (sex) and 1.635
(RRP), p value = 0.2478 (sex) and 0.2011 (type of RRP)].
The average time until recurrence occurred after

Eur Arch Otorhinolaryngol


Table 4 Number of surgeries after cidofovir injections
No. of surgeries after
cidofovir

AoRRP

JoRRP

Total

12

Z-statistics
(p value)
1.369 (0.1707)

11

1.083 (0.2801)

-0.994 (0.3222)

-2.631 (0.0085)

Total

18

12

31

AORRP adult-onset recurrent respiratory papillomatosis, JORRP


juvenile-onset recurrent respiratory papillomatosis, Z-statistics Z-test
for comparison of two proportions

intralesional cidofovir injection was 27.53 11.24 days.


Table 3 shows the results according to sex, RRP, and
number of cidofovir injections.
A statistically significant difference was found between
the proportion of patients undergoing more than three
surgeries per year after cidofovir injection and the onset
type of recurrent respiratory papillomatosis (see Table 4).
No statistically significant differences were identified
between the number of female and male patients undergoing more than three surgeries (three women and nine
men, Z-test = -0.970, p value = 0.3320).
Twenty-one patients (67.74 %, 95 % CI [48.4883.77])
had an aggressive form of RRP and underwent more than
three surgeries per year, and 13 of them agreed with Silgard vaccination. Six patients who had recurrences after
intralesional cidofovir injection refused to be vaccinated.
Another two patients had no recurrences after the first and
third injections, respectively. The patients without recurrence after cidofovir injection were not vaccinated.
The number of patients with JoRRP and who underwent
more than three surgeries (66.67 %, 95 % CI
[42.3690.97]) proved to be significantly higher as compared to the number of patients with AoRRP and who
underwent more than three surgeries (22.22 %, 95 % CI
[5.8649.69]; Z-test = 2.434, p value = 0.015). A percentage of 37.04 % (95 % CI [18.6659.12]) of the
patients with HPV-6 were vaccinated, while 75.00 %
(95 % CI [31.2593.75]) of the patients with HPV-11 were
vaccinated.
Three patients out of thirteen had side effects after each
dose of Silgard (23 %, 95 % CI [8.2853.25]), namely:
one patient had a fever (38 C), one patient had local
redness, and another one had labial herpes.
Two male patients had recurrences after HPV vaccination (15 %, 95 % CI [0.5945.56]) as follows: one had
JoRRP, was infected with HPV-6 and underwent seven
prior surgeries over 17 months; the other one had AoRRP,
was infected with HPV-11 and underwent three prior surgeries over 8 months. Both patients had recurrences after

Fig. 3 Laryngeal recurrence after the first dose of Silgard

Fig. 4 Regression of papillomas after the third dose of Silgard


Table 5 Recurrences after cidofovir injections and Silgard
RRP type

CIDO
recurrences

Silgard
recurrences

Z-test
(p value)

AoRRP (n = 18)

8 (44 %
[2372])

1 (6 % [027])

2.694
(0.0071)

JoRRP (n = 12)

9 (75 %
[4291])

1 (8 % [149])

3.312
(0.0009)

Z-statistics
(p value)

-1.655
(0.0989)

-0.299
(0.7642)

In the body of the table the values represents: number of cases,


% = percentage, [] = boundaries of 95 % confidence interval
RRP recurrent respiratory papillomatosis, AORRP adult-onset recurrent respiratory papillomatosis, JORRP juvenile-onset recurrent
respiratory papillomatosis

cidofovir injections and were 28-year old. Both recurrences


appeared after the first Silgard dose (Fig. 3) and underwent progressive regression over the subsequent months.

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One month after the third Silgard dose, each patient


underwent new surgery for remaining papillomas (Fig. 4),
with no recurrences at their 1-year follow-up visits. Table 5
shows the summary of recurrences after Cidofovir injections and Silgard.

Discussion
As a highly recurrent disease, RRP requires repeated
manipulations of the larynx, increasing the risk of complications [18]. In our series of RRP patients, combined
treatment (surgery ? cidofovir ? Silgard) led to good
results, and the aggressiveness of the disease was stopped
at least for 1 year, to the great satisfaction especially those
of patients with recurrences within 34 weeks. In our
study, we made the division between AoRRP and JoRRP
similar with Tjon Pian Gi Rea and his group [13], taken as
limit the age of 17.
The prevention of airway HPV infection is difficult
because the means of transmission and the details of the
host response are not precisely known [19]. The virus
primarily infects the epithelial cells through abrasions of
the skin or the mucosa, where it can stay as a long-term
latent infection that can reactivate or persist [9]. None of
the surgical therapies is curative. Surgery is considered a
hair cut or a lawn mowing, in which the obstructing
papillomas are removed down to the level of the adjacent
normal mucosa without damage to the underlying structures, to avoid complications of scarring, webbing, and
stenosis [4]. Several other adjuvant therapies were used
with different success results: Cidofovir, interferon alpha,
the photodynamic therapy using 5-aminolevulinic acid,
celecoxib, bevacizumaba human monoclonal antibody
that neutralizes vascular endothelial growth factor; the
mumps vaccine, and indole-3-carbinol (found in cruciferous vegetables) [1921].
Cidofovir is antiviral medication that selectively inhibits
viral DNA polymerase, which prevents viral replication
and transcription [22, 23]. Serial surgical debulking and/or
focal infiltration of antiviral agents (cidofovir) constitute
the current treatment options available to patients [24].
After debulking, cidofovir can be injected intralesionally at
the base of the papilloma and in the normal mucosa surrounding it, in an attempt to cause remission or a reduction
in the severity of the disease and to prolong the interval
between surgeries. The results of our series of cases with
intralesional cidofovir injections are in agreement with
those reported in the specialty literature [12, 25]; cidofovir
stopped the course of the medium severity disease but had
no effects in the patients with very aggressive papillomatosis. It is known that the use of cidofovir did not induce
severe adverse reaction on patients with RRR [13] but its

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use is still off-label (European Laringology Society newsletter 105, June 13, 2013).
Considering that there is no cure and all surgical and
adjuvant therapies serve only to reduce the severity of the
illness, eliminating the primary source of disease would be
of great benefit [4]. A polyvalent genital HPV vaccine that
includes virus-like particles of the low-risk and high-risk
types of the virus might be able to also prevent recurrent
respiratory papillomatosis, if the original source of the
virus in this disease is genital HPV infection [19]. An
effective HPV (types 6/11/16/18) vaccine would target the
HPV types that cause approximately 70 % of cervical
cancers and high-grade pre-cancerous lesions, roughly onethird of the low-grade dysplastic lesions, and the majority
of the genital wart cases and cases of recurrent respiratory
papillomatosis [26]. In 2006, Vila et al. [26] pointed out
that women who were baseline anti-HPV-positive developed a booster response to the vaccine. The vaccine was
reported to be effective prophylactically, in preventing
infection recurrence, and it was also found to reduce progression to CIN II/III when used for post-exposure prophylaxis [2729]. Also in 2006, Freed and Derkay [2]
showed that the quadrivalent product (Gardasil/Silgard)
could have a significant impact on RRP based on the preclinical, rodent data, which showed high levels of protective antibodies against HPV-6 and -11 in the offsprings of
vaccinated animals at 13 weeks postpartum.
In our study, surgery and/or intralesional injection of
cidofovir proved not be able to prevent the recurrence of
papillomas in some patients (see Tables 3, 4). The decrease
in number of interventions in other patients could also have
been a consequence of the natural course of the RRP.
Immunization with Silgard influenced the aggressive
course of the disease and interrupted the series of surgeries
for at least 1 year (follow-up period in this study). In both
cases with relapses after vaccination, ablation of remaining
papillomas 1 month after the last dose of vaccine also
stopped the aggressiveness of the illness. A patient with
HPV-11 positive sinonasal papillomas (another possible
site for RRP) and a 12-year-old girl were added to the
group treated with Cidofovir, both of whom had an evolution without recurrences 1 year after immunization. In
our view, the vaccine changed the immunologic response
of the host and prevented the infection recurrence. At the
same time the quality of life of our patients increases
despite the significant financial burden imposed by the
repeated surgeries they have to undergo, but this aspect was
beyond the aim of this study.
The HPV vaccine could have major impact on the RRP.
Recurrent respiratory papillomatosis can be fought against
in two ways: first, the quadrivalent HPV vaccine reduces
the HPV infection rate in young women [4, 19, 2729],
with the hope that by eliminating this source of disease, the

Eur Arch Otorhinolaryngol

incidence of HPV-related illnesses will drop; second, those


patients who are baseline anti-HPV-positive could develop
a booster response to vaccination which prevents infection
recurrence.
The current study has two limitations. First, we did not
assess the vaccine-type antibodies or DNA at baseline or
after immunization. The study was designed for the
assessment of the tolerability and clinical efficacy of the
quadrivalent HPV (types 6/11/16/18) vaccine in patients
with recurrent respiratory papillomatosis. Second, the
number of patients was too small so a strong conclusion
could not be drawn. Therefore, large multi-center collaborative clinical trials are further required to demonstrate the
therapeutic effect of quadrivalent HPV (types 6/11/16/18)
vaccine in RRP. However, this is extremely difficult to
organize, especially in Europe where research is governed
by different laws in each country.

7.

8.

9.

10.

11.

12.

Conclusion
13.

The HPV vaccine including HPV 6 and 11 had a good


effect and proved to be efficient in the treatment of our
patients with RRR without appearance of recurrence in
85 % of the patients during 1-year follow-up. In both
patients with recurrences after HPV vaccination, the
relapses occurred after the first Silgard dose and their
removal were done after the third Silgard dose, leading to
the absence of any recurrence at 1-year follow-up visit.
Acknowledgments We thank Marc Remacle, Academic Professor
of the Faculty of Medicine at the University of Louvain, Belgium, for
his critical review of the manuscript.
Conflict of interest

None.

14.

15.

16.
17.

18.

References
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seroprevalence of human papillomavirus types 6, 11, 16, and 18
in men, women, and children in Australia. Clin Infect Diseas
46(11):16471655
2. Freed GL, Derkay CS (2006) Prevention of recurrent respiratory
papillomatosis: role of HPV vaccination. Inter J Ped Otorhinolaryngol 70(10):17991803
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