Respiratory Papillomatosis

LARYNGOLOGY

Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccinein 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 Cluj-

Napoca, 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

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 transfor-

mation [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 affec-

ted 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

M. Chirila (&)ENT Department, Iuliu Hatieganu University of Medicine

and Pharmacy, 13 Emil Isac, 400023 Cluj-Napoca, Romania

e-mail: [email protected]

M. Chirila

ENT Department of the Emergency County Hospital,

Cluj-Napoca, Romania

S. D. Bolboaca

Medical Informatics and Biostatistic Department,

Iuliu Hatieganu University of Medicine and Pharmacy,

Cluj-Napoca, Romania

123

Eur Arch Otorhinolaryngol

DOI 10.1007/s00405-013-2755-y

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 intrale-

sional 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 positivelythe aggressive course of the disease in a 2-year-old boy by

immunization with the quadrivalent HPV vaccine Garda-

sil. 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 Cluj-

Napoca, 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 papil-

lomatosis (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

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 consider-

ation. 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 Sil-

gard 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 fol-

lowing: 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 wasinjected (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 nephro-

toxicity, neutropenia, and oncogenicity following the

off-label use of cidofovir, mostly after intraocular

application, but there was no information about inci-

dents 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 otorhinolar-

yngology 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 mon-

itored with caution before and after Cidofovir [13].


123

Silgard vaccination. The vaccine was administeredafter 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 Hatieganu University of Medicine and Pharmacy,

Cluj-Napoca, Romania.

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 fre-

quencies associated with 95 % confidence intervals (pro-

vided in square brackets as []), confidence intervals being

calculated using a formula similar to the algorithm pre-

sented 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 (Stat-

Soft, Tulsa, OK, USA), version 8.0, was used for the sta-

tistical analysis; all the tests were applied at a significance

level of 5 %.

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 per-

formed. Fourteen patients had previous RRP histories: all

of them were diagnosed with laryngeal papillomatosis in

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

Table 1 Characteristics of the investigated patients

Variable Value 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

Pathology, n (%)

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

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

max)

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) -2.251 (\0.0001)a

F: 6 vs. 11 11 (100) vs. 16 (0) n.a.

M: 6 vs. 11 16 (80) vs. 4 (20) -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 0 (0.00) vs. 2 (10.00) -1.084 (0.2801)a

3: F vs. M 3 (27.27) vs. 6 (30.00) -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

a Z-test for proportionsb t test for two independent samples assuming equal variancesc MannWhitney test


123

diagnosed with inverted sinonasal papilloma. He under-

went 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

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 (Chi-

square 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 sino-

nasal papillomas. In Table 2, the ages at the time of RRP

diagnosis are presented.

All the patients received cidofovir injections (a mini-

mum 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 clin-

ical 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 ci-

dofovir: 95 % CI [38.0575.74]), the recurrences after ci-

dofovir 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 sta-

tistics 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

Fig. 1 Laryngeal and tracheal papillomatosis

Fig. 2 Papillomas at the level of the right inferior turbinate andadjacent 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)

2 16 10.38 5.42

RRP recurrent respiratory papillomatosis, AORRP adult-onset recur-

rent respiratory papillomatosis, JORRP juvenile-onset recurrent

respiratory papillomatosis, n number of patients, Min minimum, Max

maximum, Stdev standard deviation

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

Variable Mean stdev

(min, max)

Statistics (p value)

Sex -1.194 (0.242)a

Female 28.75 11.15 (21, 45)

Male 27.15 11.69 (14, 54)

HPV 0.405 (0.689)a

6 (15, 55.56 %) 28.00 11.92 (14, 54)

11 (2, 50.00 %) 24.00 1.41 (23, 25)

AoRRP 25.13 4.85 (21, 35) -1.920 (0.065)a

JoRRP 29.67 14.87 (14, 54)

No. CIDO injections 2.631 (0.070)b

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 maximuma Independent samples t test assuming equal variancesb ANOVA test


123

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 under-

going 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 Sil-

gard 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 recur-

rence 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 com-

pared 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 per-

centage 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 localredness, and another one had labial herpes.

Two male patients had recurrences after HPV vaccina-

tion (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 sur-

geries over 8 months. Both patients had recurrences after

cidofovir injections and were 28-year old. Both recurrences

appeared after the first Silgard dose (Fig. 3) and under-

went progressive regression over the subsequent months.

Table 4 Number of surgeries after cidofovir injections

No. of surgeries after

cidofovir

AoRRP JoRRP Total Z-statistics

(p value)

0 9 3 12 1.369 (0.1707)

1 8 3 11 1.083 (0.2801)

2 1 2 3 -0.994 (0.3222)

3 0 4 4 -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

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 recur-

rent respiratory papillomatosis, JORRP juvenile-onset recurrent

respiratory papillomatosis


123

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 injec-

tions and Silgard.

Discussion

As a highly recurrent disease, RRP requires repeated

manipulations of the larynx, increasing the risk of com-

plications [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 struc-

tures, 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 crucifer-

ous 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 sur-

rounding 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 papilloma-

tosis. It is known that the use of cidofovir did not induce

severe adverse reaction on patients with RRR [13] but its

use is still off-label (European Laringology Society news-

letter 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 one-

third 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 devel-

oped 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 pro-

gression to CIN II/III when used for post-exposure pro-

phylaxis [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 pre-

clinical, rodent data, which showed high levels of protec-

tive 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 evo-

lution 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


123

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 collab-

orative 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.

Conclusion

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 Professorof the Faculty of Medicine at the University of Louvain, Belgium, for

his critical review of the manuscript.

Conflict of interest None.

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Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosisAbstractIntroductionMaterials and methodsStatistical analysis

ResultsDiscussionConclusionAcknowledgmentsReferences

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Respiratory Papillomatosis