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DOI 10.1007/s00405-013-2755-y
LARYNGOLOGY
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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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)
3.379 (0.0007)a
F vs. M
-1.235 (0.227)b
AoRRP
(n = 18,
58.06 %)
-1.055 (0.2891)a
JoRRP
(n = 12,
38.71 %)
1.342 (0.1802)a
Sinonasal
papillomas
(n = 1,
3.23 %)
-0.754 (0.4533)a
Pathology, n (%)
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
F vs. M
85.5 (0.3172)c
F: 6 vs. 11
M: 6 vs. 11
-2.251 (\0.0001)a
n.a.
-6.708 (\0.0001)a
1: F vs. M
1.854 (0.0643)a
2: F vs. M
3: F vs. M
-1.084 (0.2801)a
-0.610 (0.8729)a
4: F vs. M
-1.352 (0.1770)a
5: F vs. M
-0.123 (0.9045)a
6: F vs. M
1.371 (0.1707)a
7: F vs. M
-0.754 (0.4533)a
11: F vs. M
-0.754 (0.4533)a
MannWhitney test
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Mean stdev
(min, max)
-1.194 (0.242)a
Sex
Female
Male
HPV
6 (15, 55.56 %)
11 (2, 50.00 %)
AoRRP
JoRRP
-1.920 (0.065)a
2.631 (0.070)b
Statistics (p value)
1 (n = 7)
2 (n = 7)
3 (n = 3)
Min
Max
Mean stdev
18
43
26.50 6.91
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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ANOVA test
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
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)
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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
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11.
12.
Conclusion
13.
None.
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15.
16.
17.
18.
References
19.
1. Newall AT, Brotherson JML, Quinn HE et al (2008) Population
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
3. Bonagura VR, Hatam LJ, Rosenthal DW, DeVoti JA, Lam F,
Steinberg BM, Abramson AL (2010) Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to
human papillomavirus-6 and -11. APMIS 118(67):455470
4. Hoff SR, Koltai PJ (2012) Operative management of juvenileonset recurrent respiratory papillomatosis. Oper Tech Otolaryngol 23:117123
5. Peng S, Best SR, Hung CF et al (2010) Characterization of human
papillomavirus type 11specific immune responses in a preclinical model. Laryngoscope 120(3):504510
6. Blumin JH, Handler EB, Simpson CB, Osipov V, Merati AL
(2009) Dysplasia in adults with recurrent respiratory
20.
21.
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23.
24.
25.
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