Download Juvenile recurrent respiratory papillomatosis

CLINICAL REVIEW
Mark K. Wax, MD, Section Editor
JUVENILE RECURRENT RESPIRATORY PAPILLOMATOSIS:
STILL A MYSTERY DISEASE WITH DIFFICULT MANAGEMENT
Sofia Stamataki, MD,1 Thomas P. Nikolopoulos, MD, DM, PhD,2 Stavros Korres, MD, PhD,2
Dimitrios Felekis, MD,2 Antonios Tzangaroulakis, MD, PhD,2 Eleftherios Ferekidis, MD, PhD2
1
ENT Department, Johns Hopkins Hospital, Baltimore, Maryland
1st and 2nd Otorhinolaryngology Department of Athens University, Athens, Greece.
E-mail: [email protected]
2
Accepted 11 May 2006
Published online 4 October 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20491
Abstract: Juvenile recurrent respiratory papillomatosis (RRP) is
the most common benign neoplastic disease of the larynx in children and adolescents and has a significant impact on patients
and the health care system with a cost ranging from $60,000 to
$470,000 per patient. The aim of this paper is to review the current literature on RRP and summarize the recent advances. RRP
is caused by human papillomavirus (HPV; mainly by types 6
and 11). Patients suffer from wart-like growths in the aerodigestive tract. The course of the disease is unpredictable. Although
spontaneous remission is possible, pulmonary spread and malignant transformation have been reported. Surgical excision,
including new methods like the microdebrider, aims to secure
an adequate airway and improve and maintain an acceptable
voice. Repeated recurrences are common and thus overenthusiastic attempts to eradicate the disease may cause serious
complications. When papillomas recur, old and new adjuvant
methods may be tried. In addition, recent advances in immune
system research may allow us to improve our treatment modalities and prevention strategies. A new vaccine is under trial to
prevent HPV infection in women; the strongest risk factor for
juvenile RRP is a maternal history of genital warts (transmitted
from mother to child during delivery). Better understanding of
the etiology of the disease and the knowledge of all available
therapies is crucial for the best management of the affected
C 2006 Wiley Periodicals, Inc. Head Neck 29: 155–
patients. V
162, 2007
Correspondence to: T. P. Nikolopoulos
C
V
2006 Wiley Periodicals, Inc.
Juvenile Respiratory Papillomatosis
Keywords: recurrent laryngeal papillomatosis; human papillomavirus; epidemiology; management; treatment; surgical excision; adjuvant treatment
EPIDEMIOLOGY
Recurrent
laryngeal papillomatosis (RRP) is a
rare disease. It was first described 300 years ago
and is characterized by wart-like growths in the
aerodigestive tract, with predilection for the larynx. RRP has a bimodal age distribution.1 Juvenile
RRP occurs in patients younger than 5 years of age,
with approximately 25% of juvenile cases presenting in infancy. Adult RRP typically presents during
the third decade of life.2 Juvenile RRP is more
aggressive, has a more significant impact on quality of life, and accounts for greater health care
costs. We will focus on this more severe form of
RRP in this review.
In the pediatric population, RRP is the most
common benign tumor of the larynx, afflicting 4.3
per 100,000 infants and children in the United
States.3,4 Approximately 75% of affected children
are the first-born, vaginally delivered infants of
teenage mothers, a clinical triad that is recognized
as a risk factor for the disease.5 Boys and girls are
almost equally affected.6
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155
The disease is caused by the human papillomavirus (HPV). HPV is most likely transmitted to
infants during delivery through a vaginal canal
harboring an active or latent infection.5 Silverberg et al,7 in a retrospective study from 1974 to
1993, examined the relationship between vaginal
warts in pregnant women and the onset of RRP in
their children. They concluded that the strongest
risk factor for juvenile RRP is a maternal history
of genital warts.
The disease, although benign, has a potentially fatal course. Excision of the laryngeal papillomas aims to prevent asphyxiation and improve
voice. Despite surgical treatment, the growth of
papillomas typically recurs within months or even
weeks.8,9
Children with juvenile RRP undergo repeated
costly treatments—sometimes more than 100—to
reduce the size of recurrent warty lesions in the
upper airway. The total lifetime cost to treat 1 case
of RRP is $60,000 to $470,000.10
The course of RRP is variable, ranging from
spontaneous remission to multiple recurrences
and malignant transformation. Spontaneous remission may occur, but the age of remission is
highly variable and unpredictable.11 Some children never enter remission and carry the disease
into adulthood. Therefore, juvenile RRP, although
relatively rare, has a tremendous impact on
patients, their families, and the health care system.
ETIOLOGY
Gissmann et al11 and Mounts et al12 first demonstrated the presence of human papillomavirus
(HPV) DNA in papillomas of the larynx from
patients with juvenile RRP. HPV is a papova virus, icosahedrally shaped with a circular, doublestranded DNA genome surrounded by an outer
capsid of protein. The HPV genome consists of
approximately 7900 bp. All papilloma viruses
share the same genomic organization, with all
putative open reading frames (coding sequences)
arranged on one DNA strand. Two of the most
interesting proteins coded by HPV are E6 and E7.
E6 binds to the p53 tumor suppressor gene product and stimulates abnormal cell growth by accelerating its degradation. E7 binds to the retinoblastoma tumor suppressor gene product (pRB)
and blocks its growth-suppressive activity.13 E6
and E7 have been the subjects of extensive investigation to gain insight into the pathophysiology
of juvenile RRP. More than 92 distinct types of
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Juvenile Respiratory Papillomatosis
HPV have now been characterized, and many more
have been recognized.13 HPVs are host specific,
and each type is more or less associated with a distinct histopathologic process. HPV 6 and 11, and
rarely 16 and 18, have been implicated in causing
juvenile RRP. These same types are commonly
associated with benign genital warts.12,14,15 This
led to the hypothesis that juvenile RRP is transmitted from mother to child during delivery,
whereas adult RRP is transmitted sexually.5 Prolonged exposure to the virus during a prolonged
second stage of labor, such as that experienced by
many primigravid mothers, may lead to a higher
risk of infection in firstborn children. Kashima
et al5 also suggested that newly acquired genital
HPV lesions are more likely to shed virus than
long-standing lesions. This may explain the
higher incidence of papilloma disease observed
among offspring of young mothers. However, in
contrast to the low incidence of RRP, genital HPV
infection is common. This means that there is
insufficient evidence to support delivery by cesarean section in all women with condylomata.16 It is
indicated that other factors may contribute to the
pathogenesis of RRP. One such factor might be a
host immune deficit. HPV infection is often more
severe in patients with primary or secondary immunodeficiencies, although, in the majority of
cases, patients do not appear to be more susceptible to other infectious agents and no consistent
immune deficit has been demonstrated. Gelder
et al17 identified a genetic association between the
presence of HLA DRB1*0301 and susceptibility to
juvenile RRP. The mechanism underlying this
association is unknown; it will be of great interest
to determine whether the presence of this allele
predicts clinical severity or response to therapy in
prospective studies.18 Vambutas et al19 proposed
that disease prognosis and therapeutic response
in any given patient with HPV infection might be
predicted by sequencing HLA genes and the associated transporter TAP1 (transporter associated
with antigen presentation). In this paper, they
concluded that TAP1 polymorphism in the ATPase
domain is correlated with the severity of the disease in patients with RRP. They also reported that
HLA-B14-DRB1*0102 and HLA-B8-DRB1*03011
to DQB1*0201 haplotypes also modulate the severity of RRP.
Recently, gastroesophageal reflux has been
implicated in RRP. Holland et al20 suggest antireflux treatment in patients who undergo surgery
for RRP to avoid soft tissue complications such
as scarring. Moreover, McKenna and Brodsky21
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reported a link between the presence of extraesophageal disease and RRP. The inflammation
induced by chronic acid exposure may result in
the expression of HPV in susceptible tissues.
HISTOLOGY
Histologically, papillomas appear as pedunculated
masses with wart-like projections of nonkeratinized stratified squamous epithelium supported
by a core of highly vascularized connective tissue
stroma. Cellular differentiation appears to be
abnormal, with altered expression and production
of keratins. The degree of atypia may be a sign of
premalignant tendency.
The most common sites for juvenile RRP are
the lumen vestibule, the nasopharyngeal surface
of the soft palate, the midline of the laryngeal surface of the epiglottis, the upper and lower margins
of the ventricle, the undersurface of the vocal
folds, the carina, and the bronchial spurs. RRP
lesions occur most often at anatomical sites in
which ciliated and squamous epithelium are juxtaposed to repeated trauma and replaced with
nonciliated one.22 Papillomas may also develop in
iatrogenic squamociliary junctions, for example,
in tracheotomized patients.22
CLINICAL DIAGNOSIS AND COURSE
Children with juvenile RRP commonly present
with symptoms of an obstructed airway. The average duration of symptoms before diagnosis is
reported to be longer than 13 months. Commonly,
children are misdiagnosed as having asthma,
croup, or chronic bronchitis.23 The classic triad of
RRP symptoms are progressive hoarseness, stridor, and respiratory distress. Any infant or child
with these symptoms may need a laryngoscopy to
rule out neoplasia, with juvenile RRP being the
most common.23 Other symptoms are persistent
cough, recurrent pneumonia, dysphagia, failure
to thrive, or acute life-threatening respiratory
event. Differential diagnosis includes asthma,
croup, and bronchitis, in addition to laryngomalacia, vascular rings, or mediastinal mass.
Because the disease is rare and frequently misdiagnosed, there is a delay in treatment. As a
result, children may present with almost totally
obstructed airway, and require tracheotomy to alleviate acute respiratory distress. Cole et al24
have suggested that tracheotomy may activate or
spread the disease lower in respiratory tract. Shapiro et al25 noted that RRP tracheotomy patients
Juvenile Respiratory Papillomatosis
present at a younger age and with more widespread disease, often involving the distal airway
before tracheotomy. Derkay23 reports that tracheotomy itself can spread the disease outside of the
larynx. Most of the above mentioned authors
agree that tracheotomy is a procedure to be avoided unless absolutely necessary. In addition, decannulation should be considered as soon as the disease is managed effectively.
Extralaryngeal spread of respiratory papillomas has been identified in approximately 30%
of children.23 The most frequent sites of extralaryngeal spread are the oral cavity, trachea, and
bronchi.
The growth rate of papillomas is extremely
variable; some patients require monthly removal
of the lesions, whereas other patients with active
disease require 1 or 2 annual procedures. Rabah
et al26 showed that HPV 11 infection confers a
more aggressive course of RRP. In their study, patients with HPV 11 were mostly African-Americans who were diagnosed at younger ages and
tended to have longer periods of disease activity.
Typing of HPV is suggested by Gerein et al27 at
the first biopsy. Wiatrak et al28 reported that HPV
11 is associated with a worse outcome in infants
younger than 3 years at diagnosis. Infants with
HPV 11 are prone to develop more aggressive disease represented by higher severity scores, more
surgical procedures per year, and likely requirement for adjuvant therapies. Poetker et al29
reported that a possible explanation of variable
growth of papillomas may be alterations in the
process of apoptosis or programmed cell death.
Disruption of the balance between proapoptotic
and antiapoptotic factors may affect differential
cell growth and the development of neoplasms. In
this paper, a significant increase in the expression
of the antiapoptotic factor survivin in papilloma
specimens sampled from patients with juvenile
RRP was found. Dysregulation of cellular apoptosis by HPV infection could play a critical role in
defining the ultimate outcome of this disease.
These apoptotic mediators that are aberrantly
expressed in papillomas may be novel therapeutic
targets.29
Williams et al30 demonstrated significant crossreactivity of CD4+ T-cell responses to HPV 11 in
both healthy subjects and subjects with other skin
and genital HPV types. They suggest that this
may aid in developing various vaccine strategies.
Rahbar et al31 studied the role of vascular endothelial growth factor A (VEGF-A) in RRP. It is
known that VEGF-A plays an important role in
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the angiogenic response, which is essential for
tumor growth in a variety of human and experimental tumors. Rahbar et al report that VEGF-A
is strongly expressed in the epithelium of squamous papillomas in RRP. Further investigation
of growth factor expression may provide better
insight into the pathogenesis and recurrence of
RRP disease.
Malignant transformation of RRP to squamous
cell carcinoma has been documented.3 There have
been more than 60 single case reports in the literature of spontaneous malignant conversion of RRP
to squamous-cell carcinoma.32 These patients generally have had long-standing, persistent disease
requiring frequent surgical treatment. As already
mentioned, the most common types of HPV virus
are 6 and 11, but HPV 16, the more oncogenic variant, has also been shown to be present in some
patients.2 Katz et al33 report a case of remote intrapulmonary spread of RRP with malignant transformation. It is not known what causes this spontaneous conversion of RRP to malignant tumor.9 It has
been suggested that integration of HPV DNA and
mutation of specific oncogenes are important for
the conversion process.34 Oncoproteins E6 and E7
seem to be implicated. Loss of control over proliferation and cell division contributes to the development of a malignancy.34 Lele et al35 studied 4
patients with RRP who underwent malignant
transformation. Only HPV 11 was identified in the
examined tissue. It was also noted that increased
expression of p53 and retinoblastoma (prb) protein,
combined with a reduced expression of pd p21 protein, appeared to be significant events associated
with the progression to carcinoma.35 Go et al32
examined 7 patients with RRP who developed carcinoma. They concluded that the spontaneous
transformation of RRP to squamous carcinoma
is not characterized by a histologic progression
through dysplasia over time. Transformation can
result in the loss of HPV expression. It does not
appear that p53 is a molecular marker for monitoring the transformation process. Yet much needs to
be clarified.
STAGING
Although several scoring and staging systems
have been proposed, clinicians have not adopted a
uniformly acceptable system. Assessing the severity and clinical course of RRP disease is very important. One of the most popular staging systems
is the one proposed by Coltera/Derkay.8 This system is based on an anatomical breakdown of the
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Juvenile Respiratory Papillomatosis
aerodigestive tract into 25 subsites. The different
anatomical areas are evaluated according to the
presence and the severity of the disease. Physicians who are using this system can choose between different options such as 0, none; 1, surface
lesion; 2, raised lesion; 3, bulky lesion. Symptoms
are likewise evaluated. The summation of these
scores gives a good overall evaluation of the extent of the disease, allowing for better management decisions. Clinicians have found the Coltera/Derkay36 system to be a reliable tool because
it demonstrates a high level of surgeon to surgeon
reliability.
SURGICAL MANAGEMENT
Although there is no definite treatment for RRP,
the most widely used treatment is surgical excision with microlaryngoscopy. The goals of any
treatment modality are to secure an adequate airway, to improve and maintain an acceptable voice,
and to facilitate disease remission while limiting
morbidity and complications.37 Accomplishment
of these goals is promoted by secure airway provision, careful examination of the airway, and precise removal of papillomas. Regardless of the
method, care should be taken at induction of anesthesia to prevent the loss of an already compromised airway. The most common techniques used
include spontaneous respiration,38 in which patients during anesthesia do not undergo neuromuscular paralysis, and apneoic technique,39 in
which patients undergo neuromuscular paralysis
but they also get intermittent endotracheal intubation. In every case, the anesthesia team should
be very experienced and skillful.
Removal of papillomas with microlaryngoscopy instruments is the oldest method, but many
surgeons still prefer it because it does not burn
healthy tissue, which may result in scarring and
loss of vocal function. On the other hand, there is
more blood loss, and there is also a possibility that
blood and fragments of infected tissue can contaminate the lower airway.3
CO2 laser has been a favored method of endoscopic laryngeal surgery in children since the
1970s.40 When used at a low power setting with
an operating microscope, the laser offers precise
excision, excellent hemostasis, and minimal thermal injury to underlying tissues. Disadvantages
of the CO2 laser include increased operative time,
increased cost, and the need for special precautions to reduce the risk of airway fire and the exposure of the staff to the virus.
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Microdebrider resection of papillomas has
been reported to be relatively safe and effective by
Patel et al.41 Patel et al42 have found that total
surgical time, including preparation time, to be
shorter for microdebrider resection than for CO2
laser resection of papillomas in children. Pasquale
et al43 reported that patients who underwent
microdebrider excision had quicker improvement
in voice quality, shorter procedure times, and
lower overall procedural costs versus patients
who underwent CO2 laser treatment. Microdebrider resection of papillomas avoids the risk of
airway fire. Less postoperative pain after treatment using the microdebrider has been reported
anecdotally by the parents of children with juvenile RRP.42–44
Recently, pulse dye laser excision has been recommended as a method of treatment. Franco
et al45 reported that this laser type, which is primarily for treatment of vascular lesions, is relatively effective and safe for the treatment of RRP.
However, this method seems less effective for
large papillomas.
The most common complications of all surgical
treatment modalities include scarring, webbing,
and alteration of the mucosal wave. Because reliable eradication of juvenile HPV is impossible, it
is wise to leave minimal amounts of papillomas at
sites where irreparable scarring may occur, especially at the anterior commissure and the posterior glottis. More rare complications include airway stenosis, airway perforation, hemorrhage,
and airway fire.
ADJUVANT METHODS OF MANAGEMENT
Although surgical management remains the main
therapy for juvenile RRP, ultimately, many of the
patients with the disease require some form of adjuvant therapy. The most widely adopted criteria
for initiating adjuvant therapy are a requirement
for more than 4 surgical procedures per year, distal multisite spread of disease, and rapid regrowth
of papilloma disease with airway compromise.37
Approximately 10% of the patients with juvenile
RRP need adjuvant treatment.37 The most commonly recommended adjuvant therapy is a-interferon.8
a-interferon is a group of proteins produced by
leukocytes in response to viral stimulation. It is a
biologic response modifier that stimulates existing host defenses into an antiviral state, modulates immune responses, inhibits cell growth, and
induces several enzyme systems.37 Recombinant
Juvenile Respiratory Papillomatosis
a-interferon is currently used. Responsiveness of
juvenile RRP to a-interferon has been demonstrated in several studies. Szeps et al46 report in
their study of a heterogeneous group of patients
that there was a tendency that cases of HPV 6 to
respond better to a-interferon to HPV 11 or HPV
negative cases. In the same paper they mention
that there was no significant difference in viral
load and hyperproliferative state of the HPVaffected epithelium post-treatment in patients
who responded well to a-interferon. Gerein et al27
reveal maximal effectiveness of a-interferon treatment in a 20-year follow-up of RRP patients. They
also suggest HPV typing in RRP patients after the
first biopsy due to worse prognosis with HPV 11.
Side effects include flu-like syndrome, leucopenia,
coagulopathy, alopecia, and neurological complications. a-interferon is administrated intramuscularly, intravenously, or subcutaneously. The
dose is increased gradually to a target of 3 MU/m2
body surface daily for a month, and then the dose
is reduced to 3 times/week for at least 6 months.
Afterward, the dose may be slowly tapered or reintroduced in those children with recurrence. The
role of intralesion injection of interferon is under
investigation.
Indole-3-carbinol (I-3-C) is a derivative of cruciferous vegetables. The ability of I-3-C to slow
papilloma growth is believed to be caused by its
influence on estradiol metabolism. By altering the
site of estradiol hydroxylation, I-3-C decreases the
production of 16a-hydroxyestrone and increases
the production of 2-hydroxyestrone. In breast tumors, the former estradiol derivative has a proliferative effect, while the latter has an antiproliferative effect.47 I-3-C is best administered as a dietary supplement because the quantity present in
cruciferous vegetables is highly variable and
unpredictable. The proposed dose for children
weighing less than 25 kg is 100 to 200 mg daily. It
is well tolerated. Side affects that have been
reported are dizziness and headache.34 The recent
study of Rosen and Bryson48 of long-term results
of I-3-C treatment for RRP argued that it is a safe
and efficacious treatment because 70% of their
patients had complete or partial response to it. Pediatric patients as well as adults, in this same
study, did not respond to I-3-C, implying that juvenile form of the disease is more aggressive. Further studies are needed.
Cidofovir is a cytosine nucleotide analog that
has been shown to have potent antiviral activity
against a broad spectrum of herpes viruses. Its
mechanism of action is through the active intra-
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cellular metabolite cidofovir dihydrate, which
inhibits cytomegalovirus DNA polymerase. Cidofovir dehydrate has an intracellular half-life
between 17 and 65 hours, which permits continuous antiviral efficacy with infrequent dosing. The
cidovofir injection is performed under general anesthesia using spontaneous ventilation. The cidofovir injection is administered at the maximum
dose of 1 mg/kg every 2 to 3 weeks.49,50 Cidofovir
can be toxic. Animal studies have identified nephrotoxicity, which appears to be related to dosage.
Neutropenia has also been reported. The results
of cidofovir use are promising and offer hope to
those who are most severely affected with juvenile
RRP. Pransky et al51 in a study of 10 children
reported that patients with severe RRP showed
good response with intralesional cidofovir treatment, but it is necessary for safety profiles to be
established. Recently, a case report of intravenous
administration of cidofovir in an 8-year-old has
been reported.52 The patient had lung lesions that
completely resolved with local and intravenous
cidofovir plus I-3-C treatment. A review of cidofovir treatment by Shehab et al53 concludes that
long-term risks associated with cidofovir remain
to be seen and that further studies are necessary
to determine the most appropriate dose, frequency, and duration of therapy.
Acyclovir is an acyclic purine nucleoside analog. When acyclovir metabolites are incorporated
into DNA, they cause breaks in the DNA strand.
The exact mechanism of acyclovir’s function in
juvenile RRP is uncertain but may be related to
coinfection with a member of the herpes virus
family.37 Side effects are rare and include nausea,
vomiting, diarrhea, fatigue, and dull headache.
Liver function is monitored at the beginning of
therapy and every 8 weeks. The beneficial effect of
acyclovir is not well documented.54,55
Photodynamic therapy is based on the selective uptake of hematoporphyrins by neoplastic
cells, including papillomas.56 A photosensitizing
factor is administered intravenously, and after
6 days, activation of the factor is accomplished by
red light laser. Some studies have shown a
decrease in the rate of papillomas recurrence.57
Shikowitz et al58 reported that RRP patients
who underwent photodynamic treatment with mTHPC as a photosensitizer showed improvement
of their disease, possibly through an immune
response, but remission was not permanent.
Mumps is a viral illness against which most
children are immunized at around 1 year of age
(MMR vaccine). In 1980, it was suggested that the
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Juvenile Respiratory Papillomatosis
mumps virus and human papillomavirus might
have similarities that could translate into papilloma treatment by simple immunization using
mumps vaccine. Local infiltration of mumps vaccine, when combined with serial, prospective laser
excision of respiratory papillomas to maintain airway and maximize voice, has been found capable
of improving the emission rate.59 It is reported
that mumps vaccine can be administered intralesionaly more than once in the same site. Pashley
states that it is safe, readily available, and easy to
use.59 It is not clear how this occurs and certainly
needs further investigation by other studies to confirm these results. Moreover, Lieu and Molter60
stated that high doses of mumps vaccine may be
not without risks.
Gene therapy may be an important key in the
treatment of juvenile RRP. Sethi and Palefsky61
designed an HPV specific therapy using the herpes simplex virus type 1 thymidine kinase gene.
They transferred this gene into HPV 16 infected
cells expressing E2 protein. Treatment of these
cells with either ganciclovir or acyclovir resulted
in cell death. They suggested that this may be a
clinically feasible therapeutic strategy. Recently,
therapeutic vaccination has gained great interest.62 By reinforcing the immune system, better
control of the disease can be achieved. A candidate
therapeutic vaccine, named HspE7, has completed phase II testing in juvenile RRP patients.63
It consists of a recombinant fusion protein (heat
shock protein Hsp65 of Mycobacterium bovis var.)
expressed in E. coli. A confirmatory phase III
study of this vaccine is under development.
PREVENTION
Given the challenges in managing juvenile RRP,
the most important measure is prevention of RRP.
It is well established that maternal infection with
HPV is a risk factor for juvenile RRP. Unfortunately, the mechanism of transmission is not absolutely clear. This makes management uncertain.
The proposed cesarean section is not a widely
accepted way to prevent neonatal HPV infection
for various reasons.64 Perhaps the solution to the
juvenile RRP problem would be the prevention of
genital HPV infections.62 Vaccines designed to
prevent specific types are currently under development.65 A quadrivalent HPV vaccine (against
types 6, 11, 16, and 18) has the broadest coverage,
while other vaccines target fewer types.66 Recent
accomplishments in developing vaccines based
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February 2007
upon virus-like particle technology have brought
this possibility close to reality in coming years.67
CONCLUSION
Overall, juvenile RRP is a relatively rare disease.
This has had a negative impact on the systematic
evaluation of treatment modalities by scientists.
Patients may have a poor quality of life due to
multiple recurrences of airway obstruction or
altered vocal quality. Treatments may be numerous and costly, with devastating results for patients and their families. Recent advances in
surgical excision of the papillomas have improved
the safe maintenance of the airway and offer an
acceptable voice to the patients. However, overenthusiastic surgical management attempting to
eradicate the disease may cause serious complications. Adjuvant medications have reduced the frequency of surgical excisions and hospitalization,
but it seems that none of the adjuvants can eradicate the disease. There are still missing data
regarding the HPV virus and the pathogenesis of
juvenile RRP. Ongoing studies may give the answer to the missing links, and thus prevention,
early diagnosis, and effective management may
be a reality in the near future.
Acknowledgments. We thank Erika Krezmer
for her valuable contribution to the grammar and
syntax editing of the paper.
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