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<body lang=3DEN-US link=3Dblue vlink=3Dpurple style=3D'tab-interval:36.0pt'>

<div class=3DSection1>

<p class=3DGRTitle style=3D'margin-left:0pt'>TITLE: Recurrent Respiratory
Papillomatosis<br>
SOURCE: Grand Rounds Presentation, <st1:PlaceType w:st=3D"on">University</s=
t1:PlaceType>
of <st1:PlaceName w:st=3D"on">Texas</st1:PlaceName> Medical Branch, Dept. of
Otolaryngology<br>
DATE: June 25, 2008<br>
RESIDENT PHYSICIAN: Ryan Ridley, MD<br>
FACULTY PHYSICIAN: <st1:City w:st=3D"on">Jing Shen</st1:City>, <st1:State w=
:st=3D"on">MD</st1:State><br>
DISCUSSANT:<span style=3D'mso-spacerun:yes'>&nbsp; </span>Charles Vaughn, M=
D, <st1:place
w:st=3D"on"><st1:PlaceName w:st=3D"on">Boston</st1:PlaceName> <st1:PlaceTyp=
e w:st=3D"on">University</st1:PlaceType></st1:place><br>
SERIES EDITORS: Francis B. Quinn, Jr., MD</p>

<div class=3DMsoNormal align=3Dcenter style=3D'text-align:center'><i><span
style=3D'font-size:10.0pt;mso-bidi-font-size:12.0pt'>

<hr size=3D2 width=3D"100%" align=3Dcenter>

</span></i></div>

<p class=3DMsoNormal><i><span style=3D'font-size:10.0pt;mso-bidi-font-size:=
12.0pt'>&quot;This
material was prepared by resident physicians in partial fulfillment of
educational requirements established for the Postgraduate Training Program =
of
the UTMB Department of Otolaryngology/Head and Neck Surgery and was not
intended for clinical use in its present form. It was prepared for the purp=
ose
of stimulating group discussion in a conference setting. No <span class=3DG=
ramE>warranties,</span>
either express or implied, are made with respect to its accuracy, completen=
ess,
or timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes=
 of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion.&quot; <o:p></o:p></span></i></p>

<div class=3DMsoNormal align=3Dcenter style=3D'text-align:center'><i><span
style=3D'font-size:10.0pt;mso-bidi-font-size:12.0pt'>

<hr size=3D2 width=3D"100%" align=3Dcenter>

</span></i></div>

<p class=3DMsoNormal><o:p>&nbsp;</o:p></p>

<p class=3DGR-Heading1>Introduction</p>

<p class=3DGRIndent-Normal>Recurrent respiratory papillomatosis (RRP) is a
disease of viral etiology caused by HPV types 6 and 11 <span class=3DGramE>=
which<span
style=3D'mso-spacerun:yes'>&nbsp; </span>results</span> in<span
style=3D'mso-spacerun:yes'>&nbsp; </span>exophytic lesions in the airway.<s=
pan
style=3D'mso-spacerun:yes'>&nbsp; </span>There are two distinct forms recog=
nized:
juvenile onset (most aggressive) and adult onset (less aggressive).<span
style=3D'mso-spacerun:yes'>&nbsp; </span>RRP is the most common benign neop=
lasm
of the larynx in children and the second most cause of pediatric
hoarseness.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Juvenile RRP, the=
 main
focus of this discussion, is mostly diagnosed between the ages of 2 and 4 y=
rs
old with a delay of symptom onset at approximately 1 year (Silverberg).<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Children with RRP are diagnosed be=
fore
their 5<sup>th</sup> birthday 75% of the time.<span
style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal>Incidence is estimated at 2 per 100,000 in adult=
s and
4 per 100,000 in <span class=3DGramE>children<span
style=3D'mso-spacerun:yes'>&nbsp; </span>which</span> equals over 15,000 su=
rgical
procedures totaling in excess of<span style=3D'mso-spacerun:yes'>&nbsp;
</span>one-hundred million dollars per year for childhood procedures! (Derk=
ay,
1995)<span style=3D'mso-spacerun:yes'>&nbsp; </span>Plainly stated, 1,500-2=
,000
new cases of childhood onset RRP occur in the <st1:place w:st=3D"on"><st1:c=
ountry-region
 w:st=3D"on">US</st1:country-region></st1:place> each year.<span
style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal>RRP not only involves the larynx but can spread =
into
the entire aerodigestive tract.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Children whose RRP was diagnosed at ages &lt; 3 years old have 3.6 t=
imes
more chance to have &gt; 4 surgeries per year and almost twice as likely to
have 2 or &gt; anatomic sites affected than children diagnosed at &gt; 3 ye=
ars
old. (Wiatrak) </p>

<p class=3DGRIndent-Normal><span class=3DGramE>Although RRP is a benign dis=
ease it
ahs extremely morbid potential due to its airway involvement and potential =
for
malignant transformation.</span></p>

<p class=3DGR-Heading1>Etiology</p>

<p class=3DGRIndent-Normal>HPV is the etiological agent in RRP, first disco=
vered
in laryngeal papillomas <span class=3DGramE>in<span
style=3D'mso-spacerun:yes'>&nbsp; </span>1982</span>.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>HPV is also the cause of the 2<sup=
>nd</sup>
most common female cancer&#8212;cervical cancer.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>It is also <span
class=3DGRIndent-NormalChar>associated with anogenital cancers such as anal,
penile, vulval, and vaginal carcinomas. (Goon)<span
style=3D'mso-spacerun:yes'>&nbsp; </span>HPV is a DNA containing, nonenvelo=
ped,
icosehedral (20 sided) capsid virus with double stranded DNA ~ 7,900 bp
long.<span style=3D'mso-spacerun:yes'>&nbsp; </span>HPV types 6 and 11, as =
stated
earlier are the most prevalent types with type 11 having the worst
prognosis.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Other types of HPV
encountered in RRP include types 16 and 18 (highly malignant) and <span
class=3DGramE>types</span> 31 and 33 (malignant potential more than types 6=
 and
11, but less than types 16 and 18).<span style=3D'mso-spacerun:yes'>&nbsp;
</span>It is believe that HPV infects cells by getting set up in the basal
layer and releasing its DNA into the cell.<span style=3D'mso-spacerun:yes'>=
&nbsp;
</span>This DNA is then transcribed into RNA which is then translated in to
viral proteins.<span style=3D'mso-spacerun:yes'>&nbsp; </span>These protein=
s will
go on to assemble new virions and once they are released, the cycle will
continue as these virions infect other cells. The HPV genome is made up <sp=
an
class=3DGramE>of<span style=3D'mso-spacerun:yes'>&nbsp; </span>early</span>=
 genes
(designated &#8220;E&#8221;) and late genes (designated &#8220;L&#8221;) ea=
ch
with unique purposes. Specifically, HPV L1 and L2 genes encode viral capsid
proteins while E1 and <span class=3DGramE>E2<span style=3D'mso-spacerun:yes=
'>&nbsp;
</span>are</span> responsible for replication and transcription.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>E4 aids in virus release from infe=
cted
cells and E6/E7 have transforming abilities. (Goon)<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Interestingly, following infection=
 of
stem cells in the basal layer, the infection can be actively expressed or
become latent.<span style=3D'mso-spacerun:yes'>&nbsp; </span>To demonstrate=
 this
fact, HPV DNA can be detected in normal appearing mucosa in patients with R=
RP
who are in remission.<span style=3D'mso-spacerun:yes'>&nbsp; </span>The fac=
t that
infection can be latent explains why reactivation and clinical occurrence c=
an
take place following years of remission.<span style=3D'mso-spacerun:yes'>&n=
bsp;
</span>Host immune response is thought to play a role in the pathogenesis of
HPV lesions.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Malfunction of c=
ell
mediated immune response in patients with juvenile-onset RRP has been
demonstrated. Some papillomas may evade immune </span>surveillance and perm=
it a
more rapid progression of the disease.<span style=3D'mso-spacerun:yes'>&nbs=
p;
</span></p>

<p class=3DGRIndent-Normal>Below is a graphic from Nature Reviews to help
illustrate the process of HPV infection as briefly described above:</p>

<p class=3DMsoNormal><!--[if gte vml 1]><v:shapetype id=3D"_x0000_t75" coor=
dsize=3D"21600,21600"
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=3D"f"
 stroked=3D"f">
 <v:stroke joinstyle=3D"miter"/>
 <v:formulas>
  <v:f eqn=3D"if lineDrawn pixelLineWidth 0"/>
  <v:f eqn=3D"sum @0 1 0"/>
  <v:f eqn=3D"sum 0 0 @1"/>
  <v:f eqn=3D"prod @2 1 2"/>
  <v:f eqn=3D"prod @3 21600 pixelWidth"/>
  <v:f eqn=3D"prod @3 21600 pixelHeight"/>
  <v:f eqn=3D"sum @0 0 1"/>
  <v:f eqn=3D"prod @6 1 2"/>
  <v:f eqn=3D"prod @7 21600 pixelWidth"/>
  <v:f eqn=3D"sum @8 21600 0"/>
  <v:f eqn=3D"prod @7 21600 pixelHeight"/>
  <v:f eqn=3D"sum @10 21600 0"/>
 </v:formulas>
 <v:path o:extrusionok=3D"f" gradientshapeok=3D"t" o:connecttype=3D"rect"/>
 <o:lock v:ext=3D"edit" aspectratio=3D"t"/>
</v:shapetype><v:shape id=3D"_x0000_i1027" type=3D"#_x0000_t75" style=3D'wi=
dth:6in;
 height:318pt'>
 <v:imagedata src=3D"respir-papill-recur-080625_files/image001.png" o:title=
=3D""/>
</v:shape><![endif]--><![if !vml]><img width=3D576 height=3D424
src=3D"respir-papill-recur-080625_files/image002.jpg" v:shapes=3D"_x0000_i1=
027"><![endif]></p>

<p class=3DMsoNormal><o:p>&nbsp;</o:p></p>

<p class=3DGR-Heading1>Epidemiology</p>

<p class=3DGRIndent-Normal>Childhood-onset RRP is most often diagnosed betw=
een
the ages of 2 and 4 with an estimated incidence of 4 per 100,000 (2 per 100=
,000
in adults).<span style=3D'mso-spacerun:yes'>&nbsp; </span>Briefly, adult RRP
peaks between ages of 20-40 yrs and has a slight male predilection.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Adult-onset RRP could reflect acti=
vation
of a virus present at birth or infection acquired in adolescence or adult
life.<span style=3D'mso-spacerun:yes'>&nbsp; </span>A U.S. survey of practi=
cing
otolaryngologists revealed that half the adults with RRP required fewer tha=
n 5
procedures over their lifetime as opposed to &lt;25% of children who can sh=
are
this same statistic.<span style=3D'mso-spacerun:yes'>&nbsp; </span>In the <=
st1:country-region
w:st=3D"on"><st1:place w:st=3D"on">U.S.</st1:place></st1:country-region>, t=
he mean
number of surgical procedures per child is estimated at 19.7 with an averag=
e of
4.4 procedures per year.<span style=3D'mso-spacerun:yes'>&nbsp; </span>(Der=
kay,
1995)<span style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal>In terms of distal airway spread and malignant
transformation, HPV 11 is more likely to be the culprit than HPV 6.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>HPV 11 <span class=3DGramE>is<span
style=3D'mso-spacerun:yes'>&nbsp; </span>thought</span> to integrate itself=
 into
the host genome and mutate tumor suppressor p53. (Rady)</p>

<p class=3DGR-Heading1>Transmission</p>

<p class=3DGRIndent-Normal>The exact mode of HPV transmission remains uncle=
ar but
the most likely method of maternal-fetal HPV transmission is through direct
contact via the birth canal.<span style=3D'mso-spacerun:yes'>&nbsp; </span>=
This
may explain the clinical observation that most children in whom recurrent
respiratory papillomas develop are delivered vaginally to mothers with a
history of condylomata.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Stati=
stics
reveal that not only are children with RRP commonly born vaginally to mothe=
rs
with a history of condylomata, but they are first-born as well.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>This fact is significant because
primigravid mothers have a large 2<sup>nd</sup> stage of labor and prolonged
infant exposure to the virus leads to higher risk of infection.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Maternal <span class=3DGramE>condy=
lomata
during pregnancy was</span> associated with a 200-fold increase in risk of =
RRP
in the child. (Silverberg) In one group of children with juvenile laryngeal
papillomatosis, 54% had a maternal history of vulval condyloma at delivery
(Hallden<span class=3DGramE>)<span style=3D'mso-spacerun:yes'>&nbsp; </span=
>Despite</span>
the apparent close association between maternal condylomata and RRP
development, few children exposed to genital warts at birth actually develop
clinical symptoms.<span style=3D'mso-spacerun:yes'>&nbsp; </span>The estima=
ted
risk of a child contracting the disease from a mother who has an active
condylomatous lesion and delivers vaginally is 1 in 400.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>What separates this one child from=
 the
other 399 is unknown at this point.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Although HPV could be recovered in approximately 30% of infants expo=
sed
to HPV in the birth canal, only a small fraction of these will exhibit evid=
ence
of RRP.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Another study found t=
hat in
77 mothers with condylomata at delivery, 9 children (11.6%) were later
diagnosed with juvenile RRP. (Kjer)<span style=3D'mso-spacerun:yes'>&nbsp;
</span>It is clear that other factors must be important in determining the
development of RRP (i.e. patient immunity, timing, length and volume of vir=
us
exposure and local trauma).<span style=3D'mso-spacerun:yes'>&nbsp; </span>In
contrast, to studies that link childhood RRP to mothers with genital HPV
infections, adult-onset RRP may be linked to oral-genital contact.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>A case control study revealed that
adult-onset RRP patients were more likely to have had increased sexual part=
ners
and oral sex than their controls.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>(Kashima)<span style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal>Since the main theory regarding transmission of =
RRP in
juvenile-onset cases is contact via birth canal, it seems reasonable that
cesarean section would eradicate this risk altogether.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Unfortunately, there is insufficie=
nt
evidence to support cesarean section in the prevention of childhood RRP in =
lieu
of the maternal risks associated with this procedure.<span
style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGR-Heading1>Histology and Lesion Characteristics</p>

<p class=3DGRIndent-Normal>RRP lesions occur where ciliary and squamous <sp=
an
class=3DGramE>epithelium are</span> juxtaposed.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Ciliated epithelium undergoes squa=
mous
metaplasia when exposed to repeated trauma and is replaced with nonciliated
epithelium that creates an iatrogenic squamociliary junction.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>This is probably whey RRP is exace=
rbated
in the presence of reflux.<span style=3D'mso-spacerun:yes'>&nbsp; </span>In
tracheotomized patients, RRP is often found at the stoma and in midthoracic
trachea (i.e. iatrogenic squamociliary junction). Histologically, the lesio=
ns
are pedunculated masses with finger-like projection of nonkeratinized
stratified squamous epithelium supported by a core of highly vascularized
connective tissue stroma. Grossly, papillomas may be sessile or pedunculated
and usually occur in exophytic clusters.<span style=3D'mso-spacerun:yes'>&n=
bsp;
</span>They appear pinkish/white in color.<span style=3D'mso-spacerun:yes'>=
&nbsp;
</span></p>

<p class=3DGR-Heading1>Clinical Characteristics</p>

<p class=3DGRIndent-Normal>RRP has a hallmark triad of progressive hoarsene=
ss,
stridor, and respiratory distress.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Due to the fact that the most common symptoms are related to airway
obstruction, many children are misdiagnosed with croup, asthma, or chronic
bronchitis.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Any child with vo=
ice
changes, obstructive airway symptoms should get fiberoptic laryngoscopy or
direct laryngoscopy to rule out neoplasia with RRP being high on the
differential.<span style=3D'mso-spacerun:yes'>&nbsp; </span>RRP presenting =
in the
neonatal period is thought to be a negative prognostic factor with a greater
likelihood for mortality and need for tracheotomy.<span
style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal>Extralaryngeal spread of respiratory papillomato=
sis
has been identified in 13-30% of children and in 16% of adults with RRP.<sp=
an
style=3D'mso-spacerun:yes'>&nbsp; </span>The most common sites for RRP are =
as
follows:<span style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-limen vestibuli, </p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-nasapharyngeal surface of soft palate</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-midline of laryngeal surface of epiglottis<=
/p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-upper and lower margins of ventricle</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-undersurface of vocal folds</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-carina</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l15 level1 lfo21;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-bronchial spurs</p>

<p class=3DMsoNormal style=3D'margin-left:36.0pt;text-indent:36.0pt'><o:p>&=
nbsp;</o:p></p>

<p class=3DGRIndent-Normal>The most frequent extralaryngeal sites were (in =
order
of frequency):<span style=3D'mso-spacerun:yes'>&nbsp; </span>oral cavity,
trachea, and bronchi.</p>

<p class=3DGRIndent-Normal>There is controversy as to whether tracheostomy
exacerbates distal spread of disease.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Certain authors such as Cole <i>et al</i> reported that increased
tracheal spread occurred in their patients with RRP who received
tracheotomy.<span style=3D'mso-spacerun:yes'>&nbsp; </span>(<st1:City w:st=
=3D"on"><st1:place
 w:st=3D"on">Holland</st1:place></st1:City>) However, in opposition to <span
class=3DGramE>this ,</span> Shapiro <i>et al</i> did not believe that place=
ment
of tracheotomy contributed to distal spread of disease.<span
style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGR-Heading1>Patient Assessment/Gathering history</p>

<p class=3DGRIndent-Normal>Hoarseness, although a common/benign complaint in
children, always indicates some abnormality of structure or function.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Important information to gather is=
:</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l16 level1 lfo22;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Time of symptom onset</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l16 level1 lfo22;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Airway trauma?<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Previous intubation?</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l16 level1 lfo22;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Characteristics of cry</p>

<p class=3DMsoNormal><o:p>&nbsp;</o:p></p>

<p class=3DGRIndent-Normal>Voice assessment should involve determination of=
 the
quality of voice:</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l13 level1 lfo23;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-low pitched, coarse, fluttering voice sugge=
sts
subglottic lesion</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l13 level1 lfo23;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>-high pitched cracking voice aphonia or brea=
thy
voice suggests glottic lesion or subglottic lesion</p>

<p class=3DMsoNormal><o:p>&nbsp;</o:p></p>

<p class=3DGRIndent-Normal>Other important things to assess:</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l19 level1 lfo24;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>age of onset</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l19 level1 lfo24;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>rate of progression</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l19 level1 lfo24;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>associated infection</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l19 level1 lfo24;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>history of trauma or surgery</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l19 level1 lfo24;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>presence of<span style=3D'mso-spacerun:yes'>=
&nbsp;
</span>respiratory or cardiac distress</p>

<p class=3DMsoNormal><o:p>&nbsp;</o:p></p>

<p class=3DGRIndent-Normal>Also, it is important to not be fooled by strido=
r that
is present at birth.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Although=
 this
is most likely laryngomalacia, subglottic stenosis, vocal cord paralysis or
vascular ring, you must remember that neonates also can present with
papillomatosis.<span style=3D'mso-spacerun:yes'>&nbsp; </span>In addition, =
it is
important to review the perinatal period for a history of maternal or pater=
nal
condylomata.<span style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal><b>Physical exam:<o:p></o:p></b></p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l17 level1 lfo25;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Assess respiratory rate and degree of distre=
ss
first </p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l17 level1 lfo25;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Observe for flaring of nasal ala, use of
accessory<span style=3D'mso-spacerun:yes'>&nbsp; </span>neck/chest muscles<=
/p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l17 level1 lfo25;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Cyanosis or air hunger( child my sit with ne=
ck
hyperextended)</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l17 level1 lfo25;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]>Be careful in very sick children.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Detailed physical exam should be d=
one in
the OR, ER, or ICU where equipment for resuscitation, intubation, and
tracheotomy can be performed</p>

<p class=3DMsoNormal style=3D'margin-left:36.0pt'><o:p>&nbsp;</o:p></p>

<p class=3DGR-Heading1>Malignant Transformation</p>

<p class=3DGRIndent-Normal>Malignant transformation of laryngeal or pulmona=
ry
lesions is considered rare and is estimated to occur in 1-7% of patients wi=
th
RRP (Gerien).<span style=3D'mso-spacerun:yes'>&nbsp; </span>Typically, mali=
gnant
transformation occurs in those patients with advanced disease, usually
pulmonary extension of RRP, who are subsequently diagnosed with lung carcin=
oma.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>This lung carcinoma will have the =
same
virus as benign papillomas in the larynx.<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp; </span>This usually occurs during t=
he
third or fourth decade of life.<span style=3D'mso-spacerun:yes'>&nbsp; </sp=
an>As
described earlier, the majority of these lesions contain HPV type 11 as opp=
osed
to type 6.<span style=3D'mso-spacerun:yes'>&nbsp; </span>The reliability of
prognostic factors other than age of onset for predicting severity of RRP
(including malignant transformation) is undefined.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Gerien <i>et al</i> demonstrated t=
hat
the average duration of RRP until malignant transformation lies within a ra=
nge
of approximately 19-35 yrs and approximately 9-21 yrs from the time pulmona=
ry
extension is diagnosed.</p>

<p class=3DGR-Heading1>Treatments</p>

<p class=3DGRIndent-Normal>Surgical debridement is the mainstay of treatmen=
t with
the aims of maintaining a safe airway and a good voice.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>The most favored method currently =
is
usage of the powered microdebrider instead of CO<sub>2</sub> laser due to
decreased surgical time, less cost and better voice quality, with no increa=
se
in pain. (Pasquale)<span style=3D'mso-spacerun:yes'>&nbsp; </span></p>

<p class=3DGRIndent-Normal>Existing adjuvant therapy is considered
&#8220;off-label&#8221; usage; however the following medical treatments have
been explored thus far:</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>Interferon-</b> <br>
Has antiviral, antiproliferative and immunomodulatory effects by binding to
membrane receptors and altering cell metabolism. Exact mechanism is unknown=
.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>The conclusion is that interferon =
is
neither curative alone nor of any value as adjunctive treatment (Healy)</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>Cidofovir</b>- <br>
A cytosine analogue that is active against many DNA viruses.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Precise mechanism unknown but thou=
ght to
induce apoptosis and augment the immune response.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Prospective studies have shown int=
ralesional
cidofovir to promote regression (partial and complete) of papillomas and
decrease frequency of surgical debulking. (Tasca)</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>Antivirals</b>-<br>
Namely Ribavirin and acyclovir.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Evidence proving efficacy for these is weak/anecdotal.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Effect is not directed at HPV but
against co-infecting viruses.</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>Indole-3-carbinol</b><span class=3DGramE>=
-<span
style=3D'mso-spacerun:yes'>&nbsp; </span></span><br>
Derived from cruciferous vegetables.<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Thought to<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span>affect papillomas via effect on estrogen metabolism.<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span><span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;</span>Prospective
study has shown some benefit but evidence<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span>of clinical efficacy is equivocal.<span style=3D'mso-spacerun:yes'>&=
nbsp;
</span></p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>Mumps vaccine<span class=3DGramE>-<span
style=3D'font-weight:normal;mso-bidi-font-weight:bold'><span
style=3D'mso-spacerun:yes'>&nbsp; </span></span></span></b><br>
Unclear mechanism but authors feel that intralesional mumps vaccine promotes
induction of remission in children with RRP.</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>Control of GERD</b><span class=3DGramE>-<=
span
style=3D'mso-spacerun:yes'>&nbsp; </span></span><br>
LPR is thought to exacerbate severity of RRP.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Prospective study by authors like
McKenna <span class=3DGramE>Demonstrates <span
style=3D'mso-spacerun:yes'>&nbsp;</span>improved</span> control of RRP and
ometimes remission when GERD is controlled. (McKenna)</p>

<p class=3DGR-No-Indent-Normal style=3D'margin-left:36.0pt;text-indent:-18.=
0pt;
mso-list:l12 level1 lfo20;tab-stops:list 36.0pt'><![if !supportLists]><span
style=3D'font-family:Symbol;mso-fareast-font-family:Symbol;mso-bidi-font-fa=
mily:
Symbol'><span style=3D'mso-list:Ignore'>&middot;<span style=3D'font:7.0pt "=
Times New Roman"'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span></span></span><![endif]><b>HspE7</b><span class=3DGramE>-<span
style=3D'mso-spacerun:yes'>&nbsp; </span></span><br>
Recombinant fusion protein of Hsp65 of <i>M. bovis</i> and E7 protein<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span>from HPV 16.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Open label
study has shown statistically<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span>significant decrease in the patient&#8217;s annual frequency of
surgery<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span>and decreased absolute number of surgeries. (Derkay, 2005)</p>

<p class=3DMsoNormal><b style=3D'mso-bidi-font-weight:normal'><u><o:p><span
 style=3D'text-decoration:none'>&nbsp;</span></o:p></u></b></p>

<p class=3DGR-Heading1>Conclusion</p>

<p class=3DGRIndent-Normal>RRP although rare, is a debilitating disease with
grave consequences to the airway if left unnoticed and uncontrolled.<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Currently great locoregional contr=
ol is
possible through frequent surgical debridement which adjuvant treatment may=
 be
able to decrease.<span style=3D'mso-spacerun:yes'>&nbsp; </span>At this poi=
nt,
not only must more research be undertaken to find a solution, more research
must be performed to understand more about the problem&#8212;the HPV
virus.<span style=3D'mso-spacerun:yes'>&nbsp; </span>Fortunately, with the
advancements currently accomplished, the future looks promising.</p>

<b style=3D'mso-bidi-font-weight:normal'><span style=3D'font-size:14.0pt;
mso-bidi-font-size:10.0pt;font-family:Arial;mso-fareast-font-family:"Times =
New Roman";
mso-bidi-font-family:"Times New Roman";mso-ansi-language:EN-US;mso-fareast-=
language:
EN-US;mso-bidi-language:AR-SA'><br clear=3Dall style=3D'page-break-before:a=
lways'>
</span></b>

<p class=3DGR-Heading1>Discussant:<span style=3D'mso-spacerun:yes'>&nbsp;
</span>Charles Vaughn, <st1:place w:st=3D"on"><st1:PlaceName w:st=3D"on">Bo=
ston</st1:PlaceName>
 <st1:PlaceType w:st=3D"on">University</st1:PlaceType> <st1:PlaceType w:st=
=3D"on">School</st1:PlaceType></st1:place>
of Medicine</p>

<p class=3DGRIndent-Normal>You may recall <span class=3DGramE>that<span
style=3D'mso-spacerun:yes'>&nbsp; </span>BU</span> had a large experience w=
ith
this disorder, eventually totaling close to 400 patients. It was a biased
cohort, almost all referred because of prior treatment failure. Even so, our
experience supports your report.</p>

<p class=3DGRIndent-Normal>May I add a few comments?<span
style=3D'mso-spacerun:yes'>&nbsp; </span>First a couple of minor (unscienti=
fic)
ones:</p>

<p class=3DGRIndent-Normal>Regarding infection: &#8220;It is clear that oth=
er
factors must be important in determining the development of RRP (i.e. patie=
nt
immunity, timing, length and volume of virus exposure and local trauma).&#8=
221;
...At one time I was treating (with the CO2 laser) 4-5 cases/day several da=
ys/wk
and because a laser impact on a surgical glove caused a more painful burn t=
han
that onto skin, I did not wear gloves. I never developed papilloma, etc., n=
or
did any of my family (wife and 4 daughters).</p>

<p class=3DGRIndent-Normal>Regarding: &#8220;There is controversy as to whe=
ther
tracheostomy exacerbates distal spread of disease.&#8221;&#8230; Many of our
patients arrived with tracheotomy in place and all of these had distal spre=
ad.
Others, even those with massive RRP, but without trach on arrival, were kept
trach free by diligent RX (surgical debridement) and none developed distal
spread.</p>

<p class=3DGRIndent-Normal>Note the logical discord in these two quotes fro=
m your
article:</p>

<p class=3DGRIndent-Normal>1.<span style=3D'mso-spacerun:yes'>&nbsp; </span=
>&#8220;Since
the main theory regarding transmission of RRP in juvenile- onset cases is
contact via birth canal, it seems reasonable that cesarean section would
eradicate this risk altogether&#8230;&#8221;<span
style=3D'mso-spacerun:yes'>&nbsp; </span>(&quot;<span class=3DGramE>altho</=
span>
there is no evidence to support this&quot;).</p>

<p class=3DGRIndent-Normal>2.<span style=3D'mso-spacerun:yes'>&nbsp; </span=
><span
class=3DGramE>&#8220; ...</span>you must remember that neonates also can pr=
esent
with papillomatosis.&#8221;<span style=3D'mso-spacerun:yes'>&nbsp; </span><=
span
style=3D'font-size:10.0pt;font-family:"Courier New"'>I have provided malpra=
ctice
defense based on #2.</span></p>

<p class=3DGRIndent-Normal>Finally, the purpose of this discourse:</p>

<p class=3DGRIndent-Normal>Regarding: &#8220;Surgical debridement is the ma=
instay
of treatment with the aims of maintaining a safe airway and a good
voice.&#8221;</p>

<p class=3DGRIndent-Normal>&#8220;In the <st1:place w:st=3D"on"><st1:countr=
y-region
 w:st=3D"on">U.S.</st1:country-region></st1:place>, the mean number of surg=
ical
procedures per child is estimated at 19.7 with an average of 4.4 procedures=
 per
year. (Derkay, 1995)&#8221;</p>

<p class=3DGRIndent-Normal>I wish that your article had defined more clearl=
y the
limits of &#8220;Surgical debridement is the mainstay of treatment with the
aims of maintaining a safe airway and a good voice.&#8221;<span
style=3D'mso-spacerun:yes'>&nbsp; </span>It lacks discussion of complicatio=
ns
from the &#8220;average of 19.7 surgical procedures&#8221;- when performed =
for
cure. In those referred to us we saw far too many glottic cripples when the
surgical purpose had been, as it commonly was, and still often is:
&#8220;cure&#8221;, i.e., elimination of all evidence of papilloma by
removal/destruction of its mucosa base. In such circumstance, scar (and voc=
al
and respiratory pathology) is inevitable.</p>

<p class=3DGRIndent-Normal>As your article states, virus can be recovered f=
rom
any location at any time, despite all known treatment. There is no known cu=
re.
Thus, surgical treatment purpose can only be relief of symptoms, not cure.<=
/p>

<p class=3DGRIndent-Normal>One should remove only papilloma that debilitate,
sparing all mucosa. Remission will occur when the fates, not the physician,
dictate.</p>

<p class=3DGRIndent-Normal>And be not surprised at recurrence- at any time.
(Recently I received a phone call from a young female, now a Resident in our
specialty. She gave her name and inquired if I remembered her, which, of
course, I did. At age 4-5 I had treated her for massive RRP, attempting onl=
y to
maintain an airway sans trach. Eventually remission occurred, leaving a nor=
mal
larynx. Why then did I detect some hoarseness when she spoke?</p>

<p class=3DGRIndent-Normal>She now, in her late twenties, had recurrence!!)=
</p>

<p class=3DGRIndent-Normal>Otherwise the article was well written and I enj=
oyed
reading it.</p>

<b style=3D'mso-bidi-font-weight:normal'><span style=3D'font-size:14.0pt;
mso-bidi-font-size:10.0pt;font-family:Arial;mso-fareast-font-family:"Times =
New Roman";
mso-bidi-font-family:"Times New Roman";mso-ansi-language:EN-US;mso-fareast-=
language:
EN-US;mso-bidi-language:AR-SA'><br clear=3Dall style=3D'page-break-before:a=
lways'>
</span></b>

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<p class=3DGR-No-Indent-Normal><o:p>&nbsp;</o:p></p>

<p class=3DGR-No-Indent-Normal><a
href=3D"http://www.ncbi.nlm.nih.gov/pubmed/12514398?ordinalpos=3D52&amp;ito=
ol=3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum"><span
style=3D'color:black;text-decoration:none;text-underline:none'>Pasquale K,
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<p class=3DGR-No-Indent-Normal><o:p>&nbsp;</o:p></p>

<p class=3DGR-No-Indent-Normal>Pashley, Nigel R.T. Can Mumps Vaccine Induce
Remission in Recurrent Respiratory Papilloma?<span
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2002; 128: 783-786<span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
</span><span
style=3D'mso-spacerun:yes'>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;=
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nb=
sp;&nbsp;&nbsp;</span></p>

<p class=3DGR-No-Indent-Normal><o:p>&nbsp;</o:p></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf>Silverberg MJ, Thorsen P,
Lindeberg H, et al. Clinical course of RRP in Danish children. </span><span
class=3Demphi><i>Arch Otolaryngol Head Neck Surg</i></span><span class=3Ddr=
f><i>
2004</i>; 130:711&#8211;7116.<o:p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span class=3DGramE><span class=3Ddrf>Derkay=
 CS. Task
force on recurrent respiratory papillomas.</span></span><span class=3Ddrf> =
</span><span
class=3Demphi><i>Arch Otolaryngol Head Neck Surg</i></span><span class=3Ddr=
f> 1995<span
class=3DGramE>;121:1386</span>&#8211;1391.<o:p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf>Wiatrak BJ, Wiatrak DW, Br=
oker TR,
<span class=3DGramE>Lewis</span> L. RRP: a longitudinal study comparing sev=
erity
associated with HPV types 6 and 11 and other risk factors in a large pediat=
ric
population. </span><span class=3Demphi><i>Laryngoscope</i></span><span clas=
s=3Ddrf>
2004<span class=3DGramE>;114:1</span>&#8211;23<o:p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'>Rady PL, Schnadig VJ, Weiss RL, Hughes TK, Tyring SK (1998)
Malignant transformation of recurrent respiratory papillomatosis associated
with integrated human papillomavirus type 11 DNA and mutation of p53. <i>La=
ryngoscope</i>
108:735&#8211;740</span></p>

<p class=3DGR-No-Indent-Normal><o:p>&nbsp;</o:p></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'>Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, Shah KV (2003)
Condyloma in pregnancy is strongly predictive of juvenile onset recurrent
respiratory papillomatosis. <i>Obstet Gynecol</i> 101:645&#8211;652<o:p></o=
:p></span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'><o:p>&nbsp;</o:p></span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'>Hallden C, Majmudar B (1986) <span class=3DGramE>The</span>
relationship between juvenile laryngeal papillomatosis and maternal condylo=
mata
acuminata. <i>J Reprod Med </i>31:804&#8211;807<o:p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'><o:p>&nbsp;</o:p></span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'>Kashima HK, Shah F, Lyles A, Glackin R, Muhammad N, Turner L, =
Van
Zandt S, Whitt S, Shah K (1992) A comparison of risk factors in juvenile-on=
set
and adult-onset recurrent respiratory papillomatosis.<span
style=3D'mso-spacerun:yes'>&nbsp; </span><i>Laryngoscope</i> 102:9&#8211;13=
<o:p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'><o:p>&nbsp;</o:p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf>Holland BW, Koufman JA, Po=
stma GN,
McGuirt WF Jr. Laryngopharyngeal reflux and laryngeal web formation in pati=
ents
with pediatric recurrent respiratory papillomas. </span><span class=3Demphi=
><i>Laryngoscope</i></span><span
class=3Ddrf><i> </i>2002<span class=3DGramE>;112:1926</span>&#8211;1929.<o:=
p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf>Healy GB, <i>et al</i>.<sp=
an
style=3D'mso-spacerun:yes'>&nbsp; </span><span class=3DGramE>Treatment of r=
ecurrent
respiratory papillomatosis with human leukocyte interferon.</span><span
style=3D'mso-spacerun:yes'>&nbsp; </span>Results of a multicenter randomized
clinical study.<span style=3D'mso-spacerun:yes'>&nbsp; </span><i>N Engl J M=
ed</i>
1988; 319: 401-407.<span style=3D'mso-spacerun:yes'>&nbsp; </span><o:p></o:=
p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><span lang=3DFR style=3D'm=
so-ansi-language:
FR'>Derkay, Craig S. <i>et al</i>.<span style=3D'mso-spacerun:yes'>&nbsp; <=
/span></span>HspE7
Treatment of Pediatric Recurrent Respiratory Papillomatosis:<span
style=3D'mso-spacerun:yes'>&nbsp; </span>Final Results of an Open-Label
Trial.<span style=3D'mso-spacerun:yes'>&nbsp; </span><i>Ann Otol Rhinol Lar=
yngol</i>
2005; 114:<span style=3D'mso-spacerun:yes'>&nbsp; </span>730-7<o:p></o:p></=
span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-size:8.5pt;font-family:T=
imes-Roman;
mso-bidi-font-family:Times-Roman'><o:p>&nbsp;</o:p></span></p>

<p class=3DGR-No-Indent-Normal><span style=3D'font-family:Times-Roman;mso-b=
idi-font-family:
Times-Roman'>Kjer JJ, Eldon K, Dreisler A (1988) <span class=3DGramE>Matern=
al</span>
condylomata and juvenile laryngeal papillomas in their children. <i>Zentral=
bl
Gynakol</i> 110:107&#8211;110</span><span class=3Ddrf><o:p></o:p></span></p>

<p class=3DGR-No-Indent-Normal><span class=3Ddrf><o:p>&nbsp;</o:p></span></=
p>

<p class=3DGR-No-Indent-Normal><span class=3DGramE><span class=3Ddrf>Gerien=
, <i>et al</i>.</span></span><span
class=3Ddrf><span style=3D'mso-spacerun:yes'>&nbsp; </span>Incidence, age a=
t <span
class=3DGramE>onset ,</span> and potential reasons of malignant transformat=
ion in
recurrent respiratory papillomatosis patients:<span
style=3D'mso-spacerun:yes'>&nbsp; </span>20 years experience.<span
style=3D'mso-spacerun:yes'>&nbsp; </span></span><i>Otolaryngol Head Neck Su=
rg </i>2005;
132: 392-394.<span class=3Ddrf><o:p></o:p></span></p>

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