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Can Mumps Vaccine Induce Remission in Recurrent Respiratory Papilloma?
Nigel R. T. Pashley, MB,BS, FRCSC
Arch Otolaryngol Head Neck Surg. 2002;128:783-786.
ABSTRACT
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Objective To describe our experience using laser excision and locally injected
mumps vaccine to induce remission in patients with recurrent respiratory papilloma
(RRP).
Setting Tertiary care regional medical center.
Participants Initially, 11 children with RRP treated in a pilot study with laser
excision at regular intervals for at least a year without adjuvant therapy;
later, a series of 18 children and 20 adults with RRP, some of whom had used
various adjuvant therapy with interval laser excision.
Interventions Both patient groups continued their same interval laser excision with
the same or similar laser, same clinical setting, and same surgeon. Locally
injected mumps vaccine was then administered into the excision site after
each laser removal of papilloma.
Outcome Measures Larynx and trachea were microphotographed with each treatment. Two consecutive
disease-free intervals and a follow-up of at least 1 year were required criteria
for remission.
Results In the pilot study, remission was induced in 9 (82%) of 11 patients
by 1 to 10 injections, with follow-up of 5 to 19 years. In the subsequent
series, remission was induced in 29 (76%) of 38 patients by 4 to 26 injections,
and follow-up was 2 to 5 years.
Conclusions Combined with serial laser excision, mumps vaccine positively influences
induction of remission in children with RRP. The mechanisms of this effect
are unclear, but the treatment is readily available, inexpensive, and has
a low risk of adverse effects.
INTRODUCTION
RECURRENT RESPIRATORY papilloma (RRP) is a protean disease caused by
infection with the human papilloma virus and for which there is currently
no single effective treatment. In children, frequent surgical removal is common
to maintain an airway. Adults and children suffer loss of voice and, in aggressive
cases, a tracheostomy is sometimes required. Tracheal seeding and lung involvement
can occur with fatal outcome.
Recurrent respiratory papilloma is rare (254-763 US children affected
per year) but may cost $40 million to $123 million annually.1
It also is the most common benign laryngeal tumor in children. Papillomas
may develop in any mucosal area of the aerodigestive tract, with the vocal
cords the most commonly affected site. Why this particular site is so consistently
involved is unclear, but from the various adjuvant treatments tried, there
is implied agreement that a local immunoincompetence to the viral agent may
be present in susceptible patients. A variety of adjuvant therapies for RRP
have been tried with varying success, including interferon alfa, photodynamic
therapy, indole-3-carbinol,2 acyclovir, retinoic
acid, cidofovir,3 topical fluorouracil, and Thuja, a homeopathic antiviral preparation.
Surgical removal has evolved from debulking with cup forceps, which
is still useful, to the more standard use of the laser and microscope. This
latter treatment allows precise removal but is not without the risks of scar,
webbing, and stenosis. Rarely, fire from inadvertent endotracheal tube ignition
has occurred, with tragic outcome, and many surgeons have adopted a proximal
jet ventilation technique that reduces this hazard. Excision using a microdebrider
has also been tried by some surgeons, and with the recurrent nature of the
disease, some surgeons set regular intervals for patients to return for laser
endoscopy. This approach aims to keep the airway open and maximize the voice
while avoiding tracheostomy. The treatment interval can be shortened or lengthened
as needed.
Although spontaneous remission is alleged to occur, I have never seen
it. Accurate reporting of the varied therapies used has been improved by the
adoption of a scoring system proposed in 1998 by Derkay et al.4
This allows the surgeon to stage and/or score a patient's disease manually
or directly into a computer. The operating surgeon assigns a score of 0 to
3 where 0 indicates no lesion; 1, surface lesion; 2, raised lesion; and 3,
bulky lesion. Four questions about voice, stridor, the urgency of that day's
intervention, and the level of respiratory distress are also scored, and a
clinical score is generated by summation.
Mumps is a viral illness against which most children are immunized at
around age 1 year (measles, mumps, and rubella immunizations are given together).
Mumps vaccine contains a live attenuated virus of the Jeryl Lynn strain with
a long history of safe use.5-7
In 1980, it was suggested that the mumps and human papillomaviruses might
have similarities that could translate into papilloma treatment by simple
immunization using mumps vaccine (unpublished discussion). Although both viruses
are viscerotopic, this would seem to be their only similarity. The human papillomavirus
is a papovavirus in the group of DNA viruses, and the mumps virus is a paramyxovirus
in the family of RNA viruses. The RRP viruses have been studied phenotypically,8 but no clinical correlate has been found to site,
extent, or severity of involvement, and coinfection with up to 6 different
types of virus in the larynx at once have been noted.
METHODS
My first use of mumps vaccine as RRP therapy (in 1980) and my second
use (1989) were 9 years apart. Both resulted in spectacular remission, and
a pilot study was then prospectively undertaken in 9 patients who, without
much change in their recurrence interval, had been under treatment for at
least a year. The results in these first 11 cases were encouraging enough
to continue using this off-label treatment in a subsequent group of patients.
No patient agreed to participate in a prospective blinded trial, even though
crossover would have ensured that all participants could have eventually received
mumps vaccine. This report should therefore be considered as preliminary.
Additionally, there were no controls.
Each patient was treated with laser vaporization of papilloma in an
identical manner at a treatment interval determined by the extent and severity
of their disease. I used a prospective approach to recurrence, shortening
the treatment interval when recurrence increased in extent, and lengthening
it when recurrence had diminished. Photography through an endoscope and an
illustration by the surgeon were used for retrospective analysis of disease
severity. No phenotypic analysis of the causative virus was performed. The
criteria for remission were at least 2 consecutive disease-free intervals,
with a follow-up of at least 1 year.
I used proximal jet ventilation through a custom-made suspension laryngoscope
(Sontec, Denver, Colo) to apply laser vaporization to affected areas after
removal of tissue for histologic examination by cup forceps. Settings were
2 to 5 W with a spot size of 0.5 to 0.75 mm and continuous mode on a carbon
dioxide laser (Coherent, Santa Clara, Calif). In the last 2 years, I have
used a carbon dioxide laser (SSI Laser Engineering, Nashville, Tenn) with
an "ultrapulse" mode, which provides a 40-microsecond pause between energy
bursts and allows tissue cooling and less char. I still use 2 to 5 W of energy,
but the spot size is smaller at 0.1 to 0.2 mm. To open the ventricle in the
adult patients, a larger custom laryngoscope (Sontec) was made.
Each ampule of mumps vaccine was initially reconstituted to 2 mL (the
needle for infiltration has a dead space of 0.5 mL) and injected into the
tissue at the base of the site of laser excision of any papilloma using microscopic
control and a laryngeal injection needle (Piling Co, Philadelphia, Pa) with
a working length of 30 cm. From my experiences with adult patients, I theorized
that their response to treatment with mumps vaccine was related to the number
of ampules administered. The dilution of each ampule was reduced to 0.5 mL
to allow the number of ampules injected with each treatment to be increased,
and this is my current technique in adults and children.
No oral or parenteral steroid medication was used during or after laser
therapy despite the presence of (injected) edema. This was based on my supposition
that any steroid administered might be immunosuppressive; it is important
that all treating staff, particularly the anesthesiologist, be alerted to
this. Edema or bleeding intraoperatively was managed by the use of topically
applied 0.25% phenylephrine on a cotton pledget. After the mumps vaccine was
injected, virtually complete occlusion of the airway was common. This was
managed by gentle suspension of the airway for a few minutes, using the laryngoscope
or a bronchoscope, but neither was forced into the airway, and commonly a
topical application of racemic epinephrine was used. This can be applied by
direct instillation of a measured dose based on weight, with the larynx suspended,
or by nebulized droplets in a postanesthesia recovery unit.
RESULTS
INITIAL PATIENTS
In 1980, the first patient for whom I used mumps vaccine as a treatment
for RRP was a 5-year-old girl who, after 3 years of regular laser treatment,
suddenly saw her treatment interval shorten from every 6 weeks to every 14
days. A single intralaryngeal immunization into the base of the lasered area
was used, and immediately the patient was able to revert to a 6-week treatment
interval. With 3 subsequent intralesional injections at the time of laser
removal of papilloma, there was complete remission. This was not immediately
apparent, however, because there was a 6-year interval between the last treatment
and the next contact for treatment of a small anterior web causing hoarse
voice. This patient remained in remission as of December 2000.
The second patient presented for treatment at age 1 year and initially
was treated at intervals of 3 to 5 weeks. At age 2 years, there was
gradual worsening, shorter intervals between surgical procedures, several
increasingly longer episodes of respiratory support by intubation after laser
excision of papilloma, scar formation with recurrent disease, and later tracheostomy
with the development of peristomal papillomata infiltrating the skin. Interferon
was used 4 times without discernible effect. This was the only patient in
this group to receive adjuvant therapy other than mumps vaccine. A single
intralaryngeal injection of mumps vaccine produced marked flattening of intralaryngeal
papilloma and loss of a bulky papilloma in the right main stem bronchus without
laser removal at this site. Five serial injections at 3- to 5-week intervals,
including infiltration of the skin within the tracheal stoma, produced complete
remission. A laryngotracheoplastic reconstruction of the patient's stenotic
subglottis was then possible, and decannulation successful.
PILOT GROUP
Retrospective severity scores before treatment of these 2 patients under
the schematic suggested by Derkay et al4 were
23 for the first and 25 for the second. After treatment, each patient had
a severity score of 1. These 2 original patients were observed at regular
intervals, and a pilot study was undertaken to see if their results could
be duplicated. A total of 9 consecutive patients, aged 18 months to 8 years,
who had been under treatment for at least a year by the same surgeon using
the same laser endoscopic equipment at regular 3- to 12-week intervals, were
prospectively treated with locally infiltrated mumps vaccine at each regularly
scheduled suspension laryngoscopy (Table
1).
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Table 1. Pilot Study Group
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SUBSEQUENT SERIES
The subsequent treatment group consisted of patients who had requested
mumps therapy with their regularly scheduled laser debulking. A total of 38
patients (16 female and 22 male), including 18 children aged 1 to 11 years
and 20 adults aged 19 to 57 years, were treated at the same regular interval
of treatment that had been established prior to introduction of the mumps
vaccine therapy (Table 2). Treatment
was altered slightly for some of these patients when I switched from using
the Coherent carbon dioxide laser to the SSI carbon dioxide laser equipped
with ultrapulse. If necessary, up to 9 ampules of mumps vaccine diluted to
4.5 mL were later used for each treatment. Eighteen of the 38 patients had
previously used some adjuvant therapy, and 4 continued to use indole-3-carbinol
during our treatment. No patient had used interferon within the past 2 years
prior to our treatment.
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Table 2. Subsequent Group Results for Children and Adults
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Histologic examination of papillomas from all patients revealed benign
squamous papilloma with mild atypia and koilocytic changes and changes typical
of viral-induced papilloma. As remission was induced in patients, biopsy specimens
did not demonstrate any particular change; ongoing mild acute and chronic
inflammation was present in all patients at some stage in their illness. Biopsy
specimens from areas where complete remission had been induced showed fibrosis,
but these specimens were not consistently taken because taking them in some
instances could have adversely affected voice quality. Additionally, these
areas were often difficult to locate by the time of the next treatment. No
phenotyping of papilloma was undertaken.
COMMENT
Local infiltration of mumps vaccine, when combined with serial, prospective
laser excision of respiratory papilloma to maintain airway and maximize voice,
is capable of improving the remission rate. It is not clear how this occurs,
and there are a number of variables, none of which is truly addressed in this
report. After initial excision and injection, the placement of injected liquid
around remaining papilloma in the larynx provided a much improved view of
the tissue separation and less collateral thermal injury when the laser was
used, and an improved clearance was achieved. The removal of papilloma at
the apparent point of origin was therefore possible with this method, but
I have not attempted this with saline or other liquid. No phenotyping of papilloma
was undertaken in any of my patients because of the lack of apparent clinical
correlation reported.8
During the follow-up of this small series of patients, the following
observations have helped modify our approach. In all patients, the lateral
posterior ventricle was the last site where papilloma was found and eliminated
other than the anterior commissure. In patients who had persistent hoarseness
without obvious papilloma, it was the rule to see scar partially or completely
webbing the ventricle (bridging from the false to the true cord). An incision
laterally into the ventricle often resulted in uncapping of a mucus-containing
microcyst with papilloma within it. Opening the ventricle, therefore, might
be essential if complete remission is to be achieved. Some modification of
the severity score4 might be appropriate in
this area, which is not a separately named area in the published assessment.
The results from the pilot study group would indicate that the apparent
improvement in remission rate for these patients was not simply due to the
better or more complete removal of their papilloma when liquid was placed
into the tissue spaces. All of these patients had been receiving the same
treatment by the same surgeon using the same equipment and approach for at
least 1 year, and the only variable was the introduction of mumps vaccine.
Two patients in the subsequent group, both younger than 1 year, required
only 1 injection of mumps vaccine for the induction of complete remission.
Neither patient had been immunized with a measles-mumps-rubella (MMR) vaccine.
Additionally, 3 other patients in this group went into remission despite papilloma
at sites within the trachea that were not directly infiltrated with mumps
vaccine. Four parents of affected children have independently suggested that
the timing of their child's obstructed airway coincided with their 1-year
immunization with MMR vaccine. Each of these patients had altered voice from
the neonatal period but had not sought medical attention until the airway
suddenly became more obstructed after their immunization. This suggests that
an agent in the MMR vaccine triggers an inflammatory change in respiratory
papilloma growing harmoniously in the airway of children with RRP. The numbers
here might be at the anecdotal level, but it is difficult to deny that there
may be an effect that is not caused solely by improved ability to remove the
papilloma at a local site but is the result of a systemic, probably immune,
agent.
The adult patients in our series do not seem to be a recognizably different
clinical group. Their disease in some cases had been present for a shorter
time than in the pediatric group, but in others, longer; and 2 adult patients
were childhood papilloma "graduates" with persistent papilloma. Interestingly,
most of the affected adults older than 40 years had not been immunized against
measles, mumps, or rubella in childhood and had immunity only from acquiring
the diseases.
Although it would be interesting to measure the patients' antibody response
to the repeated mumps vaccinations, I have not done so. The quantity of vaccine
given varied not only by patient size and area of papilloma involvement, but
by frequency of injection and simple tolerance of the larynx to what is essentially
directly injected edema. My approach was to inject to the point of tolerance.
My impression is that the more extensive the papilloma, the greater the "antigen
load," and the more vaccine is required to see an effect. However, the present
report does not analyze this impression, and it is unknown whether a threshold
amount of mumps vaccine has to be given before an effect is seen. It is also
unknown whether the remission effect is related at all to the amount of antigen
or papilloma present. Nor have I compared the patient's baseline lymphocyte
count (T cells and in particular natural killer cells) with that of a population
without active or previous infection with the papilloma virus. However, the
successful use of an off-site immunization with a proven track record against
1 virus to treat a viral infection caused by a different category of virus
in another anatomic location might imply stimulation of the patient's own
impaired immunity to viruses in that location.
Interestingly, the mode of administration of mumps vaccine used in the
present study is identical to that described by Pransky et al3
with intralesional cidofovir to induce remission in patients of similar age
with the same disease. The remission rate is also strikingly similar in their
series of patients, and they too discussed the patient's ability to "mount
an adequate immune response to HPV [human papillomavirus] once the tumor burden
is decreased."3 We may be approaching this
disease by similar methods from 2 opposing directions. Cidofovir treatment
might reduce the tumor burden locally to the point at which the patient's
own immune is able to function; and the mumps vaccine might be stimulating
the immune system systemically to the point of competence for this particularly
pernicious virus. Clearly there is much research to be performed before clear
answers are available.
Coincidence is also a possibility, but intralesional mumps vaccine is
safe, readily available, easy to use, and, at a cost of approximately $25
per ampule, inexpensive to administer. If the results of the present report
can be duplicated by other surgeons, further study of possible mechanism of
action might provide aid for this group of patients.
AUTHOR INFORMATION
Accepted for publication January 8, 2002.
This study was presented at the annual meeting of the American Society
of Pediatric Otolaryngologists, Scottsdale, Ariz, May 10, 2001.
Corresponding author and reprints: Nigel R. T. Pashley, MB, BS, FRCSC,
1601 E 19th Ave, Suite 5500, Denver, CO 80218 (e-mail: npashley{at}aol.com).
From Presbyterian/St Luke's Hospital, Denver, Colo.
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