Original Research—Laryngology and Neurolaryngology

Otolaryngology–
Head and Neck Surgery

Adult Recurrent Respirator 148(2) 253–260

Ó American Academy of
Otolaryngology—Head and Neck
Papillomatosis: A New Therapeutic Surgery Foundation 2013
Reprints and permission:
Approach with Pegylated Interferon sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599812466226

Alpha 2a (Peg-IFNa-2a) and GM-CSF http://otojournal.org

Teresita Suter-Montano, MD1, Efraim Montaño, MD2,

Carmen Martı́nez, MD3, Teresita Plascencia, MD4,
Mayra T. Sepulveda, MD5, and Miguel Rodrı́guez, MD2

No sponsorships or competing interests have been disclosed for this article. Keywords
adult recurrent respiratory papillomatosis, human papilloma-
Abstract virus, Peg-IFNa-2a, GM-CSF, laryngeal papillomatosis
Objective. To determine a new therapeutic approach using
granulocyte monocyte–colony-stimulating factor (GM-CSF) and Received March 18, 2012; revised September 17, 2012; accepted
pegylated interferon alpha 2a (Peg-IFNa-2a) as adjuvant ther- October 9, 2012.
apy in patients with adult recurrent respiratory papillomatosis.
Study Design. Descriptive observational clinical trial.

T
he treatment of laryngeal papillomatosis (LP) is sur-
Setting. Departments of Otolaryngology and Immunology. gically based. Many surgeons have found CO2
lasers to be best for excising the larynx papillomas.
Methods. Fourteen patients with adult recurrent respiratory Nevertheless, other surgeons have been convinced in using
papillomatosis were examined regarding medical history and other surgical tools, such as microdebriding,1 phonosur-
number of operations before and after treatment. Voice dis- gery,2 and cold instruments.3
order and glottal stop were evaluated using the Voice- Laryngeal papillomatosis has a major impact on patients’
Related Quality-of-Life instrument. Papilloma staging was quality of life and the cost of health care. Both patients and
determined using the Coltera/Derkay diagram. The patients physicians are challenged by this difficult disease, for which
received Peg-IFNa-2a at 180 mcg weekly for 6 months. In no effective treatment currently exists. Ten percent of all
the third month, the patients began GM-CSF treatment at patients require adjuvant therapy.4
400 mcg weekly for 2 months. The patients were observed The clinical course of respiratory papillomatosis is unpre-
for 12 months after treatment ended. dictable; many patients relapse and develop a chronic ill-
Results. Eleven patients met the study criteria; 3 patients had ness, adult recurrent respiratory papillomatosis (ARRP).
tracheotomies before treatment, and they were decannu- These patients may require additional surgeries. Aggressive
lated after treatment. Before treatment, the scale of voice lesions require emergency surgical procedures. Malignant
quality ranged from 34 to 45 points (mean, 38.31). After degeneration occurs in 3% to 7% of cases.5 Seven percent
treatment, the range was 12 to 35 points (mean, 21.09; P \ of patients require more than 100 surgical procedures during
.001). Prior to therapy, the glottal stop ranged from 50% to
90% (average, 62.27%). After therapy, the range decreased 1
Medical Practice of Dr R. Engler ENT (Buchs SG), Daenikon-Zürich,
to 0% to 15% (mean, 4.63%; P \.001). The number of surgi- Switzerland
2
cal interventions decreased. Two patients each had 1 surgi- Department of Immunology and Allergy, Hospital de Especialidades,
Centro Médico Nacional de Occidente, Guadalajara, Jalisco, Mexico
cal intervention after treatment began. 3
Department of Otolaryngology and Endoscopy, Hospital de Especialidades,
Conclusion. A new adjuvant treatment based on immunoge- Centro Médico Nacional de Occidente, Guadalajara, Jalisco, Mexico
4
Department of Pathology, Hospital de Especialidades, Centro Médico
netic mechanisms against human laryngeal papilloma virus, Nacional de Occidente, Guadalajara, Jalisco, Mexico
with expectations of reducing disease aggressiveness and 5
Department of Pediatrics, Hospital de Especialidades, Centro Médico
the number of operations, avoids the risks of surgery. Nacional de Occidente, Guadalajara, Jalisco, Mexico

Implication for Practice. Peg-IFNa-2a and GM-CSF is an adju-

Corresponding Author:
vant therapy for treating adult recurrent respiratory Teresita Suter-Montano, MD, Medical Practice of Dr R. Engler ENT (Buchs
papillomatosis. SG), Switzerland Lettenring 21, CH-8114 Daenikon-Zürich, Switzerland
Email: [email protected]

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254 Otolaryngology–Head and Neck Surgery 148(2)

their lifetime,6 and patients can occasionally require surgery significantly improve the primary response and conse-
every month. Adult recurrent respiratory papillomatosis is a quently a stronger secondary immune response against the
frustrating disease that requires extensive surgical treat- virus.
ments, resulting in prolonged physical and emotional suffer-
ing and the possibility of acute airway obstruction.7 Hypothesis
Emotions are manifested primarily in the voice and face, As discussed above, ARRP is a difficult disease that requires
and the voice is one of the most important vehicles of com-
lifelong treatment, profoundly affecting patients’ quality of
munication.8 Patients with ARRP can suffer from social dis-
life and involving risks with every surgery. The current adju-
crimination caused by vocal dysfunctions and can also
vant therapies for recurrent respiratory papillomatosis/ARRP
experience discrimination in employment. In addition, many
have had negative or unsatisfactory results. Therefore, we
patients are stigmatized because the disease is transmitted
considered an alternative new adjuvant therapy to improve
sexually.
patients’ quality of life and decrease the frequency of sur-
The first line of defense against human papillomavirus
geries. The synergistic effects of Peg-IFNa-2a and GM-CSF
(HPV) is the innate immune response.9 The subsequent acti- could produce an increased innate immune response suffi-
vation of monocytes/macrophages and the secretion of inter-
cient to achieve better control the viral infection.
feron (IFN)–a, interleukin (IL)–12, and tumor necrosis
We designed a descriptive observational clinical trial to
factor (TNF)–a induces a predominantly T helper 1 (Th1)–
determine the effectiveness of therapy with Peg-IFNa-2a and
cell response and the acquired immunity that has been used
GM-CSF that has not been previously reported in the litera-
clinically to treat viral infections.10
ture. We expected an improved innate immune response with
Dendritic cells (DCs) are well known to participate in the
initial effects on immune modulation, considering the action
innate antiviral immune response by producing interferon after
of DCs against virus replication. Through this direct action
viral exposure.11 They are the principal initiators of the immune on the immune response, we used Peg-IFNa-2a and GM-
phenomena involved in the antiviral response.12 Dendritic cells
CSF to determine whether this therapy could improve
are strong antigen-presenting cells characterized by their anti-
patients’ clinical conditions. Our hypothesis is that the use of
viral activity and effects on the cells of the innate immune
2 cytokines related to the activation and maturation of DCs
response.13 They also are a bridge to connect innate and adap-
would result in a stronger immunological response that
tive immunity by acting on immune cells, such as T cells.14
would inhibit viral replication, resulting in better clinical out-
Interferon a (IFNa) is an immunomodulatory cytokine
comes and quality of life for patients with ARRP.
originally characterized by its antiviral and antiproliferative
activity15 and its effects on the cells of the innate immune
response, which are considered inflammatory cytokines and
Patients and Methods
are essential for eliminating viral particles and regulating The study was performed from December 2005 through
phagocytic activity.16 It plays an important role in connect- May 2006. All patients in the study had been diagnosed
ing innate and adaptive immune responses by acting on with ARRP, and the age range of the patients was 21 to 74
highly specialized immune cells, such as T cells.17 It also years. Patients who did not have contraindications for the
can activate immature DCs to promote an adequate immune use of Peg-IFNa-2a and GM-CSF signed a letter of informed
response,18 and the pegylated form (Peg-IFNa-2a) of this consent according to the institutional policies of the Specialty
cytokine enhances IFNa’s activity.19 Hospital, National East Medical Center (IMSS). This study
Granulocyte monocyte–colony-stimulating factor (GM- was assessed and approved by the institutional review board/
CSF) has been used as an immune-modulating agent20 and ethics committee of medical research.
is an excellent drug for promoting humoral and cellular The inclusion criteria included a diagnosis of ARRP, age
immune responses.21 It belongs to the family of colony- older than 16 years, a signed letter of informed consent, and
stimulating factors and is a powerful immune stimulant.22 It normal laboratory testing.
is essential for the differentiation, maturation, and mobility The exclusion criteria included a history of renal or liver
of DCs23 and is capable of inducing the maturation of per- disease, malignant hematological diseases, high-grade cellu-
ipheral DCs, regulating the expression of the major histo- lar atypia on a biopsy specifically from the affected area,
compatibility complex (MHC II), and secreting stimulating intolerance to cytokines, alterations in clinically significant
factors that contribute to the presentation of antigens by laboratory results, and concomitant medication that could
DCs. Granulocyte monocyte–colony-stimulating factor is interfere with the pharmacological effects of cytokines.
critical for the development of an adequate immune Information about the schedule of visits, timing, and LP
response, promoting an optimized local immune microenvir- relapse is documented in Table 1. During the first visit, the
onment, and enhancing specific immunity.24 patient’s clinical status was assessed through a medical his-
Herein, we offer a new adjuvant therapy for the treatment tory, sexual behavior history, drug use history, and a physical
of ARRP. Based on the multiple actions of these cytokines, examination that included blood pressure, weight, and height
they were expected to increase and strengthen the immune measurements; pretreatment laboratory testing, including uri-
response. We believe that the synergistic action of these 2 nalysis; assays for serum urea, creatinine, electrolytes, liver
cytokines (Peg-IFNa-2a and GM-CSF) on DCs will function, blood chemistry, CD4 and CD8, lymphocytes,
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Suter-Montano et al 255

Table 1. Clinical Course of Each Patient and Information about the Visiting Schedule and Side Effects of Peg-IFNa-2a and GM-CSF
Patient 12 mo of
No. Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Clinical Observation

1 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a

Nasopharyngoscopy GM-CSF GM-CSF Nasopharyngoscopy
Pain and redness at the injection site No relapse
2 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a
Nasopharyngoscopy GM-CSF GM-CSF Nasopharyngoscopy
Decreased appetite Pain and redness at the injection site Decannulation No relapse
Headache Headache Headache Headache Headache

3 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a

Nasopharyngoscopy GM-CSF GM-CSF No relapse
Surgical removal Pain and redness at the injection site Nasopharyngoscopy
Headache Flu-like syndrome, headache Headache Headache

4 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapse

Nasopharyngoscopy GM-CSF GM-CSF Nasopharyngoscopy
Surgical removal Pain and redness at the injection site Decannulation Subglottic
Flu-like symptoms Stenosis
5 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Surgical removal Surgical removal
Nasopharyngoscopy GM-CSF

6 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a

Nasopharyngoscopy GM-CSF GM-CSF No relapse
Flu-like syndrome Pain and redness at the injection site Nasopharyngoscopy
Decreased appetite Decreased appetite

7 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapsing

Nasopharyngoscopy GM-CSF GM-CSF Nasopharyngoscopy
Headache Pain and redness at the injection site, fever Complete remission

8 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapse

Nasopharyngoscopy GM-CSF GM-CSF Nasopharyngoscopy
Pain and redness at the injection site

9 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapse

Nasopharyngoscopy Pain and redness at the injection site Nasopharyngoscopy
Bronchial papilloma Decannulation

10 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a

Nasopharyngoscopy GM-CSF Surgical removal
Pain and redness at the injection site
Started treatment with both cytokines, but patient did not attend the appointments each month

11 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapse

Nasopharyngoscopy Pain and redness at the injection site Nasopharyngoscopy
Asthenia, adynamia Complete remission
12 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a
Nasopharyngoscopy GM-CSF
Pain and redness at the injection site Surgical removal
Bone and muscle pain

13 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapse

GM-CSF GM-CSF
Nasopharyngoscopy Pain and redness at the injection site Nasopharyngoscopy
Flu-like syndrome, headache Total remission

(continued)
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256 Otolaryngology–Head and Neck Surgery 148(2)

Table 1. (continued)
Patient 12 mo of
No. Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Clinical Observation

14 Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a Peg-IFNa-2a No relapse

Nasopharyngoscopy GM-CSF GM-CSF Nasopharyngoscopy
Decreased appetite Pain and redness at the injection site
Headache Headache Headache
Patients 5, 10, and 12 were eliminated from the study because they stopped the treatment. Four had a headache, 4 reported flu-like symptoms, and 3 suf-
fered loss of appetite. One patient had bone pain and myalgia. Patients 3 and 4 underwent surgery at the beginning of treatment and did not relapse during
the observation time. Comorbidity: patient 7 had sinus bradycardia, and patient 11 had leukopenia. Abbreviations: GM-CSF, granulocyte monocyte–colony-stimulating
factor; Peg-IFNa-2a, pegylated interferon alpha 2a.

subpopulations, and antinuclear antibodies; and a complete et al.25 The original meaning of Coltera’s diagram study was
hemogram. maintained and used to stage the papillomas (assigning a
To evaluate the operations, we compared the number of numeric score: 0 = none, 1 = surface lesion, 2 = raised lesion,
surgeries over the previous 18 months before the start of and 3 = bulky lesion) before and after treatment.
treatment with the posttreatment number of surgeries. The Nasopharyngoscopy was performed with a flexible fiber
posttreatment period included 6 months of treatment and endoscope (Fujinon 4400; Fujinon, Fort Lee, New Jersey)
12 months of observation (18 months in total). passed through the nasal cavity and hypopharynx until the
We did not use a control group for the following reasons: glottis was visualized while the patient was under local
(1) the ethics committee decided to provide the same oppor- anesthesia. The image was viewed on a monitor. The per-
tunity to all patients with ARRP; (2) the first cases we centage of functional obstruction caused by the papillomato-
observed had excellent results and, therefore, we did not sis lesions of the glottis was evaluated while the glottis was
want to deny ARRP patients treatment with the new adju- in an abducted position.
vant therapy; (3) we knew from the historic behavior of the To measure the degree of voice disorder (dysphonia), we
disease that the multiple surgeries that pose a high risk to used the V-RQOL instrument.26 The V-RQOL questionnaire
the patients are inevitable; and (4) because this treatment is based on 10 core items, and the responses are scored on a
was experimental, we decided to administer it in a small scale from 1 (excellent) to 5 (very bad). We evaluated the
number of cases that would allow us to conduct a more in- improvement in the patients’ quality of life through assess-
depth study. Fourteen patients were included: 3 women ment of the voice quality before and after treatment.
(21.5%) and 11 men (78.5%). Direct laryngoscopy was per-
formed for each patient before and after treatment to assess Results
the degree of glottal obstruction. The following results were obtained. One patient was homo-
Medical visits were scheduled each month until the end sexual (7.14%), 13 were heterosexual (92.86%), and 30% of
of the protocol. At the second visit, if no abnormalities were these patients reported having more than 1 sexual partner.
found in the laboratory tests, the patients began a treatment Three patients had a tracheotomy before starting treatment.
regimen of weekly 180-mcg subcutaneous injections of Peg- These patients presented with severe and rapidly growing
IFNa-2a (PEGASYS; Roche, Basel, Switzerland) for a LP that provoked severe glottal obstruction; the distal airway
period of 6 months. In the third month, the patients began was also involved. During treatment, the growth of these LP
treatment with weekly 400-mcg subcutaneous injections of lesions slowed, and the lesions were no longer present in
GM-CSF (molgramostim [GRAMAL]; Probiomed, Mexico some anatomic subsites, prompting decannulation of these
D. F., Mexico) for 2 months. The patients remained under patients before treatment ended.
observation for a total of 18 months: 6 months while the When we assessed voice quality prior to treatment, we
patients were undergoing cytokine therapy and 12 months obtained a range of 34 to 45 points, with a mean of 38.31.
after the treatment ended. At the end of the study, the After treatment, the maximum voice quality was 35 points,
patients again responded to the health-related Voice-Related and the minimum was 12 points; the mean voice quality
Quality-of-Life (V-RQOL) questionnaire, and nasopharyn- after treatment was 21.09 points. All patients exhibited
goscopy was performed to assess the state of the vocal improvement in their voice quality and quality of life. The
cords and glottal stop. Statistical analysis of the data was difference between pre- and posttreatment voice quality was
performed using SPSS version 15.0 for Windows (SPSS, significant at P \ .001, as shown in Figure 1.
Inc, an IBM Company, Chicago, Illinois). Before treatment, we found a maximum glottal occu-
The papillomatosis lesions of the larynx were evaluated pancy of 95% and minimum occupancy of 50%, with a
according to the diagram developed by Marc Coltera of the mean of 62.27%. After treatment, the maximum glottal
University of Washington and presented in a study by Derkay occupancy was 15%, and the minimum was 0% (average,
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Suter-Montano et al 257

Figure 3. Surgical interventions before treatment and during the

Figure 1. Patients’ scores on the 10-question Voice-Related observation period, after the conclusion of treatment.
Quality-of-Life (V-RQOL) instrument.

the minimum score was 0, with an average of 1.81. The dif-

ferences were statistically significant (P \ .0001).
Regarding the evaluation of the surgeries, the patients
exhibited improvement because the number of surgical
interventions significantly decreased in frequency.
The posttreatment results exhibited values lower than the
pretreatment values and were highly statistically significant
(P \ .0000; Figure 3 and Table 2). In our study, 1 patient
had undergone 75 surgical interventions over 14 years. The
3 patients who were eliminated from the study for nonmedi-
cal reasons were followed and underwent further surgical
Figure 2. Improvement in glottic occupancy (glottal stop) before
treatments over the study period.
and after treatment.
Because of the doses used, the side effects were mild and
treated symptomatically (with paracetamol), and the use of
GM-CSF and Peg-IFNa-2a was not discontinued. The
4.63%), a statistically significant improvement (P \ .001) patients reported the following side effects: flu-like
(Figure 2). symptoms (3 patients), headache (4 patients), decreased
We scored the papillomas before and after treatment appetite (3 patients), and bone pain (1 patient). All
according to the staging assessment system described in patients reported painful erythema and hardness at the injec-
Coltera’s diagram. Prior to treatment, we obtained a maxi- tion site. No hematological disturbances, psychiatric altera-
mum score of 36 and a minimum score of 15, with a mean tions, or autoimmune diseases were reported. Laboratory tests
of 22.68. After treatment, the maximum score was 7, and for hematological evaluation were performed at each visit,

Table 2. Information Concerning the Surgeries of Each Patient

Average No. of
Years of No. of Surgeries Observation Surgery Surgeries per Relapse
Patient No. Evolution of the Disease during Lifetime before Treatment during Study Year of Disease during Treatment

1 3 3 1 0 2
2 2 7 1 0 4
3 31 51 1 1 2 1
4 5 11 2 1 3 1
5 10 32 2 0 3
6 2 5 2 0 32
7 3 5 3 0 2
8 14 75 4 0 5
9 3 4 1 0 2
10 2 5 2 0 2
11 10 11 2 0 1
Average 7.72 19 1.90 0.18 5.27 0.18
The mean average was 7.72 years of evolution of disease per year, per patient, with an average of 19 surgeries per year, per patient, and average of 5.27 sur-
geries per year of disease.

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258 Otolaryngology–Head and Neck Surgery 148(2)

but these results were not considered significant enough to factor facilitates the migration, activation, and differentiation
suspend treatment. of DCs, improving the innate immune response and optimiz-
ing the local microenvironment.46 Based on the investigations
Discussion of Majewski and Jablonska,35 the best way to control this dis-
The goal of surgery is the removal of whole HPV lesions ease is by breaking the viral life cycle, which limits the
without damaging the adjacent or underlying tissue; such HPV-infected cells and makes the infected cells more sensi-
injuries result in alteration of the mucosa, irreparable scars, tive to the inflammatory response. We seek an alternative to
and stenosis, especially of the anterior and posterior com- improve the immune response and break the ARRP disease
missure of the glottis. These scars lead to severe, irreparable cycle via the therapeutic action of GM-CSF and Peg-IFNa-
postoperative dysphonia. To minimize the untoward effects 2a as immune modulators for local DCs and the innate
of surgery, various surgical tools have been used.1-3 immune response stimulation.47 Further studies are needed to
Conventional surgical methods are not sufficient to eliminate confirm that adjuvant therapies directed against either viral
the active regrowing HPV infection and/or prevent further protein are beneficial.48
LP.27 Other adjuvant therapies for recurrent respiratory papil- The antiviral effects of IFNa alone result in complete
lomatosis treatment have had variable success, including remission in approximately 40% of patients after 6 to 12
intralesional cidofovir injections,28 oral indole-3-carbinol,29 months of treatment.49 Therefore, we are committed to
interferon,30 and the antiviral ribavirin.31 offering more rational adjuvant therapy based on immuno-
Human papillomavirus establishes itself in the basal pathogenic mechanisms. In our experience, Peg-IFNa-2a
layer of the mucosa, where it can remain in a latent form32 and GM-CSF as adjuvant therapy decreased the recurrence
or cause the transcriptional activation of cell nucleus RNA. of HPV infection and the need for surgical removals, lead-
Subsequently, the RNA is translated into viral proteins ing to an improved quality of life.
(viral particles), which themselves promote the production Adult recurrent respiratory papillomatosis requires many
and replication of HPV-infected cells.33 surgical interventions and prolonged medical treatments,
After stem cell infection, viral DNA is actively expressed increasing the difficulty of completely eradicating the HPV
and multiplies into the upper layers of the epithelium, infection. Endoscopic debridement of HPV lesions is the
where hyperproliferative HPV lesions manifest,34 thus caus- only method to maintain the permeability of the airways.
ing cellular proliferation instead of cell lysis. Therefore, Vocal function is an integral part of human communication.
inflammatory responses are not induced, and the cytokine Individuals who are unable to speak, express themselves, or
anti-HPV effect is not activated35; thus, release of the proin- show emotions often suffer from emotional distress. The
flammatory cytokines required to activate DCs36 and pro- ability to express oneself and communicate is important
mote their migration to the larynx-associated lymphoid for a high quality of life. Therefore, it is important to
tissue (LALT) does not occur.37 Human papillomavirus determine methods for improving these patients’ poor
infection is associated with local intraepithelial immune quality of life.
deficiency,38 a required factor for ARRP development that This therapy is recommended after the first relapse or for
might be a host immune deficit.39 Moreover, HPV uses vari- patients who have required 2 operations in a short period.
ous mechanisms to protect itself from the innate immune There are limitations of this study to consider. For exam-
system of the host. No induction of IFNa occurs,40 allowing ple, the specific immunodeficiency of patients with ARRP
HPV to avoid the innate immune antiviral response and is not yet well defined. The aim of this adjuvant therapy is
thus41 avoid recognition and elimination, slowing the activa- to strengthen the immune response to HPV infection. This
tion of the adaptive immune response.42 Therefore, the study was small because of the relatively low frequency of
host’s DCs are exposed to viral proteins in a noninflamma- ARRP. This study could be biased because of the absence
tory milieu. of a control group; this point is already justified in the
A specific production pattern of cytokines in ARRP is a method. Although the results obtained in this study suggest
paramount step toward inactivating or inhibiting the synth- statistical significance, we suggest more research and longer
esis of HPV viral particles/proteins and HPV-infected periods of observation on this topic; such studies are
cells.43 Granulocyte monocyte–colony-stimulating factor, required to elucidate the molecular immune system mechan-
IFNa, and IL-4 enhance the activation of unstimulated DCs ism underlying ARRP. Further studies are required to con-
through the activity of viral particles and strengthening of firm that the adjuvant therapy is useful. A next step could
the LALT.44 be a double-blind, placebo-controlled study.
The laryngeal mucosal immune system45 may cooperate
with cell-mediated immunity to control HPV disease. We Conclusion
believe that the humoral and cellular immune systems are The present descriptive, observational clinical trial con-
stimulated in response to cytokines, thus influencing the nat- firmed the possibility/utility of a new adjuvant therapy
ural history of HPV disease. based on the immunomodulatory effects of Peg-IFNa-2a
We have used the therapeutic antiviral effects of Peg- and GM-CSF, which act synergistically to enhance the
IFNa-2a and the immunomodulatory effects of GM-CSF as innate immune response against laryngeal HPV, thus
adjuvant therapies. Granulocyte monocyte–colony-stimulating achieving partial or complete remission of the disease. The
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Suter-Montano et al 259

objectives of this study were to improve quality of life by not DC activation of virus-specific T cells. J Virol. 2008;82:
decreasing the number of operations and avoid the risks of 5329-5339.
surgery. With these goals in mind, other cytokines could 10. Schiller M, Metze D, Luger TA, Grabbe S, Gunzer M.
potentially be used to initially improve the innate immune Immune response modifiers: mode of action. Exp Dermatol.
response and better manage this challenging disease. 2006;15:331-341.
11. Lenz P, Lowy DR, Schiller JT. Papillomavirus virus–like parti-
Acknowledgments
cles induce cytokines characteristic of innate immune
We thank Miguel Rodrı́guez, MD, and Efraim Montaño, MD, for responses in plasmacytoid dendritic cells. Eur J Immunol.
their input and support in this multidisciplinary work on adult 2005;35:1548-1556.
recurrent respiratory papillomatosis treatment with Peg-IFNa-2a 12. Takayama T, Morelli AE, Robbins PD, Tahara H, Thomson
and GM-CSF, as well as Eduardo Garcia de Alba, MD, for his AW. Feasibility of CTLA4Ig gene delivery and expression in
help with the statistical analysis of the data. We extend a special
vivo using retrovirally transduced myeloid dendritic cells that
thanks to Craig S. Derkay, MD, for his permission to use the ana-
induce alloantigen-specific T cell anergy in vitro. Gene Ther.
tomic staging and scoring system.
2000;7:1265-1283.
13. Mount AM, Smith CM, Kupresanin F, Stoermer K, Heath WR,
Author Contributions Belz GT. Multiple dendritic cell populations activate CD41 T
Teresita Suter-Montano, research, study design, drafting and cell after stimulations. PLoS ONE. 2008;3:e1691.
reviewing the manuscript; Efraim Montaño, examining and treat- 14. Steinman RM, Hemmi H. Dendritic cells: translating innate to
ing patients; Carmen Martı́nez, examining and treating patients, adaptive immunity. Curr Top Microbiol Immunol. 2006;311:
laryngoscopy; Teresita Plascencia, revision of histopathological 17-58.
sections; Mayra T. Sepulveda, data collection; Miguel 15. Reuman P. Inmmunomodulators. Pedriatr Infect Dis J. 2001;
Rodrı́guez, study design, treating patients, and reviewing the 20:995-996.
manuscript. 16. Belardelli F, Ferrantini M. Cytokines as a link between innate
Disclosures and adaptive antitumor immunity. Trends Immunol. 2002;23:
Competing interests: None. 201-208.
17. Huber K, Sadick H, Götte K. Current therapeutic options for
Sponsorships: None.
recurrent respiratory papillomatosis [in German]. HNO. 2005;
Funding source: None. 53:921-927.
18. Curiel-Lewandrowski C, Mahnke K, Labeur M, et al.
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