Human papilloma virus vaccination in patients with an aggressive course of recurrent respiratory papillomatosis

In the case of an aggressive course of recurrent respiratory papillomatosis (RRP), adjuvant therapy can be used besides surgery. The aim of the study was to investigate the influence of vaccination with a quadrivalent vaccine against human papilloma viruses (HPV) types 6, 11, 16 and 18 on the course of RRP. Eleven subjects aged 13–46 years with a rapid growth of laryngeal papillomas were included in the study. They were vaccinated with three doses of the quadrivalent prophylactic HPV vaccine (Silgard^®, MSD) and followed up for 12–52 months. The intervals between the successive surgical procedures, the extension of the disease (Derkay score) at each surgery, and the number of surgical procedures per year before vaccination and after its completion were compared. The mean interval between the surgical procedures was 271.2 days before the vaccination and 537.4 days after it (p = 0.034). The mean number of surgeries per year was 2.16 before the vaccination and 0.93 after it (p = 0.022). The Derkay score did not change significantly after vaccination. Complete remission of the disease was observed in one patient, partial response to the vaccination was observed in seven patients and no response was observed in three patients. In conclusion, vaccination with the quadrivalent HPV vaccine can favorably influence the course of RRP in patients with the rapid growth of the papillomas. It significantly prolongs the intervals between the surgical procedures and reduces the number of procedures needed in the majority of patients. The present investigation can serve as a pilot study for further research. For a final conclusion a longer follow-up and studies on more patients are necessary.     

Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up

OBJECTIVES: The aim of this study was analysis of the results of use of interferon-alpha (IFN-alpha) in patients with recurrent respiratory papillomatosis (RRP) and correlation of the results with human papillomavirus (HPV) type. METHODS: A multicenter prospective series (42 patients from 22 hospitals) yielded 20 years of follow-up of patients with RRP and HPV typing who were treated with IFN-alpha in doses of 3 MU/m2 3 times per week. RESULTS: During long-term follow-up (mean +/- SD, 172 +/- 36.8 months), the rate of event-free survival evaluated by Kaplan-Meier analysis was 42.8%, and the overall survival rate was 82.6%. The HPV typing revealed an association of HPV 11 with a more aggressive disease course (64% of HPV 11 patients versus 24% of HPV 6 patients), a lower incidence of long-term response to IFN-alpha therapy (14% of HPV 11 patients versus 64% of HPV 6 patients), and a higher incidence of malignant transformation and mortality during follow-up (36% and 24%, respectively, of HPV 11 patients versus 0% of HPV 6 patients). CONCLUSIONS: The obtained results revealed maximal effectiveness of IFN-alpha therapy in RRP patients with HPV 6 as compared with HPV 11. The association of HPV 11 with a worse long-term response to IFN-alpha therapy and a higher incidence of malignant transformation and mortality is clinically important and indicates the necessity of HPV typing in RRP patients after the first biopsy.     

Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosis

The aim of the study was to assess the clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosis (RRP). This was a prospective study of patients with RRP treated from January 2009 to July 2012 at the Ear, Nose and Throat Department of the Emergency County Hospital of Cluj-Napoca, Romania. Demographic characteristics, onset of RRP, HPV typing, use and number of cidofovir injections, number of surgeries for RRP per year, and use of human papillomavirus vaccine (types 6, 11, 16, 18) (recombinant, adsorbed)/Silgard^® were considered from all the patients included in the study. Charts were reviewed for follow-up after diagnosis, after cidofovir, and after Silgard; all the statistical tests were applied at a significance level of 5 %. The recurrences were observed within 27.53 ± 11.24 days after intralesional cidofovir injection. Thirteen patients with recurrence after cidofovir agreed and received Silgard^® vaccine. 85 % [54.44–99.41] of patients had no recurrences during 1-year follow-up. The recurrence of papillomas was observed in two patients (15 %, 95 % CI [0.59–45.56]), one with adult-onset RRP and one with juvenile-onset RRP. Both recurrences appeared after the first Silgard dose; one month after the third vaccine dose each patient underwent a new surgery for remaining papillomas with no recurrences at 1-year follow-up visit. Silgard^® vaccination had a good effect and proved to be efficient in the treatment of our patients with RRR without appearance of recurrence in 85 % of the patients during 1-year follow-up.     

Prevalence and clinical implications of low-risk human papillomavirus among patients with recurrent respiratory papillomatosis in Rio de Janeiro,Brazil

ObjectiveThe aim of this study was to investigate the presence of human papillomavirus (HPV) in biopsy specimens from juvenile and adult patients with histopathological diagnosis of recurrent respiratory papillomatosis (RRP) treated in two public hospitals in Rio de Janeiro, Brazil.MethodsWe performed the detection and genotyping of HPV by PCR technique for the types 6, 11, 16, and 18 in biopsy specimens from 41 RRP patients.ResultsThe juvenile onset RRP (JoRRP) corresponded to 61% and the adult onset RRP (AoRRP) corresponded to 39% of the study group. Prevalence of males was observed in both the adult (81.3%) and the juvenile (56%) groups. Lesions in the larynx were more frequent in the glottis (46%). Genotyping analysis only revealed patients with HPV-6 (34.1%), HPV-11(17.1%), and co-infection HPV-6 and -11 (48.8%). RRP severity was significantly associated with the JoRRP (p < 0.001), with extralaryngeal disease and more surgeries. However, no significant association between RRP severity and HPV types was found. One co-infected patient in the JoRRP died due to the evolution of the disease with lung involvement.ConclusionThese results show the strong association of HPV-6 and/or HPV-11 types with RRP and could complement the diagnosis, prognosis, and therapies for these patients. In addition, the HPV vaccination should be encouraged to prevent the disease.     

复发性呼吸道乳头状瘤病

本文结合一组63例复发性乳头状瘤的基础及临床研究资料进行分析，其中16例的瘤组织以Slotblot和Southernblot杂交技术检测HPV－DNA，其阳性率：HPV6b为87.5％，HPV11为93．7％，HPV16为81．2％。本文就病因学、感染途径、复发部位与上皮组织特性及治疗选择进行讨论。     

The impact of cidofovir treatment on viral loads in adult recurrent respiratory papillomatosis

Cidofovir is an antiviral agent used in the therapy of recurrent respiratory papillomatosis (RRP). In this study, we hypothesized that cidofovir is effective in decreasing the viral load of human papillomavirus (HPV). We established a type specific real-time PCR and measured HPV DNA loads. The course of viral load of HPV types 6 and 11 after repeated applications of cidofovir intralesionally was compared to the clinical outcome using a modified Derkay score. In 6 of the 8 (75?%) patients, we detected HPV 6. In 2 (25?%) patients, we detected HPV 11. In all of the patients, the viral load and the modified Derkay score decreased significantly during the treatment. We conclude that viral load of HPV can be monitored using the technique described here. Cidofovir in combination with surgical debulking reduces the viral load in patients with RRP. Relapses of the symptoms cannot be avoided but might be delayed.     

Effectiveness of the human papillomavirus (types 6, 11, 16, and 18) vaccine in the treatment of children with recurrent respiratory papillomatosis

ObjectiveTo evaluate whether the quadrivalent human papillomavirus (HPV) (types 6, 11, 16, and 18) vaccine influences the clinical course of juvenile-onset recurrent respiratory papillomatosis (RRP) when administered to a group of patients with this condition.MethodsUncontrolled intervention study of patients with juvenile-onset RRP examined at the Pediatric Otorhinolaryngology Clinic, Federal University of São Paulo, where nine patients between the ages of nine and 17 received three doses of the prophylactic quadrivalent HPV vaccine (Gardasil^®) and were followed for one year. Disease staging, intervals between relapses, intervals between surgeries, and the number of surgeries during the year prior to vaccination and during the first year after vaccination were compared.ResultsEight patients were infected with HPV-6 and one with HPV-11. There were no statistically significant differences in the clinical scores (p = 0.083), anatomical scores (p = 0.257), intervals between relapses (p = 0.062), intervals between surgeries (p = 0.357), or the numbers of surgeries (p = 0.180) when the years before and after vaccination were compared. All patients had relapses following vaccination.ConclusionPatients with juvenile-onset RRP experienced a similar clinical course in the year after versus the year before vaccination with Gardasil^®.     

Prognostic factors of recurrent respiratory papillomatosis from a registry of 72 patients

Conclusions: The database revealed severity factors relating to human papillomavirus (HPV) type and age at diagnosis. While not exhaustive, the database is easy to use and could serve for a European multicentre epidemiological study. Objectives: To propose a database as a starting point for a national registry and to estimate prognostic factors in recurrent respiratory papillomatosis (RRP). Materials and methods: This was a retrospective study carried out in a tertiary care teaching hospital. From January 2005 to July 2007, epidemiological, clinical and treatment information on patients undergoing endoscopy for RRP in the department was entered in a database. Data were collected on three forms: the first comprised information about disease history before assessment in the department, the second about the disease and its treatment in the department, and the third about evolution after treatment. Results: Data on 72 patients were entered into an RRP database between January 2005 and July 2007. In all, 82% had already been treated for RRP in a different centre; 24 had juvenile-onset (JORRP) and 48 adult-onset (AORRP) papillomatosis. Cidovir injections had been administered to 91% of the patients. Histology found nine cases of dysplasia, one of carcinoma in situ and one of invasive carcinoma. Subglottic and tracheal locations were significantly more frequent in JORRP than in AORRP, as were the maximum Derkay scores and annual numbers of endoscopies. Patients with type 11 HPV had significantly more endoscopies per year than those with type 6.     

Presence of human papillomavirus DNA in tonsillectomy specimens

OBJECTIVES: The objectives of this prospective case-control study were to study the prevalence of human papillomavirus (HPV) in tonsillectomy specimens from pediatric patients without recurrent respiratory papillomatosis (RRP), and to study methods of HPV detection. METHODS: Fifty pediatric patients without known RRP undergoing tonsillectomy for hypertrophy or recurrent tonsillitis were enrolled in the study. After tonsillectomy, a 20-mg section was subjected to DNA extraction, and DNA content and purity were confirmed with spectrophotometry. Polymerase chain reaction (PCR) was performed using consensus primer pools PGMY 09/11 targeted at the L1 region. Amplification products were detected and analyzed with standard agarose gel electrophoresis. Positive samples were then subjected to reverse line blot assay to determine virus genotype. Laryngeal papilloma specimens of 15 patients obtained during routine debulking procedures were also analyzed and served as positive controls. RESULTS: Of 50 tonsil samples tested, two were positive for HPV DNA after PCR and gel electrophoresis. One of these samples was confirmed with typing and tested positive for HPV 11. All 15 papilloma specimens were positive for DNA of HPV types 6 and/or 11. CONCLUSIONS: In the current study, the prevalence of HPV DNA in tonsillar tissue of patients without RRP is 2%, whereas the incidence of this disease is 2 to 4 cases per 100,000 (0.004%). These findings are significantly different (P = .005 within a 95% confidence interval) suggesting that host factors in addition to infection play a role in pathogenesis of RRP. The molecular methods described in this study are well suited for detection of HPV in tonsillar tissue.     

Prevalence of human papilloma virus types and their influence on the course of the disease in children suffering from recurrent respiratory papillomatosis

The type of human papilloma virus (HPV) was determined in 26 children aged between 1 year 10 months to 15 years 5 months suffering from recurrent respiratory papillomatosis (RRP). Polymerase chain reaction identified DNA of HPV type 6, 11, 16 and 18. HPV DNA was detected in all the patients including fifteen patients infected with HPV type 11; seven patients infected with HPV type 6; four children infected with HPV type 6 and 11. Types 16 and 18 of HPV were not detected. The analysis of RRP course has found that laryngeal papillomatosis runs a more aggressive course in cases with HPV type 11 infection than in those with HPV type 6.     

Long-term results of surgical treatment for recurrent respiratory papillomatosis

Conclusions. The presented results add further support to the observation that laser microsurgery is the preferential surgical treatment for recurrent respiratory papillomatosis (RRP). A meticulous follow-up for early recognition of local recurrence and malignant transformation is recommended. Objectives. Endoscopic microsurgery continues to be the treatment of choice for RRP. The aim of this study was to evaluate the outcome of patients treated surgically. We focused on demographic data, recurrence rates, and treatment-related complications. Patients and methods. The charts of 194 patients treated at our institution between 1963 and 1993 were analyzed retrospectively. Results. In all, 64 patients (33%) underwent a total of 137 operations using the CO₂ laser; 130 patients (67%) underwent a total of 565 microlaryngeal operations by surgery with cold instruments. Five percent of the patients treated with conventional microlaryngeal surgery and none of the patients treated with laser surgery required tracheostomy (p<0.05). Postoperative glottic webs and scar formations were found in 6% of all patients after laser surgery and 20% after conventional surgery (p<0.05). The different methods of treatment did not affect the rate of recurrence (p=0.61) Malignant transformation or secondary airway carcinoma were observed in 4% of all patients.     

Long-term follow-up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir

OBJECTIVE: Cidofovir is an acyclic nucleotide phosphonate antiviral medication that has been used intralesionally for the treatment of severe respiratory papillomatosis (RRP) in pediatric patients. The long-term efficacy of this medication was assessed in 11 children with severe RRP who previously required operative debulking every 2 to 6 weeks to maintain airway patency. STUDY DESIGN: Clinical case series. RESULTS: Ten of these children have completed therapy. Five are disease free over a mean follow-up period of 51.6 months. Five other patients with active RRP decreased their mean severity scores from 17.8 (range 11-26) to 4.0 (range 2-6) and no longer require cidofovir. One patient continues to receive cidofovir for recurrent disease after an initial favorable response. Throughout the 6-year observational period, no patients demonstrated any adverse effects, laboratory abnormalities, or evidence of carcinogenesis. CONCLUSION: Intralesional cidofovir is a useful adjunct for managing children with tenuous airways caused by previously uncontrolled papilloma.     

Safety of paediatric day-stay laryngeal surgery for recurrent respiratory papillomatosis

ObjectivesSafety assessment of day-stay laryngeal surgery in a cohort of children with recurrent respiratory papillomatosis (RRP). Recurrent respiratory papillomatosis is a chronic debilitating disease which usually requires multiple recurrent interventions under general anaesthesia. Day-stay surgery is an attractive option as it allows avoiding the inconvenience and costs of routine overnight admissions while recovering in the safe environment of the family home. This is the first study to assess the safety of day-stay laryngeal surgery in this cohort of patients.MethodsRetrospective cohort study of all consecutive RRP procedures performed between December 1998 and May 2015 in a single paediatric tertiary-level hospital.ResultsA total of 465 surgical procedures were performed in 20 patients. Average age on diagnosis was 4.5 years. 415 (89.25%) of the procedures were done as day cases without overnight admission. Average number of procedures per patient was 20 and 25 for Children positive to HPV6 and HPV11, respectively. Only one patient after one single procedure (presenting 0.21% of total procedures, 0.24% of day-stay procedures) represented after discharge.ConclusionsDay-stay surgery for children with RRP has a favourable safety profile in selected cases.     

Recurrent respiratory papillomatosis: an overview of current thinking and treatment

Human papillomaviruses (HPV) infection in benign laryngeal papillomas is well established. The vast majority of recurrent respiratory papillomatosis lesions are due to HPV types 6 and 11. Human papillomaviruses are small non-enveloped viruses (>8 kb), that replicate within the nuclei of infected host cells. Infected host basal cell keratinocytes and papillomas arise from the disordered proliferation of these differentiating keratinocytes. Surgical debulking of papillomas is currently the treatment of choice; newer surgical approaches utilizing microdebriders are replacing laser ablation. Surgery aims to secure an adequate airway and improve and maintain an acceptable quality of voice. Adjuvant treatments currently used include cidofovir, indole-3-carbinol, ribavirin, mumps vaccine, and photodynamic therapy. The recent licensing of prophylactic HPV vaccines is a most interesting development. The low incidence of RRP does pose significant problems in recruitment of sufficient numbers to show statistical significance. Large multi-centre collaborative clinical trials are therefore required. Even so, sufficient clinical follow-up data would take several years.     

Carcinoma ex-papilloma: Histologic and virologic studies in whole-organ sections of the larynx

A patient with adult-onset recurrent respiratory papillomatosis (RRP), initially diagnosed at age 28 years, was treated with radiation therapy due to the rapid regrowth of lesions. Following 6 years of apparently inhibited growth, papilloma recurred, and squamous carcinoma was diagnosed from a laryngeal biopsy. A spontaneous laryngocutaneous fistula developed, and laryngectomy was performed 14 years after irradiation. The laryngectomy specimen was snap frozen and representative tissues were stored frozen for viral studies. The larynx was whole-organ sectioned for histologic examinations; residual papilloma, as well as carcinoma, was observed. Koilocytosis and other virus-associated histologic changes were also found. HPV capsid antigen was present in papilloma, carcinoma, and clinically normal epithelium. HPV nucleic acids, conforming to HPV type 6, were present in keratin pearls and dysplastic cells. According to prior reports, carcinoma developing in preexisting papilloma arises from juvenile-onset RRP. Irradiated papilloma develop cancer at about 10 years, and the patients rarely survive. Nonirradiated cases develop cancer after 30 years, and some develop papilloma in the hypopharynx and trachea, but most patients survive. Irradiation is not an obligatory precursor for malignant transformation of cancer; however, until now there have been no case reports of favorable outcome after irradiation of papilloma.     

Long-term results of surgical treatment for recurrent respiratory papillomatosis

CONCLUSIONS: The presented results add further support to the observation that laser microsurgery is the preferential surgical treatment for recurrent respiratory papillomatosis (RRP). A meticulous follow-up for early recognition of local recurrence and malignant transformation is recommended. OBJECTIVES: Endoscopic microsurgery continues to be the treatment of choice for RRP. The aim of this study was to evaluate the outcome of patients treated surgically. We focused on demographic data, recurrence rates, and treatment-related complications. PATIENTS AND METHODS: The charts of 194 patients treated at our institution between 1963 and 1993 were analyzed retrospectively. RESULTS: In all, 64 patients (33%) underwent a total of 137 operations using the CO2 laser; 130 patients (67%) underwent a total of 565 microlaryngeal operations by surgery with cold instruments. Five percent of the patients treated with conventional microlaryngeal surgery and none of the patients treated with laser surgery required tracheostomy (p<0.05). Postoperative glottic webs and scar formations were found in 6% of all patients after laser surgery and 20% after conventional surgery (p<0.05). The different methods of treatment did not affect the rate of recurrence (p=0.61) Malignant transformation or secondary airway carcinoma were observed in 4% of all patients.     

Can mumps vaccine induce remission in recurrent respiratory papilloma?

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.     

Topical measles-mumps-rubella vaccine in the treatment of recurrent respiratory papillomatosis: results of a preliminary randomized, controlled trial

We conducted a study to test the hypothesis that the measles-mumps-rubella (MMR) vaccine can either prevent further recurrences of recurrent respiratory papillomatosis (RRP) or prolong its remission. Our study population was made up of 26 children with RRP. All patients underwent surgical excision of their lesions. After the lesions were removed, half of these patients were prospectively randomized to receive a topical coating of the MMR vaccine on the site of their excised lesion (intervention group); the other half were treated with excision alone (control group). The patients in the intervention group experienced a longer period of recurrence-free remission than did those in the control group (median: 160 and 133 days, respectively), but the difference was not statistically significant. Therefore, it appears that topical MMR vaccine as an adjunct to routine surgical management may not be beneficial in preventing or slowing the return of RRP. However, we believe that further studies with larger patient populations are warranted.     

Feasibility of transnasal flexible carbon dioxide laser surgery for laryngopharyngeal lesions

ObjectiveThe fiber-guided carbon dioxide (CO₂) laser is a useful device for laryngopharyngeal surgery. The flexible CO₂ wave-guide laser has been developed and commercially available for several years. However, the transnasal use of CO₂ flexible wave-guided laser surgery through the instrument channel of a flexible endoscope (CO₂ TNFLS) is not permitted in Japan. This feasibility study aimed to assess the value and the safety of an in-office CO₂ TNFLS procedure.MethodsPatients with small laryngopharyngeal diseases were enrolled from June 2015. Eligible patients had indications with lesions generally localized superficial lesions such as the benign tumor, leukoplakia, and premalignant lesion-like carcinoma in situ (CIS). Patients were locally well anesthetized using xylocaine. After removing as much of the lesion(s) as possible with flexible forceps, the remainder of the lesions were evaporated using CO₂ TNFLS through the instrument channel of a flexible endoscope under local anesthesia.ResultsEighteen surgeries involving 13 patients, including 9 papilloma (7 recurrent respiratory papilloma [RRP]), 2 carcinoma in situ, 1 leukoplakia, and 1 large epiglottic cyst), were performed. Four patients with RRP required multiple surgeries. Except for 3 patients with RRP, all patients achieved disease control without additional intervention. All procedures were completed with no severe adverse events.ConclusionOffice-based CO₂ TNFLS is safe and feasible for patients with laryngopharyngeal pathologies. It is especially valuable for RRP patients with small lesions to avoid surgery under general anesthesia.