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    Research Articles (2005-4)

    Human papillomavirus, viral load and proliferation rate in recurrent respiratory papillomatosis in response to alpha interferon treatment.
    J Gen Virol. 2005; 86(Pt 6):1695-702 (ISSN: 0022-1317)
    Szeps M; Dahlgren L; Aaltonen LM; Ohd J; Kanter-Lewenshon L; Dahlstrand H; Munck-Wikland E; Grandér D; Dalianis T
    Department of Oncology-Pathology, CancerCenterKarolinska, R8:01, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.

    The aim of this study was to identify recurrent respiratory papillomatosis patients who may benefit from interferon (IFN)-alpha treatment and to determine the means of IFN-alpha action. The presence of human papillomavirus (HPV) and viral load and proliferation rate in pre-, ongoing and post-treatment respiratory papillomatosis biopsies were examined retrospectively in 25 patients, 18 of whom were IFN-alpha treated and seven of whom were IFN-alpha non-treated. Using PCR, HPV was found to be present in 20/25 respiratory papillomatosis patients and HPV type was determined for 18/25 patients (12 HPV6 and six HPV11). Eighteen of the patients were treated with IFN-alpha, 14 of whom were HPV positive (eight HPV6, five HPV11 and one undefined HPV). Response to IFN-alpha therapy was observed in 12 patients (7/8 HPV6, 3/5 HPV11, 1/1 undefined HPV and 1/4 HPV negative), while six patients (1/8 HPV6, 2/5 HPV11 and 3/4 HPV negative) did not respond to therapy. Viral load, determined by quantitative real-time PCR (between 0.03 and 533 HPV copies per cell), and proliferation rate, determined as the percentage of Ki-67-positive cells (between 8 and 54 %), were similar in IFN-alpha-treated and non-treated patients and were generally unaffected by IFN-alpha treatment. In summary, most (12/18) IFN-alpha-treated patients responded to therapy. Moreover, there was a tendency for patients with HPV6-positive (7/8) respiratory papillomatosis to respond more frequently to IFN-alpha therapy than patients with HPV11 (3/5) or HPV-negative (1/4) respiratory papillomatosis. Finally, the presence of HPV and viral load and proliferation in respiratory papillomatosis biopsies was similar in patients treated or not with IFN-alpha and were in general unaffected by IFN-alpha treatment.

    Extraesophageal acid reflux and recurrent respiratory papilloma in children.
    Int J Pediatr Otorhinolaryngol. 2005; 69(5):597-605 (ISSN: 0165-5876)
    McKenna M; Brodsky L
    Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA. margomckenna@meei.harvard.edu

    OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is a benign infectious disease which is caused by the human papilloma virus (HPV). When it infects the larynx, hoarseness and airway obstruction are often the presenting symptoms. Latent virus is found in the laryngeal mucosa of many more patients than exhibit the disease. The factors which lead to virus activation have not been identified, however, extra-esophageal acid reflux disease (EERD) has been suggested as one of these factors. METHODS: This is a case series of four patients with RRP who had increase in severity of their disease with the recognition of concurrent extra-esophageal acid reflux. The clinical course of the papillomatosis and the diagnosis and treatment of reflux are compared over time. RESULTS: In all four cases, with identification and treatment of the EERD, control of the RRP improved, and in at least two patients, was complete with resolution of the EERD. Lapses in compliance with medications or behavioral and dietary recommendations in three out of four patients led to a rebound in symptoms and signs of RRP, including worsening of vocal quality and the endoscopic appearance of the larynx. CONCLUSION: The clinical course of these patients suggests a link between the presence of EERD and RRP. The inflammation induced by chronic acid exposure may result in the expression of HPV in susceptible tissues. Prompt diagnosis and effective treatment of EERD should be considered in all patients with difficult to control RRP or with clinical presentation or endoscopic signs of EERD.

    Role of vascular endothelial growth factor-A in recurrent respiratory papillomatosis.
    Ann Otol Rhinol Laryngol. 2005; 114(4):289-95 (ISSN: 0003-4894)
    Rahbar R; Vargas SO; Folkman J; McGill TJ; Healy GB; Tan X; Brown LF
    Dept of Otolaryngology and Communication Disorders, Children's Hospital, 300 Longwood Ave, Boston, MA 02115, USA.

    Vascular endothelial growth factor-A (VEGF-A) is known to play an important role in the angiogenic response essential for tumor growth in a variety of human and experimental tumors. This study was designed to investigate whether VEGF-A may play a role in the pathogenesis of recurrent respiratory papillomatosis (RRP). A retrospective study with institutional review board approval was performed at a tertiary care medical center on 12 patients with a history of laryngeal RRP. Their ages at the time of initial diagnosis ranged from 19 to 96 months (mean, 56 months). All patients had involvement of right and left true vocal cords. All patients required multiple endoscopic procedures (range, 4 to 66; mean, 12). Normal pediatric larynx samples from 5 autopsy patients were used as controls. Formalin-fixed, paraffin-embedded sections of laryngeal squamous papillomas from the 12 patients with a diagnosis of RRP and the 5 control patients were examined by in situ hybridization for the presence of messenger RNA (mRNA) for VEGF-A and vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2). The biopsy specimens were from the true vocal cord (N = 10) or subglottis (N = 2) in the patients with RRP and consisted of large sections of larynx including the true vocal cord in the control patients (N = 5). Strong expression of VEGF-A mRNA was noted in the squamous epithelium of papillomas of all 12 patients. Strong expression of VEGFR-1 and VEGFR-2 was noted in the endothelial cells of the underlying vessels in all 12 patients. Neither strong labeling of VEGF-A mRNA nor labeling of its receptors wasnoted in the control patients. We conclude that the angiogenic growth factor VEGF-A is strongly expressed in the epithelium of squamous papillomas in RRP. Also, VEGFR-1 and VEGFR-2 mRNAs are strongly expressed by underlying vascular endothelial cells, suggesting an important role in the pathogenesis of RRP.

    Human papillomavirus (HPV) in head and neck cancer.
    J Clin Virol. 2005; 32 Suppl 1:S59-66 (ISSN: 1386-6532)
    Syrjänen S
    Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Lemminkäisenkatu 2, FIN-20520 Turku, Finland. stina.syrjanen@utu.fi

    The term "head and neck cancer" has been widely adopted in the recent literature, to include the lesions at several anatomic sites: the lip, oral cavity, nose and para-nasal sinuses, naso-pharynx, oro-pharynx, hypo-pharynx, and larynx. In this communication, the data on human papillomavirus (HPV) involvement in oral, oro-pharyngeal, sino-nasal, and laryngeal carcinomas are reviewed. Our group was the first to present evidence on the involvement of HPV infections in both laryngeal and oral carcinogenesis, prompted by the discovery of morphological similarities between oral and cervical squamous cell lesions. The latest meta-analyses of the epidemiological studies as well as the multi-centre case-control studies have confirmed HPV as an independent risk factor for oral cancer, with a range of odds ratios (OR) between 3.7 and 5.4. Until 2002, 4768 oral carcinomas have been analysed for HPV DNA, and 22% were reported to contain HPV by any of the detection techniques. Of all non-genital cancers, tonsillar carcinomas appear to have the highest prevalence of HPV. By the end of 2002, 422 cases of tonsillar carcinoma have been analyzed for the presence of HPV DNA, with the overall detection rate of 51%. HPV 16 is the most prevalent HPV type found in 84% of HPV DNA-positive tumours. HPV seems to be mainly episomal in tonsillar carcinomas, but the significance of this observation is still obscure. Interestingly, patients with HPV 16-positive tumours seem to have a better overall- and disease-specific survival, as compared with the HPV-negative group. To date, 1041 sino-nasal papillomas have been analysed for HPV and 347 (33%) cases have been positive, whereas of the 322 sino-nasal carcinomas analysed so far, 70 (22%) have been positive for any HPV type. Laryngeal squamous cell papilloma and recurrent respiratory papillomatosis (RRP) are well-established HPV-induced tumours, whereas the role of HPV in laryngeal carcinomatosis remains controversial. The molecular mechanisms of HPV-associated carcinogenesis of the head and neck require further study.

    Incidence, age at onset, and potential reasons of malignant transformation in recurrent respiratory papillomatosis patients: 20 years experience.
    Otolaryngol Head Neck Surg. 2005; 132(3):392-4 (ISSN: 0194-5998)
    Gerein V; Rastorguev E; Gerein J; Draf W; Schirren J
    Department of Pediatric Pathology, Institute of Pathology, University of Mainz, Germany. v.gerein@web.de

    Forty-two patients with recurrent respiratory papillomatosis (RRP) were accepted into a multicenter prospective study in 1983 to 1990, treated with alfa-IFN 3 MU/m 2 3 times a week and then followed-up until August 1, 2003. All the patients who had disease progression with pulmonary spread were characterized by insufficient response to IFN-therapy and detection of HPV type 11. Five patients (4/5 smokers) presented malignant transformation in lungs or nasopharynx (mean RRP duration was 27.2 +/- 8 years from RRP onset and 14.6 +/- 6.3 years from pulmonary spread until malignant transformation) with persistent RRP in larynx. The results of long-term follow-up in RRP patients with HPV 11 underline the necessity of reanalyzing the current therapy.

    Remote intrapulmonary spread of recurrent respiratory papillomatosis with malignant transformation.
    Pediatr Pulmonol. 2005; 39(2):185-8 (ISSN: 8755-6863)
    Katz SL; Das P; Ngan BY; Manson D; Pappo AS; Sweezey NB; Solomon MP
    Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

    Recurrent respiratory papillomatosis is the most common neoplasm of the larynx in childhood. Extension into lung parenchyma occurs in less than 1% of patients and has a low risk of malignant transformation. Treatment options for intrapulmonary spread have shown limited success. We describe a case of recurrent respiratory papillomatosis with extensive parenchymal involvement and adenosquamous carcinoma in a 14-year-old girl.

    [Cidofovir activity in infantile recurrent respiratory papillomatosis]
    Acta Otorrinolaringol Esp. 2005; 56(1):22-4 (ISSN: 0001-6519)
    Palomar Asenjo V; Palomar García V; Soteras Ollé J; Ruiz Giner A
    Servicio de Otorrinolaringología y Patología Cérvico-Facial, Hospital Universitari Arnau de Vilanova de Lleida, Facultad de Medicina Universitat de Lleida. vpalomar@arnau.scs.es

    We report the case of a 4 year old boy that arrived to our department refering a 4 months history of dysphony complicated in the last week with inspiratory estridor. He was diagnosed of respiratory papillomatosis. In the next 10 months he underwent 6 operations to remove papillomas with CO2 laser. In the last operation we decided to add adjuvant therapy with intralesional injections of cidofovir once all papillomas had been removed. After more than a year of monitoring he remains disease free.

    Adjuvant antiviral therapy for recurrent respiratory papillomatosis.
    Cochrane Database Syst Rev. 2005; (4):CD005053 (ISSN: 1469-493X)
    Chadha NK; James AL
    Royal United Hospital, ENT Department, Bath, UK BA1 3NG. neil@chadhanet.com

    BACKGROUND: Recurrent respiratory papillomatosis is a condition characterised by benign papillomatous (wart-like) growths in the upper airway. It can affect both adults and children causing airway-obstruction and voice change. Treatment usually involves repeated surgical debulking of the papillomata, and several agents have been proposed as adjuvants to surgical debulking. These include antivirals, administered systemically or injected into the lesions. OBJECTIVES: To assess the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis in children and adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2004), MEDLINE (January 1966 to November 2004), and EMBASE (January 1985 to November 2004) in December 2004. We checked reference lists of articles, contacted pharmaceutical companies and contacted leading experts in the field for further studies. SELECTION CRITERIA: All randomised controlled trials. DATA COLLECTION AND ANALYSIS: One hundred references were identified from the searches. Twenty-five were appropriate for retrieval and assessed for eligibility by the authors. None met the inclusion criteria. MAIN RESULTS: No controlled trials were identified. AUTHORS' CONCLUSIONS: There was insufficient evidence from controlled trials on which to base reliable conclusions about the effectiveness of antiviral agents as adjuvant therapy in the management of recurrent respiratory papillomatosis. Further research is required before any specific antiviral adjuvant therapy can be recommended.

    The characteristics of human papillomavirus DNA in head and neck cancers and papillomas.
    J Clin Pathol. 2005; 58(1):51-5 (ISSN: 0021-9746)
    Major T; Szarka K; Sziklai I; Gergely L; Czeglédy J
    Clinic of Otorhinolarnygology and Head and Neck Surgery, Medical and Health Science Centre, University of Debrecen, 4012 Debrecen, Hungary. majortamas@freemail.hu

    AIM: To determine the prevalence, type, physical state, and viral load of human papillomavirus (HPV) DNA in cases of head and neck cancer and recurrent respiratory papillomatosis (RRP). METHODS: The prevalence and type of HPV DNA was determined in 27 fresh frozen tissue specimens from patients with head and neck cancers and 16 specimens from 10 patients with RRP by MY09/MY11 and GP5+/GP6+ nested polymerase chain reaction (PCR) and subsequent restriction enzyme cleavage. The physical state of HPV DNA was analysed by E1, E2, and E1E2 specific PCRs and Southern blot hybridisation (SBH). RESULTS: HPV DNA was detected in 13 of 27 cancers and 10 of 10 papillomas. Both low risk HPV-6 and HPV-11 and high risk HPV-16 were present in cancers in low copy numbers, whereas papillomas exclusively harboured low risk HPV-6 and HPV-11. E1E2 PCRs failed to determine the physical state of HPV in cancers except one case where HPV-6 DNA was integrated. In contrast to cancers, all papillomas showed the episomal state of HPV DNA and a relatively higher viral load. CONCLUSIONS: Based on the prevalence, type, physical state, and copy number of HPV DNA, cancers and papillomas tend to show a different HPV DNA profile. The 100% positivity rate of low risk HPV types confirms the role of HPV-6 and HPV-11 in the aetiology of RRP.

    Current diagnostic and management trends for recurrent respiratory papillomatosis.
    Curr Opin Otolaryngol Head Neck Surg. 2004; 12(6):532-7 (ISSN: 1068-9508)
    Silverman DA; Pitman MJ
    Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Vermont College of Medicine, Burlington, Vermont, USA. damon.silverman@vtmednet.org

    PURPOSE OF REVIEW: The purpose of this review is to discuss recent literature regarding diagnostic and management trends for recurrent respiratory papillomatosis (RRP) published within the past year. This includes a discussion of new information regarding the epidemiology and pathogenesis of RRP and an update on adjuvant therapy and new surgical techniques. RECENT FINDINGS: Epidemiological studies have confirmed that juvenile-onset RRP is the most common and most aggressive form of the disease. Age at diagnosis is the most important determinant of disease severity, with younger patients requiring significantly more annual surgeries and more likely to have multicentric disease. Distal tracheal or pulmonary RRP is rare, but carries a significant increase in morbidity and mortality. Research into the pathogenesis of RRP has focused on the genetics of HPV infection and host-virus interactions, suggesting a genetic basis for host susceptibility to RRP. At the present time, surgery remains the mainstay of treatment for RRP. However, recurrence after surgery is common and the search for effective adjuvant therapies is ongoing. The antiviral drug cidofovir has demonstrated efficacy against RRP and is considered a promising new adjuvant treatment of this disease. In an attempt to minimize the untoward effects of surgery, the pulsed-dye laser (PDL) has emerged as a safe and efficacious treatment for select patients with RRP. SUMMARY: While a cure for RRP remains elusive, there has been substantial progress in the diagnosis and management of this disease. Significant advances in clinical and basic science research have dramatically improved our understanding of the epidemiology and pathogenesis of the disease and led to the development of promising new adjuvant therapies and surgical techniques. This has translated to an improved quality of life for many patients with RRP.

    Efficacy of cidofovir injection for the treatment of recurrent respiratory papillomatosis.
    J Voice. 2004; 18(4):551-6 (ISSN: 0892-1997)
    Lee AS; Rosen CA
    University of Pittsburgh Voice Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    To evaluate the efficacy of intralesional cidofovir injection for the treatment of recurrent respiratory papillomatosis (RRP). It is a prospective, open-label study design. This prospective study included 16 RRP patients, ages 9 to 68 years, who were treated with intralesional injections of cidofovir combined with surgical excision of RRP. The disease states of the patients pretreatment and posttreatment were assessed by assigning RRP severity scores, examining the need for any surgical excision of RRP, and evaluating the presence of RRP upon long-term follow-up. Sixteen patients were treated with cidofovir; however, three were lost to follow-up. Thirteen patients are the subjects of this report. This study group included three pediatric patients. Ten of thirteen patients (76.9%) responded to the treatment and are presently in remission. One patient did not respond, and two patients relapsed after initial success or had a partial response. The responders consisted of eight adults and two children. The mean number of injections the responders received was 3.5, and the average follow-up period of the responders was 25.4 months. No immediate complication of cidofovir treatment was evident. However, three patients were found to have significant vocal fold scarring after long-term follow-up. Cidofovir has been found to be efficacious in treating RRP. Further study regarding long-term follow-up and the assessment of possible side effects after cidofovir intralesional injection for RRP is required.

    Recurrent respiratory papillomatosis: cytopathological findings in an unusual case.
    Diagn Cytopathol. 2004; 31(6):407-12 (ISSN: 8755-1039)
    Parwani AV; Sheth S; Ali SZ
    Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21287-6417, USA.

    Recurrent respiratory papillomatosis (RRP) primarily is a disease of children and adolescents. Most patients experience spontaneous regression at a later age, while others continue to be affected throughout their lives. Here, we present the case of a 26-yr-old man who presented with persistent cough, worsening dyspnea, and development of pneumothorax. Eight years prior, he had presented with similar complaints and an evaluation at that time had showed RRP. Follow-up since that time showed recurrent disease managed by multiple surgical procedures. At the most current admission, an ultrasound-guided fine-needle aspiration (FNA) of the lung showed numerous papillary tissue fragments and single atypical squamous cells consistent with recurrent RPR. To our knowledge, morphological findings of RRP have been reported rarely.

    Prognostic factors of recurrent respiratory papillomatosis spread to lower airway passages.
    Int J Pediatr Otorhinolaryngol. 2004; 68(12):1589-90 (ISSN: 0165-5876)
    Analysis of a staging assessment system for prediction of surgical interval in recurrent respiratory papillomatosis.
    Int J Pediatr Otorhinolaryngol. 2004; 68(12):1493-8 (ISSN: 0165-5876)
    Derkay CS; Hester RP; Burke B; Carron J; Lawson L
    Department Otolaryngology and Pediatrics, Eastern Virginia Medical School, The Children's Hospital of the King's Daughters, 825 Fairfax Avenue, Suite 510, Norfolk, VA 23507-1914, USA. Derkaycs@chkd.com

    INTRODUCTION: A staging system for assessment of recurrent respiratory papillomatosis (RRP) has been in use over the last 3 years for 17 patients at our children's hospital. OBJECTIVE: To evaluate a staging system for assessment of RRP on the basis of the predictive value on the surgical interval of: anatomic staging system score, urgency of intervention, voice quality, and stridor. To assess effect on surgical interval of the age of patient at time of surgery and use of adjuvant therapy. To develop a model based on the staging criteria to predict need for adjuvant therapy. DESIGN: Validation cohort. SETTING: Academic children's hospital. RESULTS: Estimated time to surgery decreased by "x days": "independent variable" "(95% CI)" as follows. Four days: each 1 point in total anatomical score (0.2, 8); 120 days: total anatomical score >20 (37,203); 143 days: urgent versus scheduled surgery (42, 243); 100 days: aphonic versus normal voice (-211, 343); 31 days: abnormal versus normal voice (-281, 343); 125 days: stridor at rest versus no stridor (-31, 281); 109 days: stridor with activity versus no stridor (19, 198); 26 days: each 1 year decrease in age (22, 30). Adjuvant therapy delays next surgery by 32 days (-4, 69) and average scores decreased while on adjuvant therapy. CONCLUSIONS: Elements of our proposed staging system are effective in prediction of surgical interval with statistical significance achieved for total anatomical scores, urgency of intervention and stridor with activity versus no stridor. This study is pilot in nature and provides a framework upon which future studies can be based. The analysis of a larger, more severity diverse population could yield results which lead to a model capable of effectively predicting future surgical interval based on a weighted prediction score calculated from age, comorbidities, anatomic staging score, and clinical staging score.

    Serial office-based intralesional injection of cidofovir in adult-onset recurrent respiratory papillomatosis.
    Ann Otol Rhinol Laryngol. 2004; 113(11):859-62 (ISSN: 0003-4894)
    Co J; Woo P
    Department of Otolaryngology-Head and Neck Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA.

    Intralesional injection of cidofovir is used in the treatment of recurrent respiratory papillomatosis as an adjuvant therapy after microsurgical excision and CO2 laser therapy. This is conventionally done in the operating room with the patient under general anesthesia. We report our experience with 5 patients with adult-onset recurrent respiratory papillomatosis who were treated with intralesional injections of cidofovir after recurrence of their papillomatosis. These injections were given monthly in the office without the use of general anesthesia. Before cidofovir injection, all patients required repeated CO2 laser treatments at intervals of less than 5 months. We injected 7.5 mg/mL of cidofovir transorally into the papillomas under office telescopic control. These injections were given monthly for 3 consecutive months. The patients were then followed up for 2 to 10 months after therapy to monitor the size of the papillomas. In all 5 patients, partial remission of the laryngeal papillomatosis was noted during the follow-up period. Their need for repeat microsurgery was delayed, and their vocal function improved. Intralesional injection of cidofovir in an office setting appears to be safe and effective. It might be more convenient and cost-effective than performing the same procedure in the operating room with the patient under general anesthesia.

    Intralesional cidofovir for pediatric recurrent respiratory papillomatosis.
    Arch Otolaryngol Head Neck Surg. 2004; 130(11):1319-23 (ISSN: 0886-4470)
    Mandell DL; Arjmand EM; Kay DJ; Casselbrant ML; Rosen CA
    Department of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, University of Pittsburgh Voice Center, University of Pittsburgh, Pittsburgh, PA, USA. david.mandell@chp.edu

    OBJECTIVE: To compare disease response among children with recurrent respiratory papillomatosis (RRP) who underwent combined surgical debulking and intralesional cidofovir injections vs repeated surgical debulking only. DESIGN: Retrospective medical record review; follow-up range: 16 to 56 months. SETTING: Tertiary care children's hospital. PATIENTS: Seven children with RRP, including 4 subjects treated with cidofovir and 3 controls matched for age and initial papilloma staging score. INTERVENTIONS: Subjects treated with cidofovir underwent combined surgical debulking and intralesional cidofovir injection every 2 months until disease remission. Control subjects underwent repeated surgical debulking at individually determined intervals. MAIN OUTCOME MEASURES: Intraoperative endoscopic photographs were retrospectively assigned papilloma staging scores. Cidofovir and control group comparisons were made using nonparametric 2-sample Wilcoxon rank-sum (Mann-Whitney) testing, and comparisons of initial and final papilloma staging scores were made using nonparametric matched-pair Wilcoxon signed-rank testing. RESULTS: The final cidofovir group scores were significantly lower than the control group scores (P < .05). Within-group differences between initial and final scores were not significant (cidofovir group, P = .07; control group, P = .29). CONCLUSIONS: Four children with RRP were safely and successfully treated with intralesional cidofovir injection. Consideration should be given to using cidofovir more widely for treatment of pediatric RRP. Larger numbers in the cidofovir and control groups are needed in future studies to determine the true impact of cidofovir on management of this disease.

    Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population.
    Laryngoscope. 2004; 114(11 Pt 2 Suppl 104):1-23 (ISSN: 0023-852X)
    Wiatrak BJ; Wiatrak DW; Broker TR; Lewis L
    Department of Pediatric Otolaryngology, Children's Hospital of Alabama, Birmingham, Alabama, USA.
    • OBJECTIVES/HYPOTHESIS: A database was developed for prospective, longitudinal study of recurrent respiratory papillomatosis (RRP) in a large population of pediatric patients. Data recorded for each patient included epidemiological factors, human papilloma virus (HPV) type, clinical course, staged severity of disease at each surgical intervention, and frequency of surgical intervention. The study hypothesizes that patients with HPV type 11 (HPV-11) and patients younger than 3 years of age at diagnosis are at risk for more aggressive and extensive disease. STUDY DESIGN: The 10-year prospective epidemiological study used disease staging for each patient with an original scoring system. Severity scores were updated at each surgical procedure. METHODS: Parents of children with RRP referred to the authors' hospital completed a detailed epidemiological questionnaire at the initial visit or at the first return visit after the study began. At the first endoscopic debridement after study enrollment, tissue was obtained and submitted for HPV typing using polymerase chain reaction techniques and in situ hybridization. Staging of disease severity was performed in real time at each endoscopic procedure using an RRP scoring system developed by one of the authors (B.J.W.). The frequency of endoscopic operative debridement was recorded for each patient. Information in the database was analyzed to identify statistically significant relationships between extent of disease and/or HPV type, patient age at diagnosis, and selected epidemiological factors. RESULTS: The study may represent the first longitudinal prospective analysis of a large pediatric RRP population. Fifty-eight of the 73 patients in the study underwent HPV typing. Patients infected with HPV-11 were significantly more likely to have higher severity scores, require more frequent surgical intervention, and require adjuvant therapy to control disease progression. In addition, patients with HPV-11 RRP were significantly more likely to develop tracheal disease, to require tracheotomy, and to develop pulmonary disease. Patients receiving a diagnosis of RRP before 3 years of age had significantly higher severity scores, higher frequencies of surgical intervention, and greater likelihood of requiring adjuvant medical therapy. Patients with Medicaid insurance had significantly higher severity scores and required more frequent surgical debridement. Birth by cesarean section appeared to be a significant risk factor for more severe disease and necessity of more frequent surgical intervention. CONCLUSION: Statistical analysis of the relationships among epidemiological factors, HPV type, and clinical course revealed that patients with HPV-11 and patients younger than 3 years of age at RRP diagnosis are prone to develop more aggressive disease as represented by higher severity scores at endoscopic debridement, more frequent operative debridement procedures per year, a greater requirement for adjuvant therapy, and greater likelihood of tracheal disease with tracheotomy.

    Integration of human papillomavirus type 11 in recurrent respiratory papilloma-associated cancer.
    Laryngoscope. 2004; 114(11):1906-9 (ISSN: 0023-852X)
    Reidy PM; Dedo HH; Rabah R; Field JB; Mathog RH; Gregoire L; Lancaster WD
    Department of Otolaryngology, Wayne State University, Detroit, MI 48202, USA. preidy@med.wayne.edu

    OBJECTIVES/HYPOTHESIS: The main objective was to demonstrate that human papillomavirus (HPV) type 11 is an aggressive virus that plays a significant role in the development of laryngeal cancer in patients with a history of recurrent respiratory papillomatosis (RRP). We have done so by preliminary investigation into the molecular mechanism underlying the malignant transformation of RRP to invasive squamous cell carcinoma. STUDY DESIGN: An experimental, nonrandomized, retrospective study using tissue specimens from nine patients with a history of RRP that progressed to laryngeal or bronchogenic cancer was performed. METHODS: DNA and RNA were extracted from 20 formalin-fixed, paraffin-embedded specimens from six patients with a history of early onset RRP and laryngeal cancer and from three patients with early onset RRP and bronchogenic cancer. Polymerase chain reaction (PCR) was performed on DNA to determine the HPV type in each specimen. Reverse-transcriptase PCR specific for virus transcripts was performed on RNA to determine whether the viral genome was integrated into the host genome. RESULTS: HPV-11 but not HPV-6, 16, or 18 was found in all of the laryngeal and bronchogenic cancers in patients with a history of early onset RRP in this study. RNA, sufficiently intact for examination, was obtained from seven patients. Analysis of HPV 11 transcripts revealed integration of the viral genome in three of seven patients. CONCLUSIONS: HPV type 6 and 11 are considered "low-risk" viruses and are not associated with genital cancers, as are HPV types 16 and 18. However, our data suggests that HPV type 11 is an aggressive virus in laryngeal papilloma that should be monitored in patients with RRP.

    2',5'-Oligoadenylate synthetase activity analysis and human papilloma virus typing as prognostic factors in patients with recurrent respiratory papillomatosis.
    J Laryngol Otol. 2004; 118(10):750-6 (ISSN: 0022-2151)
    Gerein V; Rastorguev E; Gerein J; Lodemann E; Pfister H; Draf W; Desloovere C
    Department of Paediatric Pathology, Institute of Pathology, Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. v.gerein@web.de

    OBJECTIVE: Determination of early prognostic factors in patients with recurrent respiratory papillomatosis is extremely important, so the major goal of our prospective, multicentre study was to evaluate (1) the feasibility of various factors to determine prognosis of the clinical course, as well as (2) the response to interferon-alpha therapy in recurrent respiratory papillomatosis. METHODS: Forty-two patients with recurrent respiratory papillomatosis were treated with interferon-alpha (3 MU/m(2) three times per week; mean therapy duration was 2.7 +/- 1.8 years) in 1983-1994 and followed-up until 2003. Human papilloma virus (HPV) type, recurrent respiratory papillomatosis severity and 2',5'-oligoadenylate synthetase activity were determined by standard methods and analysed for correlation with the results of long-term clinical outcome. RESULTS AND CONCLUSION: Patients with HPV type 11, a severity score >4, a high number of surgical procedures prior to interferon-alpha therapy and a high basal 2',5'-oligoadenylate synthetase activity should be considered at high risk of an aggressive clinical course, often with spread to lower airway passages, malignant transformation and death. Human papilloma virus type, score for recurrent respiratory papillomatosis severity, number of surgical procedures and 2',5'-oligoadenylate synthetase activity showed significant association with response to interferon-alpha therapy and the long-term clinical course, so these factors have value in predicting prognosis in recurrent respiratory papillomatosis.

    Recurrent respiratory papillomatosis in a survivor of extreme prematurity.
    Pediatr Pulmonol. 2004; 38(4):352-4 (ISSN: 8755-6863)
    Lee SL; Hui Y
    Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.

    Recurrent respiratory papillomatosis (RRP) is a rare disease in children. Previous reports suggested that prematurity and early age of presentation were poor prognostic factors. We report on a 24-week premature infant who presented with stridor, weak cry, and hoarseness of voice at age 9 months (corrected age), in whom the diagnosis of RRP was not made until age 21 months (corrected age). Laser excision of RRP was subsequently performed, and the child is still surviving at age 2.5 years. RRP should be considered in the differential diagnosis of airway problems in survivors of extreme prematurity; the prognosis is not uniformly poor in premature infants.

    Current status of antiviral therapy for juvenile-onset recurrent respiratory papillomatosis.

    Antiviral Res. 2004; 63(3):141-51 (ISSN: 0166-3542)
    Kimberlin DW
    Division of Pediatric Infectious Diseases, University of Alabama, 1600 Seventh Avenue South CHB 303, Birmingham, AL 35233, USA, dkimberlin@peds.uab.edu

    Human papillomavirus (HPV) infections are among the most prevalent of the sexually transmitted diseases, with up to 75% of women in the United States acquiring genital HPV infection at some point in their lives. HPV infections of the genital tract are of medical and public health concern due to their propensity to lead to the development of cervical cancer, and because they can be transmitted to the respiratory tract of a newborn child, resulting in juvenile-onset recurrent respiratory papillomatosis (JO-RRP). JO-RRP is the second most common cause of hoarseness among pediatric patients, and is the most common benign neoplasm in the larynx. The traditional treatment for JO-RRP is the physical removal of the wart through laryngoscopy and surgical debulking of the airway papillomas. Papillomas frequently recur following surgical resection, however, often necessitating repeated ablative efforts to maintain a patent airway. In a minority of patients, surgical management must be supplemented with adjuvant medical therapy, with interferon being the best studied and most commonly utilized. Recently, a Phase II investigation of a therapeutic vaccine yielded promising results, and a Phase III evaluation of this therapeutic modality is planned. Other adjuvant treatments currently being utilized, but for which controlled data of benefit are lacking, include cidofovir, indole-3-carbinol, ribavirin, mumps vaccine, and photodynamic therapy. As with surgical management, viral persistence occurs following treatment with these adjuvant modalities, further contributing to the challenge of managing patients with this potentially devastating disease.

    STAT3 activation in recurrent respiratory papillomatosis.

    Arch Otolaryngol Head Neck Surg. 2004; 130(9):1043-5 (ISSN: 0886-4470)
    Patel NJ; Hansen A; Merati AL; Kerschner JE
    Division of Laryngology, Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, USA. napatel@mcw.edu

    BACKGROUND: The activation of signal transducer and activator of transduction (STAT) protein is thought to lead to the genesis of neoplasia by promoting cellular growth and preventing apoptosis, and by immune system modulation; STAT3 protein has also been implicated in tumor survival and propagation in recurrent respiratory papillomatosis (RRP). OBJECTIVES: To investigate the presence and activation of STAT3 protein in papilloma specimens from subjects with RRP and compare findings with those obtained from control subjects' tissue. DESIGN: Laryngeal papilloma samples were collected from 8 nonselected consecutive patients undergoing surgery for RRP, and control samples of anterior tonsillar pillar mucosa were collected from 8 patients undergoing adenotonsillectomy. After extraction, we applied gel shifting to the nuclear protein using an electromotility shifting assay kit. Quantitative analysis of the gel shifts was performed, and levels of activated STAT3 protein in RRP specimens and tissue from controls were compared. RESULTS: There was STAT3 protein activation in the nuclear extracts of all (100%) RRP specimens, which was significantly more frequent than in normal epithelial tissue from controls (P<.03). CONCLUSIONS: We conclude that STAT3 protein activation is present in RRP. However, further study is needed to determine if STAT3 protein activation is an important pathway through which human papillomavirus results in the propagation and persistence of RRP.

    American Society of Pediatric Otolaryngology members' experience with recurrent respiratory papillomatosis and the use of adjuvant therapy.
    Arch Otolaryngol Head Neck Surg. 2004; 130(9):1039-42 (ISSN: 0886-4470)
    Schraff S; Derkay CS; Burke B; Lawson L
    Eastern Virginia Medical School and the Children's Hospital of the King's Daughters, Norfolk, VA 23507-1914, USA.

    OBJECTIVE: To evaluate how evolving treatment technologies have affected our management of recurrent respiratory papilloma (RRP) since the last comprehensive survey of pediatric otolaryngologists in 1998. DESIGN: Web-based survey of all American Society of Pediatric Otolaryngology members residing in the United States, Canada, Europe, and Australia. RESULTS: Evaluable survey results were tabulated from 74 practitioners in 62 separate practices managing 700 current children with RRP. A total of 150 (21%) of these patients presently receive adjuvant medical therapies with cidofovir and interferon, accounting for more than two thirds of the total. Sixty-one percent of patients treated with cidofovir have experienced a beneficial response. Distal spread of RRP has occurred in 94 (13%) of the 700 patients. Half of the practices surveyed have experienced a death from RRP, with 89% of deaths directly related to RRP. The laryngeal microdebrider (53%) has supplanted the carbon dioxide laser (42%) as the preferred means of surgically removing papilloma from the larynx in children. Spontaneous, apneic, and jet ventilation (88%) anesthesia techniques have replaced the use of laser-safe endotracheal tubes (10%) as the preferred anesthetic management. Routine human papillomavirus subtyping is practiced by 45% of respondents while 15% treat all their patients with antireflux medications. Half of respondents send lesions for histologic examination only if there is a change in growth pattern while one third send lesions with every surgery. CONCLUSIONS: Recurrent respiratory papilloma continues to be a frustrating disease to treat and is associated with significant morbidity and mortality. There has been an evolution in the past decade toward the increased use of antiviral adjuvant therapy and the use of microdebrider techniques for surgical management.

    Interferon alpha-2b as adjuvant treatment of recurrent respiratory papillomatosis in Cuba: National Programme (1994-1999 report).
    J Laryngol Otol. 2004; 118(9):681-7 (ISSN: 0022-2151)
    Nodarse-Cuní H; Iznaga-Marín N; Viera-Alvarez D; Rodríguez-Gómez H; Fernández-Fernández H; Blanco-López Y; Viada-González C; López-Saura P;
    Centro de Investigaciones Biológicas, La Habana, Cuba. hugo.nodarse@cigb.edu.cu

    Respiratory papillomatosis is a life-spoiling disease due to its high recurrence rate. Interferon (IFN)alpha-2b treatment, adjuvant to surgery, was assessed for its contribution to disease control and patient quality of life improvement. One hundred and sixty-nine patients (85 children and 84 adults) were included after surgical removal of the lesions followed by intramuscular IFN alpha-2b (Heberon alfa R, Heber Biotec), starting with 10(5) IU/Kg weight in children or 6 x 10(6) IU in adults, three times per week. The dose was reduced monthly, if no relapses occurred, until a monthly maintenance with 5 x 10(4) IU/Kgof weight in children or 3 x 10(6) IU in adults up to two years. In case of relapse, it was surgically removed and the patient returned to the higher dose level. The relapse frequency decreased significantly in 77 percent (69/90) of the recurrent patients both in children (34/46, 74 per cent) and adults (35/44, 79 per cent). Among patients included after their first papilloma, 67 per cent (44/66) had complete (no relapses) or partial (only one relapse) responses (children: 15/33, 45 per cent; adults 29/33, 88 per cent). One hundred and eighteen patients (73 per cent) concluded the treatment without lesions (children: 58 per cent; adults 82 per cent), while the rest showed a significant reduction in the number and size of lesions. IFN was well tolerated. Sixty-two patients (38 per cent) did not have adverse events. The main adverse reactions were fever (59 per cent), chills (24 per cent), arthralgias and myalgias (14 per cent) and headache (10 per cent). One patient developed anti-IFN alpha neutralizing antibodies and became resistant to treatment with recombinant IFN alpha-2b; he responded to natural leucocyte IFN alpha. Treatment with IFN alpha-2b, as an adjuvant to surgery represents a favourable and safe therapeutic alternative for patients with recurrent respiratory papillomatosis.

    HLA alleles, IFN-gamma responses to HPV-11 E6, and disease severity in patients with recurrent respiratory papillomatosis.
    Hum Immunol. 2004; 65(8):773-82 (ISSN: 0198-8859)
    Bonagura VR; Vambutas A; DeVoti JA; Rosenthal DW; Steinberg BM; Abramson AL; Shikowitz MJ; Gjertson DW; Reed EF
    Division of Allergy and Immunology, North Shore-Long Island Jewish Research Institute, Department of Pediatrics, Long Island Jewish Medical Center, New Hyde Park, New York, USA. bonagura@lij.edu

    Recurrent respiratory papillomatosis (RRP) remains an immunologic enigma. Human papillomavirus (HPV) types 6 and 11 are the predominant HPV viruses that cause papilloma development. However, it is unclear why only a very small fraction of HPV-exposed individuals develop RRP. We performed high-resolution HLA class I and II genotyping on 70 randomly selected patients (56 Caucasians and 14 African-Americans) with RRP. We report, for the first time, an increased frequency of HLA-DRB1*0102 in Caucasian patients with RRP, suggesting that this allele predisposes individuals to RRP. Additionally, HLA-DRB1*0301, DQB1*0201, and DQB1*0202 alleles were selectively enriched in Caucasians with severe disease, suggesting that these alleles may regulate disease severity. In contrast, HLA-DQB1*0602 was more frequent in controls than in Caucasians with severe disease, suggesting a severity-sparing effect of this allele. Furthermore, both DQB1*0201 and DQB1*0202 were enriched, whereas DQB1*0602 was absent, in African-Americans. Interestingly, HLA-DRB1*0301 and DQB1*0201 correlated with reduced interferon-gamma expression in patients with RRP. Larger studies are needed to identify other class II major histocompatibility complex alleles that may influence disease predisposition, disease severity, or both, especially in African-American patients, to ultimately illuminate the regulatory effects of these alleles in the predisposition and severity of RRP.

    Preliminary report of endolaryngeal and endotracheal laser surgery of juvenile-onset recurrent respiratory papillomatosis by Nd:YAG laser and a new fiber guidance instrument.
    Otolaryngol Head Neck Surg. 2004; 131(1):44-9 (ISSN: 0194-5998)
    Janda P; Leunig A; Sroka R; Betz CS; Rasp G
    Department of Otorhinolaryngology, Ludwig-Maximilians University, Munich, Germany. philip.janda@gmx.de

    OBJECTIVES: Recurrent respiratory papillomatosis (RRP) caused by human papilloma virus (type 6 and 11) is the most common benign neoplasm of the larynx in children. Despite being a benign disease, treatment is very difficult and is characterized by frequent recurrence, spread throughout the respiratory tract, and malignant degeneration. Besides surgical resection and the established CO(2) laser treatment, laser surgery by fiber-guided Nd:YAG laser light promises to be a bloodless and effective treatment procedure. To improve this new method, a novel fiber guidance instrument has been developed to aid in endolaryngal laser surgery of RRP.Study design and setting The method described uses a specially designed instrument for fiber guidance that is equipped with a bendable distal tip to move the fiber end precisely. Moreover, the instrument includes an additional channel for the suction of smoke and pyrolysis products. Up to now, 5 patients (aged 4 to 8 years) with RRP were treated by Nd:YAG laser light (lambda = 1064 nm; power, 10 W; irradiance, 3.5 kW/cm(2), continuous wave) with a prototype version of the new instrument and were followed up for 12 months each. RESULTS: Because of the adequate length and the bendable distal tip with a range of -5 degrees up to 45 degrees to the optical axis of the fiber and less than 10% light loss at maximal deflection, RRP can be treated by Nd:YAG laser light easily and precisely. The continuous suctioning ensured an optimum view of the operating field and a minimal load of potential infectious laser plume and toxic pyrolysis products for the patient as well as for the physician. The laser treatment of RRP with the new fiber guidance instrument was only minimally traumatic. During 1-year follow-up visits, all Nd:YAG laser light-treated patients, showed a regression of the disease. CONCLUSIONS: The new fiber guidance instrument enables a precise and easy treatment of the RRP with fiber-guided laser systems (eg, Nd:YAG-, diode-, and KTP-lasers) and an effective removal of infectious laser plume as well as toxic pyrolysis products. A follow-up period of 1 year revealed that Nd:YAG laser surgery seems to prevent a rapid recurrence of juvenile respiratory papillomatosis in the treated patients.

    Cidofovir plasma assays after local injection in respiratory papillomatosis.
    Laryngoscope. 2004; 114(7):1151-6 (ISSN: 0023-852X)
    Naiman AN; Roger G; Gagnieu MC; Bordenave J; Mathaut S; Ayari S; Nicollas R; Bour JB; Garabedian N; Froehlich P
    Otolaryngology Department, Edouard Herriot Hospital, Lyon, France.

    OBJECTIVE: To assess cidofovir plasma concentration after intralesional airway administration for recurrent respiratory papillomatosis. DESIGN: Prospective study. SETTING: Tertiary care teaching hospital. PATIENTS AND METHOD: The study comprised 21 patients (10 children and 11 adults). Plasma samples were collected at 10 and 45 minutes (T10, T45) or at 10 and 60 minutes (T10, T60) after injection. The measurements of cidofovir were performed using a high-performance liquid chromatographic method. RESULTS: Plasma samples were collected at T10 and T45 on 19 occasions from the children and on 17 from the adults. A linear relationship was found between plasma concentration and dose in children (mean dose 1.2 mg/kg; mean cidofovir plasma levels 0.91 and 0.81 microg/mL) but not in adults (mean dose 0.2 mg/kg; mean plasma levels 0.21 and 0.31 microg/mL). The same relationships were found between dose and area under the concentration/time curve (AUC). Four plasma samples were taken in children at T10 and T60: mean dose 1.2 mg/kg and mean plasma concentrations 1.11 and 1.24 microg/mL. Maximum plasma concentration averaged 34% (SD 11%) in children and 62% (SD 33%) in adults, with equivalent plasma level after intravenous infusion of the same dose. CONCLUSIONS: The cidofovir plasma levels were below those leading to toxicity. The levels and the AUC were dose dependent in children but not in adults. Diffusion from the injected site was greatest in a few adults and unpredictable. Because of the great individual variation in diffusion in adults, cidofovir should be used at less than the recommended intravenous dose to prevent any risk of systemic toxicity.

    Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results.

    J Voice. 2004; 18(2):248-53 (ISSN: 0892-1997)
    Rosen CA; Bryson PC
    University of Pittsburgh Voice Center, Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. rosenca@msx.upmc.edu

    We report the results of a clinical study using Indole-3-Carbinol (I3C) for the treatment of recurrent respiratory papillomatosis (RRP). I3C is abundant in cruciferous vegetables and has been shown to decrease papillomatous growth in cell cultures and be effective in an animal model of RRP. This is a prospective, open-label study design. Patients with RRP were enrolled from September 1996 to August 2001 and treated with I3C (adult dose of 200 mg PO BID). All patients underwent complete surgical removal and then started I3C. Further surgery was performed on an as-needed basis. Patients were categorized as having a complete, partial, or no response to I3C. Thirty-three patients treated with I3C were available for long-term follow-up (mean=4.8 years), whereas 12 patients were lost to follow-up. Eleven (33%) patients experienced remission of papillomatous growth and did not require surgery while on I3C. Ten (30%) patients had a reduction in papillomatous growth that resulted in less frequent surgery. Twelve patients (36%) had no clinical response. No patients experienced a worsening of their RRP. Of the 9 pediatric patients available, 1 experienced a complete response, 3 a partial response, and 5 had no response to I3C. Twelve patients with a positive response (partial or complete) to I3C are still taking I3C. Seven positive responders discontinued I3C, 3 of which have remained disease-free, whereas 4 continue to have RRP. No immediate or long-term side effects related to I3C were found. I3C has been found to be a successful treatment option for RRP. I3C's efficacy in pediatric patients merits further study.

    Failure of gamma interferon but not interleukin-10 expression in response to human papillomavirus type 11 E6 protein in respiratory papillomatosis.
    Clin Diagn Lab Immunol. 2004; 11(3):538-47 (ISSN: 1071-412X)
    DeVoti JA; Steinberg BM; Rosenthal DW; Hatam L; Vambutas A; Abramson AL; Shikowitz MJ; Bonagura VR
    Division of Allergy and Immunology, Department of Pediatrics, Long Island Jewish Medical Center and North Shore Long-Island Jewish Research Institute, New Hyde Park, New York 11040, USA.

    Recurrent respiratory papillomatosis (RRP) is a chronic, debilitating disease of the upper airway caused by human papillomavirus type 6 (HPV-6) or HPV-11. We describe responses of peripheral blood mononuclear cells (PBMC) and T cells from RRP patients and controls to the HPV-11 early proteins E6 and E7. PBMC were exposed in vitro to purified E6 or E7 proteins or transduced with fusion proteins containing the first 11 amino acids of the human immunodeficiency virus type 1 protein tat fused to E6 or E7 (tat-E6/tat-E7). T(H)1-like (interleukin-2 [IL-2], gamma interferon [IFN-gamma], IL-12, and IL-18), and T(H)2-like (IL-4 and IL-10) cytokine mRNAs were identified by reverse transcription-PCR, and IFN-gamma and IL-10 cytokine-producing cells were identified by enzyme-linked immunospot assay. These studies show that HPV-11 E6 skews IL-10-IFN-gamma expression by patients with RRP toward greater expression of IL-10 than of IFN-gamma. In addition, there is a general cytokine hyporesponsiveness to E6 that is more prominent for T(H)1-like cytokine expression by patients with severe disease. Patients showed persistent IL-10 cytokine expression by the nonadherent fraction of PBMC when challenged with E6 and tat-E6, and, in contrast to controls, both T cells and non-T cells from patients expressed IL-10. However, E7/tat-E7 cytokine responses in patients with RRP were similar to those of the controls. In contrast, E6 inhibited IL-2 and IL-18 mRNA expression that would further contribute to a cytokine microenvironment unfavorable to HPV-specific, T-cell responses that should control persistent HPV infection. In summary, E6 is the dominant inducer of cytokine expression in RRP, and it induces a skewed expression of IL-10 compared to the expression of IFN-gamma.

    Voice quality of prepubescent children with quiescent recurrent respiratory papillomatosis.

    Int J Pediatr Otorhinolaryngol. 2004; 68(5):529-36 (ISSN: 0165-5876)
    Lindman JP; Gibbons MD; Morlier R; Wiatrak BJ
    Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35243, USA. lindman99@hotmail.com

    OBJECTIVE: The purpose of this study was to assess the long-term impact of recurrent respiratory papillomatosis (RRP) and its treatment on voice quality in prepubescent children. STUDY DESIGN: Case-control study. METHODS: Prepubescent children with RRP in remission for at least 12 [according to MM section] months were asked to participate. Remission was documented by absence of papillomas on fiberoptic flexible laryngoscopy. An age- and sex-matched control was selected for each patient enrolled. Voice was evaluated using the voice-related quality of life (V-RQOL) questionnaire, perceptual evaluations of voice quality by speech-language pathologists using the GRBAS (grade of hoarseness, roughness, breathiness, asthenia, strain) scale, and acoustic analysis (fundamental frequency, maximal phonation time, and relative average perturbation) using the Visi-Pitch II 3300. RESULTS: Medical records of 84 patients were reviewed and 15 met study criteria. Five agreed to participate but one was excluded due to the presence of papillomas. The four study patients and four matched controls were between 9- and 11-years old. On the V-RQOL questionnaire, each control rated V-RQOL as normal (10/50) and the average patient group score was within the normal range (11.5/50). On perceptual evaluations, the patient's voices were more hoarse, breathy, and rough compared to controls'. Acoustic analysis showed that patients' voices had a lower average fundamental frequency (F(0)) (200 Hz compared to 243 Hz for controls) and a higher relative average perturbation (RAP) (1.10 compared to 0.77), although only one patient's voice actually had elevated RAP (2.89), which had a large impact on raising the average score for the patient group. The average maximal phonation times were similar for the two groups (7.8s for patients and 7.4s for controls) but lower than average normal scores reported in the literature. CONCLUSIONS: Although children with RRP do not perceive their voice quality to have a negative impact on V-RQOL, speech-language pathologist evaluations and acoustic measurements show objective differences between the voices of children with quiescent RRP and those of normal, healthy controls.

    Is cidofovir a useful adjunctive therapy for recurrent respiratory papillomatosis in children?

    Int J Pediatr Otorhinolaryngol. 2004; 68(4):413-8 (ISSN: 0165-5876)
    Peyton Shirley W; Wiatrak B
    Department of Pediatric Otolaryngology, The Children's Hospital of Alabama, 1940 Elmer J. Bissell Road, Birmingham, AL 35233, USA.

    OBJECTIVE: To assess the usefulness of cidofovir in treating recurrent respiratory papillomatosis in children. Cidofovir is an acyclic nucleoside phosphonate that has been reported to be effective in the treatment of respiratory papillomatosis in several small series of patients. METHODS: A prospective study was conducted in 11 children (mean, 2.1 years; range, 0.5-3 years at diagnosis) with recurrent respiratory papillomatosis who at the start of the study were requiring debridement of papillomas at least every 6 weeks. After microlaryngoscopy with powered microdebridement of papillomas patients received intralesional injection of cidofovir (5mg/ml). The severity of papillomatosis was rated at each visit using a standardized papilloma severity scoring system. The success of therapy was measured by the trend in the patient's papilloma severity scores before and after cidofovir therapy and by whether the frequency of operative interventions decreased in the period after treatment began. RESULTS: Three patients had impressive improvements in severity scores and a decrease in the frequency of required operative interventions after cidofovir, two patients had a partial response, and for six patients cidofovir was considered ineffective. CONCLUSIONS: Intralesional cidofovir did not decrease the severity or frequency of operative intervention for recurrent respiratory papillomas in the majority of children in this study. The drug did improve papillomatosis in the minority of patients without causing notable morbidity. A large multi-institutional controlled study is needed to better assess the efficacy of this treatment.

    Molecular characterization of mutations in patients with benign and aggressive recurrent respiratory papillomatosis: a preliminary study.
    Ann Otol Rhinol Laryngol. 2004; 113(3 Pt 1):180-6 (ISSN: 0003-4894)
    Pou AM; Weems J; Deskin RW; Nason R; Payne DA
    Department of Otolaryngology, University of Texas Medical Branch, Galveston, Texas 77555-0521, USA.

    This study was performed to determine whether genetic polymorphisms within the human papillomavirus (HPV) can predict the disease course in patients with recurrent respiratory papillomatosis. The HPV type and genomic variations were determined by comparing the sample sequence to a prototypical HPV in the database of the National Center for Biotechnology Information. The results were correlated with the clinical course. Seven children and 6 adults were studied. Six of the 7 children had aggressive disease associated with HPV type 11. The remaining child had HPV type 6. Five of the 6 adult patients had HPV type 6; 1 had a history of juvenile recurrent respiratory papillomatosis. The remaining adult had an aggressive disease course associated with HPV type 11. The HPV type and specific polymorphisms were conserved over time in serial isolates. The age of onset and medical therapy did not appear to affect the polymorphisms present. Future studies may find that the presence of certain polymorphisms is associated with different geographic locations and possibly with the disease course.

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