Recurrent respiratory papillomas are benign airway tumors caused by Human Papillomaviruses (HPVs) types 6 and 11. The disease is characterized by multiple recurrences of papillomas following surgical removal, caused by activation of latent HPV DNA. Most patients have laryngeal disease, while only a small subset has tracheal involvement. We have asked whether the lower frequency of tracheal papillomas was due to reduced prevalence of latent/subclinical tracheal HPV infection or reduced likelihood of activation to clinically apparent disease. A total of 121 biopsies of clinically normal laryngeal and tracheal tissues from 61 patients with laryngeal papillomas were analyzed for HPV DNA by polymerase chain reaction, confirmed by Southern blot hybridization. Patients were followed for 3-18 years (mean = 5.5 +/- 4.4), with only one developing subsequent tracheal disease. There was no significant difference in prevalence of latent HPV DNA between larynx and trachea, analyzing either those patients with a single biopsy or those with more than one biopsy of larynx, trachea, or both. There was also no significant difference between tracheal latency with HPV 6 and HPV 11. We conclude that HPV infects tracheal mucosa and is maintained as a latent infection in the trachea as efficiently as in the larynx. Therefore, we propose that the low frequency of tracheal disease reflects a lower frequency of HPV activation, and postulate that cellular factors that differ between the stratified squamous epithelium of the larynx and the ciliated pseudo-stratified columnar epithelium of the trachea contribute to this difference.
To determine the efficacy of photodynamic therapy (PDT) with meso-tetra (hydroxyphenyl) chlorin (m-THPC) photosensitizer for recurrent respiratory papillomatosis. Design: Parallel-arm, randomized trial of patients requiring surgery at least 3 times yearly with single PDT 6 or 18 months after enrollment and 12-month followup. Disease extent was scored and papillomas were removed during direct endoscopy every 3 months after enrollment. Setting: Tertiary medical centers. Patients: Of 23 patients aged 4 to 60 years enrolled in the study, 15 patients, plus 2 in the late group without PDT owing to airway risk, completed the study. Six patients withdrew voluntarily after PDT. Intervention: Intravenous administration of m-THPC 6 days before direct endoscopic PDT with 80 to 100 J of light for adults and 60 to 80 J for children. Main Outcome Measures: Difference in severity scores between the early and late groups and between pre-and post-PDT scores for all patients. Secondary measures were the associations between baseline characteristics and response and changes in immune response and the prevalence of latent viral DNA. Results: There were significant differences between groups, with marked improvement in laryngeal disease across time after PDT (P=.006). Five of 15 patients were in remission 12 to 15 months after treatment, but there was recurrence of disease after 3 to 5 years. Tracheal disease was not responsive to PDT. No change occurred in the prevalence of latent human papillomavirus DNA. The immune response to virus improved with clinical response. Conclusions: Use of m-THPC PDT reduces the severity of laryngeal papillomas, possibly through an improved immune response. Failure to maintain remission with time suggests that this is not an optimal treatment.
Latent human papillomavirus (HPV) infections are widespread in the genital and respiratory tracts and are a source of recurrent disease. This study used a cottontail rabbit papillomavirus (CRPV) model to determine the presence of E1, E6, and E7 transcripts in latent infection and to determine the temporal change in transcripts following UV activation. We found E1 transcripts in all latently infected sites but no detectable E6 and E7 transcripts, consistent with our earlier studies of HPV6/11 latency. These results suggest that this transcription pattern is broadly characteristic of latent papillomavirus infections. E6/E7 transcripts were detectable within 1 week of irradiation, with maximal induction (approximately 40% of sites) at 2 weeks postirradiation. Papillomas were induced in approximately 26% of irradiated sites after a 3- to 5-week lag. Sites that did not form papillomas by 3 months after irradiation were CRPV DNA positive but E6/E7 RNA negative. Thus, only a subset of latent infections can be induced to express E6/E7 transcripts and form papillomas. We propose that CRPV can be used to study the molecular processes regulating papillomavirus activation.
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