Course Of Recurrent Respiratory Papillomatosis Research Articles

Long-Term Follow-up of Parenteral Bevacizumab In Patients with Recurrent Respiratory Papillomatosis.

The clinical course of recurrent respiratory papillomatosis (RRP) varies from spontaneous remission to severe airway obstruction with wide variability in recurrence. Standard treatment involves debulking to improve voice and/or breathing. Non-surgical therapies are emerging in hopes of non-operative disease control. This retrospective review analyzes long-term safety, efficacy, and durability of clinical control in the largest reported series of parenteral bevacizumab in adults with RRP. Twenty-three patients with known RRP who have been receiving off-label systemic bevacizumab were included. Dosage, infusion interval, number of cycles, debulking requirements, subjective outcomes, adverse events, and reasons for treatment termination were investigated. Patients have been followed for an average of 791.43 (21-1468) days. The most common starting dosing regimen was 15 mg/kg at 3 weeks in 11 followed by 10 mg/kg at 6 weeks intervals in 6 individuals. Long-term maintenance dosage varied with the least intensive regimen being 10 mg/kg at 14-week intervals. Subjective improvement of voice and/or breathing was reported in 18/23 subjects. The median time for patients that needed a procedure after treatment was 634 days. Procedures after infusions decreased from 3.08 ± 2.48 procedures in the year prior to 0.52 ± 1.12 during systemic Bevacizumab, and to 0.86 ± 2.05 after stopping bevacizumab. Therapy termination occurred in 8 subjects where only 3 were due to adverse events. Parenteral bevacizumab remains a well-tolerated treatment for patients with recalcitrant RRP. There appears to be a durable reduction in the frequency of debulking surgery requirements although on a maintenance regimen. Laryngoscope, 133:2725-2733, 2023.

Prevalence of Epstein–Barr virus infection in recurrent respiratory papillomatosis and the influence on disease severity

Recurrent respiratory papillomatosis (RRP) is characterized by benign papillomatous lesions in the upper airway associated with human papillomavirus infection. It has been proposed that viral coinfections may contribute to an aggressive clinical course of the disease. For this purpose, we investigated the prevalence of Epstein-Barr virus (EBV) infection among 40 RRP patients by polymerase chain reaction assay. EBV DNA was detected in 11 cases and disease severity was observed in 54.5% of EBV-positive patients. No significant association was found between the RRP severity categories and EBV status (P > 0.05). Regardless EBV status, disease severity showed significant association with RRP diagnosis since childhood (P = 0.009). These findings indicate an absence of direct influence of EBV infection on aggressive course of RRP. However, the development of RRP since childhood increase the susceptibility to disease severity.

The Impact of Laryngopharyngeal Reflux on Occurrence and Clinical Course of Recurrent Respiratory Papillomatosis.

Laryngopharyngeal reflux (LPR) has been proposed both as a trigger for recurrent respiratory papillomatosis (RRP) onset and as a factor favoring an aggressive clinical course. In this prospective study, 106 participants were recruited within a period of 24 months at the Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana. This study compared a group of RRP patients (N=36) with a group of LPR patients (N=28) and a group of healthy participants (N=42) based on Reflux Symptom Index (RSI), Reflux Finding Scores (RFS), and saliva analyses (pH, pepsin concentration, bile acid concentration, and pepsin enzymatic activity). The RRP group compared to the LPR group showed a statistically significant difference only in RSI and RFS scores, while the RRP group compared to healthy controls showed significantly higher values in all tested parameters (RSI score, RFS, saliva pH, pepsin concentration, bile acids concentration, pepsin enzymatic activity). LPR is common in RRP patients and significantly more prevalent compared to healthy controls. Our results show that saliva analyses are a better office-based tool than RSI questionnaires and RFS scores for diagnosing LPR in RRP patients. 3 Laryngoscope, 132:619-625, 2022.

The association between gastroesophageal reflux disease and recurrent respiratory papillomatosis: A systematic review.

Antireflux therapy is incorporated in many treatment protocols for recurrent respiratory papillomatosis (RRP) because gastroesophageal reflux (GERD) is thought to worsen the disease course of RRP. It is unclear if GERD really aggravates the disease course. The aims of this systematic review were to 1) evaluate incidence of GERD among RRP patients and 2) report if GERD changes the clinical course or tissue properties of RRP. A search was conducted in PubMed, Embase, and Google Scholar, following the methods of Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Articles with original data, published after January 1, 1990, on RRP with GERD as a determinant were eligible. There was no language restriction. Data on study design, study population, statistics, outcomes (incidence and influence of GERD), and risk of bias were collected and evaluated following PRISMA protocols. Of 1,277 articles, 19 were selected. Gastroesophageal reflux was objectified in 25% to 100% of RRP patients. Subjective GERD was present in 0% to 70% of patients. There is no proof that GERD aggravated the clinical course or tissue properties of RRP, as measured by the number of surgeries, severity scoring systems, or dysplasia. One study did find a higher chance of web formation in patients with anterior or posterior glottic papillomas who did not receive antireflux therapy, but these results should be interpreted with care due to the study's quality. There is insufficient proof that GERD does or does not aggravate the clinical course or tissue properties of RRP. Laryngoscope, 126:2330-2339, 2016.

Clinical course of recurrent respiratory papillomatosis: comparison between aggressiveness of human papillomavirus-6 and human papillomavirus-11.

Recurrent respiratory papillomatosis (RRP) is mainly associated with human papillomavirus (HPV)6 or HPV11. The purpose of this study was to compare clinical outcome, aggressiveness, and treatment response between HPV6- and HPV11-associated RRP. A retrospective cohort of 55 patients with RRP (1974-2012) was used. Surgical interventions (n = 814) were analyzed, and complications scored. HPV6/11-specific polymerase chain reaction (PCR) was performed on RRP biopsies. Seventy-six percent of patients (42 of 55) were infected with HPV6 and 24% (13 of 55) with HPV11. The HPV11 group had anatomically more widespread disease. The expected number of surgical interventions was higher in the younger age (<22.4 years) HPV11 group, and the older age (<22.4 years) HPV6 group. Regardless of HPV type, earlier age of onset of RRP resulted in a higher number of surgical interventions. Anatomically, HPV11-associated RRP behaves more aggressively. Younger patients with HPV11 and older patients with HPV6 experience a worse clinical course of RRP.

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.

Degrees of dysplasia and the use of cidofovir in patients with recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP) is a benign disease characterized by recurrent lesions in the airway. The prevalence and degree of dysplasia that is present in the natural course of RRP is not well established. Adjuvant therapies, such as cidofovir, have been tried with the goal of decreasing the interval between repeat surgical treatments, the mainstay of therapy. Although, the off-label use of cidofovir to treat RRP has been common, there have been concerns regarding carcinogenic transformation following the use of cidofovir. This study aims to explore the association between increasing degree of papilloma dysplasia and the use of cidofovir in the context of the natural progression of dysplasia in RRP. Retrospective case series. Demographic data and surgical history were obtained through chart reviews for this retrospective case series of 13 patients with RRP who had histopathologic biopsies done before and after exposure to cidofovir. Pathologic data collected over 10 years from serial excisions at the University of Iowa Hospitals were reviewed by a single pathologist, and the highest degree of dysplasia was noted per excision time. Of the 176 specimens collected in these 13 patients with serial papilloma biopsies, 5.7% had no dysplasia, 57.4% had mild dysplasia (grade 1), 28.4% had moderate dysplasia (grade 2), and 8.5% had severe dysplasia (grade 3). A comparison of each patient's multiple biopsies across time suggested that the dysplastic grade was worse in two patients, better in four patients, and virtually unchanged in seven patients. There was no clear-cut pattern between the use of cidofovir and the degree of dysplasia over time. These results strongly suggest that intralesional cidofovir therapy does not correlate with worsening dysplastic progression. Dysplasia is relatively common in the setting of RRP; however, the prognostic significance of this finding is unknown. Additional research is needed to delineate the natural progression of dysplasia and its clinical significance in RRP, as well as the efficacy of cidofovir.

Time Course of Juvenile Onset Recurrent Respiratory Papillomatosis Caused by Human Papillomavirus

With the recent licensure of a new quadrivalent vaccine, many diseases caused by human papillomavirus (HPV) can now be prevented, including recurrent respiratory papillomatosis (RRP). The purpose of this study was to describe the burden and time course of juvenile onset RRP. A retrospective chart review was conducted of children with airway papillomatosis at the Hospital for Sick Children in Toronto, Canada, between 1994 and 2004. Statistical methods included descriptive statistics of the cohort, a repeated events survival model, and nonlinear modeling equations to describe the time course of illness. Nine hundred twenty-six surgical procedures in 67 patients were identified through a review of surgical records. The median age at diagnosis was 3.2 years (range, 0.1-14.8 years) and the most common presenting symptom was hoarseness (75%). Adjuvant pharmacologic therapy (interferon or cidofovir) was used in 13 cases (19%). HPV types 6 or 11 were identified most commonly as the etiologic agent. Nonlinear modeling equations (exponential and quadratic) fit the observed data well, and were superior to linear models. Repeated events survival analysis identified significant prognostic variables: surgeon, adjuvant therapy, and anatomic score. A decision rule is presented that allows the time to next surgery to be predicted based on the previous surgery and the anatomic score. Most patients have a decelerating rate of debulking surgeries over time, well described by our nonlinear modeling equations. Factors affecting the time course of RRP include: inter-surgeon variability, the extent and severity of papillomas at the time of laryngoscopy, and the use of adjuvant medical therapies.

Children and partners of patients with recurrent respiratory papillomatosis have no evidence of the disease during long-term observation

Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm affecting the larynx and upper respiratory tract. The aim of our study was to investigate whether children and partners of patients with RRP develop the same disease and to determine whether there is an impact of pregnancy on the course of RRP. Thirty-eight of 42 patients with RRP were accepted for a multicenter prospective study in Germany in 21.06.83-12.03.90. Mean follow-up duration was 15.3+/-1.8 years. The data of partners of patients with RRP was collected during the period of observation and then updated via interviews in January 2006. Twenty-nine children and four grandchildren were born to 14 patients with RRP. Fifteen of 448 cases of patients with RRP were treated in Saint Vladimir Moscow Children's Hospital in Russia in 1988-2003 and analyzed retrospectively. Sixteen children and one grandchild were born to 15 patients with RRP from Russia. In both studies, the virus type of patients with RRP was identified by nested PCR or Southern blot hybridization. Statistical analysis was performed using Fisher's exact test (probability value set at p<0.05). All children born to patients with RRP were healthy. RRP was not diagnosed in any of them on the basis of clinical or histological examination. Four of 45 children developed dysphonia, two of them had vocal cord nodules. None of the sexual partners of patients has developed RRP during the follow-up period. Pregnancy was accompanied by excessive growth of papillomas in all women (100%) with RRP associated with HPV type 11, and only in 16.7% of women with RRP associated with HPV type 6 (p=0.001). Patients with RRP are able to have healthy children regardless of the stage of the disease. Partners of RRP patients do not develop RRP during an observation period of 15 years. Pregnancy has a negative impact on the course of RRP and local laryngeal status in patients; it is more significant in HPV type 11 associated cases as it is manifested by more rapid papillomas growth and more frequent recurrence.

Clinical course of recurrent respiratory papillomatosis in Danish children.

To evaluate the clinical course of juvenile-onset recurrent respiratory papillomatosis (RP) with respect to age, disease duration, and maternal condylomas. Inception cohort study. All ear, nose, and throat departments in public Danish hospitals. Fifty-seven Danish children diagnosed with RP and born between 1974 and 1993 were observed for an average of 14 years after diagnosis. Removal of respiratory papillomas by knife biopsy, laser surgery, or cryotherapy. Children younger than 5 years diagnosed with RP underwent an average of 4.1 surgeries in the first year of disease, the highest rate among all our patients. The overall surgery rate decreased over time after initial diagnosis but remained significantly higher for children with a younger age of onset for the first 4 years of disease (P <.001) and for children with a maternal history of condylomas in pregnancy for years 4 to 10 of the disease (P <.001). We also observed an independent and statistically significant (P <.001) decreasing surgery rate with increasing age and time from initial diagnosis. The trend for children with recurrent disease was a decreasing rate of surgical procedures (28 of 42 patients with recurrent disease); however, a third of patients (14/42) demonstrated a constant or increasing rate of surgical procedures over time. The clinical course of RP is characterized by a high frequency of surgeries soon after diagnosis that diminishes over time and with increasing age. Additional studies are warranted to identify factors associated with cases that do not conform to the usual disease course.

Recurrent Respiratory Papillomatosis

Recurrent respiratory papillomatosis (RRP) is a viral-induced disease that most commonly affects the upper aerodigestive tract of adults and children. The manifestations and clinical course of RRP differ based on the age of onset. Childhood-onset RRP is more aggressive and more common than its adult counterpart. In children, the disease is usually acquired at birth from a mother infected with human papillomavirus in the urogenital tract. Adults typically acquire RRP through sexual contact. The course of the disease is variable, but many patients, usually children, require multiple surgical procedures to maintain a patent airway. Several adjuvant therapies have been studied, including the use of interferon, photodynamic therapy, indole-3-carbinol, and cidofovir, although none has been shown to eliminate the disease. In this review, we discuss what is presently known regarding the etiology, transmission, clinical course, and treatment options of RRP.

Human Papillomavirus-11-associated Recurrent Respiratory Papillomatosis is more Aggressive than Human Papillomavirus-6-associated Disease

The aim of this study was to determine whether viral type (HPV-6 vs. HPV-11) could predict the clinical course of recurrent respiratory papillomatosis in children. Viral typing, using the polymerase chain reaction, was performed on laryngeal biopsies of 61 patients treated at Children's Hospital of Michigan. HPV-6 was detected in 29 of the patients' biopsies and HPV-11 in 32 biopsies. HPV-11 was more common among the African-American patients than among Caucasians (P = 0.001). Patients with HPV-11 were diagnosed at a younger age (36.2 vs. 48.2 months; P = 0.04) and were more likely to have active disease (P = 0.0311) at the time of this study. They tended to have longer periods of disease activity (8 years vs. 5 years; P = 0.026), required more surgical procedures (42 procedures/patient vs. 13.6; P = 0.02), and more procedures per patient, per year (2.9 vs. 5.3; P = 0.0164). Three of the patients infected with HPV-11 developed invasive papillomatosis and bronchogenic squamous cell carcinoma, and two of these patients died of disease. Our findings suggest that HPV-11 infection confers a more aggressive course to recurrent respiratory papillomatosis.

Initial Results from the National Registry for Juvenile-Onset Recurrent Respiratory Papillomatosis

Objective To characterize the spectrum of juvenile-onset recurrent respiratory papillomatosis (RRP) in the United States and to obtain data about the natural course of the disease and its response to treatment. Setting Twenty tertiary-care pediatric otolaryngology centers throughout the United States. Patients All patients with active RRP aged less than 18 years at the participating sites. Main Outcome Measures Number of surgical procedures performed per year, progression of papillomas to previously nondiseased anatomical sites, drug interventions and other adjuvant therapy, and need for tracheostomy. Results Data were collected from 399 children enrolled from January 1, 1997, through December 31, 1998. There were 51.9% male; 62.7% white, 28.3% black, 9.0% other or unknown racial group; 10.8% Hispanic ethnicity. Mean age at diagnosis was 3.8 years (range, 0.1-16.3 years) and mean duration of disease was 4.4 years (range, 0.03-18.9 years). The mean number of surgical procedures per child was 4.4 per year (range, 0.2-19.3 per year). Children whose RRP was diagnosed at younger ages ( P =.001) and almost 2 times more likely to have 2 or more anatomical sites affected ( P =.008) than were children whose RRP was diagnosed at later ages (≥3.0 years), after adjusting for sex, race, and years of treatment. Conclusions Children whose disease was diagnosed before age 3 years were more likely than children aged 3 years or older to have more severe disease as measured by the mean number of surgical procedures performed and by the number of anatomical sites affected. The registry will form the basis for future analysis on the outcome of disease, natural course of RRP under management strategies, prevention strategies, and public health importance.

Initial results from the national registry for juvenile-onset recurrent respiratory papillomatosis. RRP Task Force.

To characterize the spectrum of juvenile-onset recurrent respiratory papillomatosis (RRP) in the United States and to obtain data about the natural course of the disease and its response to treatment. Twenty tertiary-care pediatric otolaryngology centers throughout the United States. All patients with active RRP aged less than 18 years at the participating sites. Number of surgical procedures performed per year, progression of papillomas to previously nondiseased anatomical sites, drug interventions and other adjuvant therapy, and need for tracheostomy. Data were collected from 399 children enrolled from January, 1, 1997, through December 31, 1998. There were 51.9% male; 62.7% white, 28.3% black, 9.0% other or unknown racial group; 10.8% Hispanic ethnicity. Mean age at diagnosis was 3.8 years (range, 0.1-16.3 years) and mean duration of disease was 4.4 years (range, 0.03-18.9 years). The mean number of surgical procedures per child was 4.4 per year (range, 0.2-19.3 per year). Children whose RRP was diagnosed at younger ages (<3.0 years) were 3.6 times more likely to have more than 4 surgical procedures per year (P=.001) and almost 2 times more likely to have 2 or more anatomical sites affected (P=.008) than were children whose RRP was diagnosed at later ages (> or =3.0 years), after adjusting for sex, race, and years of treatment. Children whose disease was diagnosed before age 3 years were more likely than children aged 3 years or older to have more severe disease as measured by the mean number of surgical procedures performed and by the number of anatomical sites affected. The registry will form the basis for future analysis on the outcome of disease, natural course of RRP under management strategies, prevention strategies, and public health importance.

Significance of DNA ploidy and cell proliferation in juvenile respiratory papillomatosis.

The clinical course of recurrent respiratory papillomatosis (RRP) in children is variable and unpredictable. At present there is no way to identify patients at risk for aggressive disease. The objective of this study was to evaluate whether DNA ploidy and cell proliferation analyses can predict the clinical course in children with RRP. Two different methods of estimating proliferation activity were compared. Nonembedded papilloma biopsy specimens from 18 pediatric patients were analyzed by flow cytometry providing DNA content with cell cycle analysis. The expression of the proliferative marker Ki-67 in papilloma tissue was quantified by immunohistochemistry. The patients were prospectively observed for 12 to 18 months. DNA content analysis and Ki-67 expression were compared to clinical information regarding number of disease sites, distal tracheobronchial spread, number of recurrences, need for tracheostomy, and disease remission. High S-phase fraction, proliferative index, and Ki-67 expression correlated with an aggressive clinical course. DNA ploidy analysis and immunodetection of proliferative markers may assist in predicting prognosis in children with RRP.

Treatment of recurrent respiratory papillomatosis with indole-3-carbinol

Recurrent respiratory papillomatosis (RRP) is a rare disease characterized by benign papillomatous growths of the aerodigestive mucosa.lJ RRP is the most common benign laryngeal tumor of childhood, but it affects all age groups, with approximately 2,350 new pediatric cases and 3,600 new adult cases diagnosed in a l-year period in the United States.3 The papillomas may develop anywhere in the aerodigestive tract with the true vocal folds being the most commonly affected site. Hoarseness is the most frequent presenting symptom. Other symptoms may include stridor, dyspnea, failure to thrive, chronic cough, and recurrent pneumonia, symptoms often mistakenly attributed to asthma, croup, chronic tonsillitis, or allergies. 4 The course of RRP varies considerably, and some patients may experience spontaneous remission, whereas others suffer from recurrent papillomatous growth. Malignant transformation, although uncommon, is well documented in RRP patients.5 The papillomas may produce respiratory obstruction and create a life-threatening situation, especially in children. Frequent surgical removal is usually required to maintain an adequate airway, and tracheotomy is often necessary in children with aggressive RRP. The human papilloma virus (HPV), types 6 and 11, has long been suspected of being the etiologic agent in RRP and has been identified in laryngeal papillomas.“~’ There is currently