The Efficacy and Safety of Systemic Treatment for Managing Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-analysis.

Recurrent respiratory papillomatosis (RRP), caused by the human papillomavirus (HPV), is associated with an unpredictable clinical course. Although the Derkay Score is widely used to determine clinical severity, its prognostic value has rarely been evaluated. We developed a pathological severity score, the Hamamatsu Recurrent Respiratory Papillomatosis Pathological (HARRP) Score and combined it with the Derkay Score to develop a novel clinicopathological system-the Derkay-HARRP (D-H) Classification. We aimed to validate its prognostic value. We retrospectively analyzed 125 patients who were clinically diagnosed with RRP from 16 Japanese institutions, randomly divided into validation (n = 38) and test (n = 87) cohorts. HPV-typing and immunohistochemistry for HPV-L1, HPV-E4, Ki-67, and p16 were performed. HPV particles were confirmed using the NanoSuit-correlative light and electron microscopy (CLEM) method. Receiver operating characteristic (ROC) curve analysis evaluated marker performance and defined recurrence cut-offs. HARRP and Derkay Scores were further assessed by ROC analysis and Cox proportional hazards models. We stratified patients using the D-H Classification and analyzed disease progression over time. No significant demographic differences were observed between the two cohorts. Positivity of HPV-L1, HPV-E4, and Ki-67 in the upper third of the epithelium was associated with recurrence. NanoSuit-CLEM confirmed HPV particles in HPV-L1-positive areas, supporting pathological relevance. The HARRP Score was calculated by assigning 1 point each for positivity of HPV-L1, HPV-E4, and ≥ 5% Ki-67-positive cells in the upper third of the epithelium. ROC analysis of the HARRP Score showed areas under the curve (AUCs) of 0.675 (validation) and 0.754 (test), whereas the Derkay Score showed AUCs of 0.709 and 0.834, respectively. The cut-off values were 1 and 4, respectively. Both scores were significant in the Cox analysis (p < 0.001). The D-H Classification stratified patients as Severe (both positive scores), Moderate (either positive), or Mild (both negative), with significant differences in relapse-free survival (p < 0.001). Severity tended to decrease with repeated surgeries and recurrence was rare in the Mild group. Findings remained consistent in HPV-positive cases only. Combination of the Derkay and HARRP Scores-the D-H Classification-provides a practical tool for risk stratification and personalized follow-up planning of patients with RRP.

Real-world Adjuvant HPV Vaccination (Gardasil) and Recurrence Burden in Recurrent Respiratory Papillomatosis: a Pre–post Analysis

The role of human papillomaviruses (HPV) in oropharyngeal squamous papillomas remains incompletely defined, in contrast to their established involvement in oropharyngeal squamous cell carcinoma and laryngeal papillomatosis. This study aimed to assess HPV prevalence, genotype distribution, and associated biomarker expression in oropharyngeal papillomas, with particular emphasis on p16 and viral E4 protein immunoexpression. We retrospectively analyzed 51 formalin-fixed paraffin-embedded oropharyngeal squamous papillomas diagnosed between 2015 and 2023. HPV DNA detection and genotyping were performed using the INNO-LiPA assay. Immunohistochemistry for p16 and E4 was correlated with HPV status. For comparison, 20 oropharyngeal squamous cell carcinomas were included as controls, comprising 10 HPV16-positive and 10 HPV-negative cases. HPV DNA was detected in 57% of papillomas, predominantly high-risk genotypes, most frequently HPV16. E4 immunoexpression was observed in 55.5% of evaluable cases and was significantly associated with HPV DNA positivity (p < 0.0001). In contrast diffuse p16 overexpression was uncommon and showed no significant association with HPV detection. The prevailing immunophenotype in HPV-positive papillomas was E4 + /p16-, whereas HPV16-positive carcinomas uniformly exhibited a p16 + /E4- profile. No statistically significant differences in recurrence, dysplasia, or malignant transformation were observed between HPV-positive and HPV-negative papillomas, although adverse events occurred exclusively in high-risk HPV-associated cases. These findings suggest that a substantial subset of oropharyngeal squamous papillomas is associated with productive high-risk HPV infection, biologically distinct from transforming infections seen in carcinoma. While combined E4/p16 immunoprofiling may contributed to lesion characterization and prognostic stratification, its clinical utility warrants validation in larger, prospective cohorts.

ABSTRACTObjectiveTo report the first clinical experience from Azerbaijan using systemic bevacizumab therapy for the treatment of recurrent respiratory papillomatosis (RRP) and to evaluate its efficacy in reducing recurrence and surgical burden in both pediatric and adult patients.MethodsA retrospective case series of five patients (four pediatric, one adult) with confirmed RRP treated at a single institution. All patients had a history of multiple surgical interventions and were considered candidates for adjuvant systemic therapy. A single intravenous dose of bevacizumab (5–10 mg/kg) was administered, and patients were followed clinically and endoscopically to assess remission duration and recurrence.ResultsAll patients achieved prolonged remission following a single intravenous dose of bevacizumab. Pediatric patients experienced remission periods ranging from 8 to 24 months, with one child remaining recurrence‐free for over 2 years. The adult patient, with severe tracheobronchial involvement and a history of 112 surgeries, achieved a 6‐month remission—the longest interval between interventions in over a decade. No adverse drug‐related events were reported. In this small series, a single bevacizumab dose was associated with prolonged remission intervals; however, these findings should be interpreted cautiously and viewed as hypothesis‐generating.ConclusionSystemic bevacizumab may be a promising adjuvant option for selected patients with severe RRP, as it was associated with longer interventional‐free intervals in this retrospective patient series. Definitive conclusions regarding efficacy and surgical burden reduction require prospective studies with standardized severity measures and comparator groups. This first reported clinical experience from Azerbaijan contributes valuable real‐world data to the emerging global evidence base supporting anti‐VEGF therapy in RRP. Larger prospective studies are needed to establish optimal dosing regimens and long‐term outcomes.

Recurrent respiratory papillomatosis (RRP) is characterized by benign papillomatous lesions of the respiratory tract, most commonly involving the larynx. Cases of RRP originating solely from the nasopharynx are rarely reported in the literature. To our knowledge, this is the first reported case of nasopharyngeal RRP causing secondary Eustachian tube dysfunction (ETD) managed by office-based laser excision. We describe a 68-year-old male with a history of nasopharyngeal RRP. The papilloma’s location resulted in diminished hearing, tinnitus, and an intermittent ear-popping sensation, findings consistent with ETD. Flexible laryngoscopy revealed a papillomatous lesion on the right torus tubarius completely obstructing the Eustachian tube. Office-based flexible laryngoscopy with laser excision was performed without the need for sedation or operating room resources. Following excision, the patient experienced resolution of symptoms. This case demonstrates the feasibility of office-based laser excision for select cases of nasopharyngeal RRP involving the torus tubarius. Compared with operative management, this approach may offer potential advantages, including reduced healthcare costs, avoidance of general anesthesia, and the ability to perform real-time functional assessment. Further study is needed to evaluate the role of office-based techniques in the management of extralaryngeal RRP.

Recurrent respiratory papillomatosis (RRP) is associated with low-risk types of human papillomavirus (HPV). With HPV DNA testing, the oral rinse of RRP patients may be a useful liquid biopsy, as previously shown in patients with oropharyngeal cancer. Oral rinse, along with palatine and pharyngeal tonsil swabs, were collected from seven patients with persistent RRP. HPV DNA detection was performed using polymerase chain reaction, followed by genotype identification. HPV DNA was detected in five of seven oral rinse samples, but not in any palatine or pharyngeal tonsil swabs. HPV6 was identified in four of the five HPV-positive oral rinses, which was consistent with the RRP tissues. HPV DNA can be detected in oral rinses from patients with RRP, suggesting the utility of the oral rinse as a liquid biopsy. In contrast, neither the palatine nor the pharyngeal tonsils were reservoirs of HPV in study patients with RRP.

Can we use peak expiratory flow rate monitoring in recurrent respiratory papillomatosis?

Surgical and Voice Outcomes of Office-Based Recurrent Respiratory Papillomatosis Surgery: A Systematic Review.

Photodynamic therapy (PDT) is an interesting approach for the treatment of various otorhinolaryngological diseases, primarily when conventional therapeutic options are restricted by antibiotic resistance, biofilms, or high relapse rates. This systematic review critically analyzes 20 open-access clinical, microbiological, and experimental studies with PDT reported between 1992 and 2025. Initial clinical pilot data suggested a well-tolerated agent that improved symptoms and disrupted biofilm. In chronic and recurrent tonsillitis, existing evidence also indicates a decrease in microbial load, clinical improvement, and (in some cases) reduced infection over time. Case-based studies provide additional evidence for PDT as a non-invasive therapeutic option in pharyngotonsillitis. PDT decreases lesion size and delays recurrence in recurrent respiratory papillomatosis when applied adjunctively to surgery. These indicate potential utility for persistent viral conditions, including HPV-related diseases. Further studies on PDT indicate the reduction of SARS-CoV-2 colonization during the COVID-19 pandemic. PDT nasal application decreases viral shedding. New technologies, such as better photosensitizers, nanoparticle carrier delivery systems and improved light-delivery devices, have broadened the application of PDT in anatomically complex areas relating to ears, nose and throat (ENT). The above have improved treatment selectivity, reduced photo toxicity and increased the antimicrobial effect. Despite these promising results, the available evidence is restricted by small sample size, heterogeneity of the protocols and inconsistency of outcome measures. Larger, uniform clinical trials are required to define the optimal treatment features and their therapeutic value. Due to its antiviral, antimicrobial, and antibiofilm potential in otorhinolaryngology, there may well be opportunities to further develop PDT field as a beneficial adjunctive treatment.

Aims: Report on our department's experience in performing surgical tracheotomies in children. Material and Methods: This was a cross-sectional, descriptive study conducted in the ENT and Head and Neck Surgery Department of the Hôpital National de Niamey over a period of nine years from January 2016 to December 2024. The study involved children under the age of 15 who had undergone surgical tracheotomy. Results: Thirty-two (32) tracheotomies were performed over nine years. These involved 22 boys (68.75%) and 10 girls (31.25%). The average age of the patients was 8 years, ranging from 10 months to 14 years. Laryngeal papillomatosis was the most common indication, accounting for 31.25% of cases (n=10). Laryngeal foreign bodies and prolonged intubation accounted for 18.75% and 15.62% of indications, respectively. Tracheotomy was elective in 68.75% of cases and urgent in 31.25%. General anaesthesia was used in 90.62% of children. Tracheal opening was performed subisthmically in all cases, and vertical "I" incision was the most common (65.63%). We recorded four (04) intraoperative complications (12.5%), including haemorrhage (two cases) and cardiorespiratory arrest (two cases). The postoperative complications noted were one case of accidental decannulation and one case of mucus plugging. We recorded one death. Conclusion: Paediatric tracheotomy is a rare surgical procedure in our department. Its indications are dominated by upper airway obstruction, particularly laryngeal papillomatosis, and the morbidity and mortality associated with this procedure is low.

Recurrent Respiratory Papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 and 11, and afflicts children (Jo-RRP, Juvenile-onset RRP) and adults (Ao-RRP, adult-onset RRP). The study objective was to describe the disease burden of RRP from three patient-relevant perspectives: economic, clinical, and humanistic. A retrospective descriptive analysis of responses to questionnaires captured within a linked Coordination of Rare Diseases (CoRDS) and the Recurrent Respiratory Papillomatosis Foundation (RRPF) (CoRDS/RRPF) patient registries from May 1, 2019, to July 31, 2023 was performed. Categorical variables were summarized using counts and proportions and continuous variables were summarized using means (standard deviations) and medians (interquartile ranges). Responses from 122 participants, 55% (67/122) Jo-RRP and 45% (55/122) Ao-RRP, were included. Forty-one percent (41/99) traveled more than 100 miles round trip to receive specialty care, and 61% (52/85) spent > 5% of their family income to pay for care. RRP resulted in increased absences from school [94% (17/18) for participants aged < 22] and work [85.5% (65/76) for participants aged > 22]. Moreover, 64.9% (48/74) of respondents perceived that RRP negatively impacted their careers. Feelings of isolation (70%) and depression (45.1%) were common, but less than 25% of respondents reported seeking mental health assistance. RRP leads to clinical, financial, and psychosocial burdens. Increased public awareness regarding HPV infection of the airway is needed, as this disease is preventable through HPV vaccination.

Therapeutic vaccines include DNA, mRNA, protein-loaded antigen-presenting cell, synthetic long peptide (SLP) and recombinant virus platforms. Only two therapeutic vaccines for neoplastic disease were approved by the Food and Drug Administration in the past 40 years: sipuleucel-T, approved in 2010 for hormone-resistant metastatic prostate cancer and targeting prostate acid phosphatase; and zopapogene imadenovec, approved in 2025 for recurrent respiratory papillomatosis, a rare, non-malignant but often invalidating disease caused by human papillomavirus (HPV) type 6 or type 11. In the last decade, DNA, mRNA and SLP vaccines directed against mutation-derived neoantigens have shown strong immunogenicity for T cells and clinical activity with or without additional immune checkpoint inhibition. Vaccine monotherapy is effective in premalignant disorders caused by high-risk HPV16 and virus-negative colonic polyps. Treatment of bulky or recurrent/metastatic (R/M) disease requires combination with surgery and/or chemotherapy or combination with an immune checkpoint inhibitor such as PD-1 blocker. In a recent study, adjuvant treatment with neoantigen-specific mRNA vaccine plus PD-1 blocker led to less melanoma recurrence than PD-1 blocker alone. In another randomized study, patients with R/M HPV16+ head and neck cancer only benefited from the combination of HPV16-specific SLP vaccine and a PD-1 blocker if they had high pretreatment PD-L1 biomarker expression in cancer tissue. Increasingly, biomarker-guided therapy is recommended.

Adjuvant intralesional administration of bevacizumab has shown promising effects in the management of recurrent respiratory papillomatosis (RRP). However, the optimal therapeutic parameters remain undefined. This prospective study aimed to compare the efficacy of two distinct intralesional bevacizumab administration protocols following surgical resection of RRP. Between 15/09/2023 and 31/12/2024, adult patients with RRP were enrolled in a prospective research study. Participants were allocated to one of two bevacizumab administration protocols, delivered intralesional during direct microlaryngoscopy and CO₂ laser excision. Disease severity was assessed using the Derkay, Dikkers and Numerical scoring systems, as well as the Voice Handicap Index (VHI), at baseline and at 8-week intervals. Both treatment regimens were associated with reduction in disease burden and improved voice outcomes. No statistically significant differences in disease control were observed between the two administration protocols. This study indicates that both dosing regimens of bevacizumab were effective as an adjunctive therapy of recurrent respiratory papillomatosis. The higher intralesional doses of bevacizumab are relatively safe and well tolerated in adult patients with laryngeal RRP. Further studies with extended follow-up are warranted to define long-term efficacy and optimal dosing strategies.

To date, there is no uniform staging system to quantify the extent of recurrent respiratory papillomatosis (RRP). In scientific research on RRP, patient factor has not been leading in developing its potential staging system. Therefore, this report investigated the association between objective anatomical measurement and Patient Reported Outcome Measures (PROMs). The extent of RRP was determined according to the Derkay score. Images from RRP patients were retrieved from laryngoscopic examinations (during phonation and respiration). Four laryngologists assigned Derkay scores independently. The RRP-specific Distress Thermometer & Problem List (DT&PL) was used as PROM. Derkay scores were compared to DT&PL scores using a linear mixed model. Eighty-eight pairs of images were studied. The linear mixed model analysis resulted in a regression coefficient of 0.54 (P < 0.001, 95% CI 0.28–0.80). The average inter-observer class correlation coefficient was 0.95 (95% CI 0.93–0.96). A moderate association was found between Derkay and DT&PL scores. Considering that RRP is a benign lesion, proper reflection of patient complaints is essential when staging the condition. Future research should consider the significance of the patient’s quality of life to develop a definitive staging method for clinical practice.

Background: Recurrent respiratory papillomatosis is a condition that occurs mainly in the pediatric population with a rate of 3.62 to 4.3 per 100,000 children.The most common clinical manifestation is dysphonia; however, the disease can progress to more severe forms, generating serious obstruction of the airway.Methods: A cross-sectional study was conducted in which patients diagnosed with laryngeal papillomatosis confirmed by histopathological analysis and polymerase chain reaction were included.The genotype of the virus and its viral load were determined through a search in the clinical records, and the clinical and genetic variables of each case were captured through a structured form.Results: A total of 32 patients were enrolled, of which the prevalence of genotype 6 was found in 41% and the same prevalence in the case of genotype 11, with a percentage of coinfection with both subtypes of 18%.Genotype 11 was found to be associated with a greater number of resections (p = 0.004), a higher score on the Derkay scale (p = 0.02) and greater severity when presenting 4 surgeries per year and/or 10 total surgeries (p = 0.04).Conclusions: Human papillomavirus genotype 11 showed a greater association with the presentation of greater severity of recurrent respiratory papillomatosis in pediatric patients; therefore, this population is more susceptible to a poor outcome (which increases the demand for medical services), as well as impact on the quality of life of minors.

Recurrent Respiratory Papillomatosis is a rare, benign papillomatous growth of the bronchial epithelium which occurs in 18 patients in a million. Due to the rareness of the disease, no general treatment consensus exists. Surgical debulking or simple excision via bronchoscopy are the most used therapeutic approaches with adjunct medical therapy, such as intra-lesional antivirals and interferon therapy, in case of recurring disease. We present the case of a 51-year-old man who presented with recurrent respiratory papillomatosis. This case made the approach more challenging as we were dealing with widespread isolated lower respiratory tract involvement (lower trachea and main bronchi) sparing the larynx and vocal cords without evidence of HPV virus infection. A decision was made to intervene with bronchoscopic electro snare and argon plasma coagulation (APC) as few reported cases highlighted the effectiveness of APCs in the treatment of Recurrent Respiratory Papillomatosis with the patients remaining lesion-free in the 5 months follow up. Moreover, its safety and low risk of perforation/cartilage damage along with its efficiency when it comes to multiple lesions in critical sites established its important role as a therapeutic option.

Juvenile-Onset Recurrent Respiratory Papillomatosis and Human Papillomavirus Vaccine Uptake: A 19-Year Retrospective Cohort Study.

Since 1993, the Australian Paediatric Surveillance Unit (APSU) has been conducting prospective national surveillance of rare conditions in Australian children, including communicable diseases and complications of communicable diseases. In 2024, fifteen communicable diseases and complications were under APSU surveillance: acute flaccid paralysis (AFP); congenital cytomegalovirus (cCMV) infection; dengue; severe acute hepatitis; neonatal/infant herpes simplex virus (HSV) infection; perinatal exposure to human immunodeficiency virus (HIV); paediatric HIV infection, juvenile-onset recurrent respiratory papillomatosis (JoRRP); severe complications of influenza (Flu); Japanese encephalitis virus infection; paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS); Q fever; congenital rubella infection/syndrome; congenital varicella syndrome; and neonatal varicella infection. A total of 1,350 paediatricians and other child health specialists received the monthly APSU report card (97% electronically) in 2024. A total of 237 notifications were received, with 174 confirmed as incident cases after excluding duplicates, errors and prevalent (historic) cases not previously reported. The incident cases included: Flu (n = 34) - one child died and only two children had received influenza vaccination; JoRRP (n = 1); NVI (n = 1); cCMV (n = 26); HSV (n = 8) - neurological sequelae were common; perinatal exposure to HIV (n = 15) - no cases of mother-to-child transmission identified; and rare emerging diseases dengue (n = 4) and PIMS-TS (n = 2). The non-polio AFP rate of ≥1case per 100,000 children aged < 15 years was again achieved. The APSU continues to be an important mechanism for obtaining enriched data on rare communicable diseases and their complications in Australian children, to better understand disease burden, and the effects of health interventions, over time.

Background: Benign vocal cord lesions, including nodules, polyps, papillomas, Reinke’s edema, and cysts, commonly cause voice changes and sometimes respiratory distress. Polyps and nodules are frequent in adults due to prolonged voice use while children may develop recurrent respiratory papillomatosis (RRP) from HPV. Occupational voice use and irritant exposure increase risk. Objective: To assess the clinical features, histopathology, and treatment outcomes of benign vocal cord lesions in a tertiary level Medical College Hospital. Methods: A prospective study was conducted at Jahurul Islam Medical College and Hospital from January 2017 to January 2019. Twenty symptomatic patients with laryngeal lesions were included. Detailed history, ENT examination, indirect and fibreoptic laryngoscopy were performed. Demographic, occupational and habit-related data were recorded. All lesions were managed surgically when indicated and histopathological evaluation was performed. Results: Out of 20 patients, 14 were male and 6 female, with a mean age of 25.5±12.9 years. Polypoidal lesions were most common (60%), equally affecting right and left vocal cords. Nodules accounted for 25%, papillomatosis for 15%, and papilloma for 5%. Lesions predominantly involved the free margin of the vocal cords (65%), with bilateral involvement in 45% of cases. High-risk occupations included teachers, religious leaders, singers and drivers. Conclusion: Benign vocal cord lesions, mainly polyps and nodules, commonly affect males with high vocal demands. Surgical excision via direct laryngoscopy is effective, though pediatric RRP may need multiple procedures. JAFMC Bangladesh, Vol 21, No 2 (December) 2025:36-39