A Consensus Statement on the Administration of Systemic Bevacizumab in Patients with Recurrent Respiratory Papillomatosis.

OBJECTIVE: To provide detailed guidance on the administration of systemic bevacizumab in patients with recurrent respiratory papillomatosis (RRP) based on a detailed review of the scientific literature and a consensus of experts with real-world clinical experience. METHODS: A bevacizumab consensus working group (N = 10) was composed of adult and pediatric otolaryngologists, adult and pediatric oncologists, and a representative from the RRP Foundation (RRPF), all with experience administering systemic bevacizumab in patients with RRP. After extensive review of the medical literature, a modified Delphi method-based survey series was utilized to establish consensus on the following key areas: clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying therapy. RESULTS: Seventy-nine statements were identified across nine critical domains, and 45 reached consensus [clinical benefits of bevacizumab (3), patient and disease characteristics for treatment consideration (7), contraindications for treatment (3), shared decision-making (incorporating the patient perspective) (5), treatment access (3), initial dosing and administration (8), monitoring (7), tapering and discontinuation (6), and reintensification (3)]. CONCLUSION: This consensus statement provides the necessary guidance for clinicians to initiate systemic administration of bevacizumab and represents a potential paradigm shift toward nonsurgical treatment options for patients with RRP. LEVEL OF EVIDENCE: 5 Laryngoscope, 2024.

Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Institution's Experience.

OBJECTIVES: Medical therapies to limit disease recurrence are critically needed for recurrent respiratory papillomatosis (RRP). Systemic bevacizumab is emerging as an exciting adjuvant therapy toward this end, but uptake has been poor due to the lack of experience and awareness of best prescribing practices. The objective of this study was to describe a single tertiary care academic medical center's experience using systemic bevacizumab for the treatment of RRP. METHODS: A retrospective review was performed to identify patients with RRP on systemic bevacizumab. Demographic and clinical characteristics, findings on imaging reports, and disease response at all anatomic subsites involved in papilloma were documented. RESULTS: Of the 17 RRP patients on systemic bevacizumab, 9 (52.9%) were male, and 12 (70.6%) were diagnosed with juvenile-onset RRP. The total lifetime number of surgeries was high, with more than half (n = 9; 52.9%) undergoing more than 50 surgeries. Following induction of systemic bevacizumab, a significant reduction in patients with laryngeal (n = 15; 94.1% vs. n = 7; 41.2%, p < 0.001) and tracheal (n = 11; 64.7% vs. n = 5; 29.4%, p = 0.04) RRP was noted. Surgical frequency was significantly lower following systemic bevacizumab (2.5 vs. 0.5 surgeries per year; p < 0.001). The most common complications were new-onset hypertension (n = 4; 23.5%) and proteinuria (n = 5; 29.4%). CONCLUSION: Systemic bevacizumab is effective in reducing the number of surgeries needed for RRP while exhibiting a relatively safe complication profile. Papillomas in the larynx and trachea are most responsive to systemic bevacizumab, while pulmonary RRP is most likely to exhibit a partial-to-stable response. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3253-3259, 2024.

Profiling of VEGF Receptors and Immune Checkpoints in Recurrent Respiratory Papillomatosis.

OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is caused by human papilloma virus (HPV) infection of the aerodigestive tract that significantly impacts quality-of-life including the ability to communicate and breathe. Treatment was traditionally limited to serial ablative procedures in the O.R. with possible local adjuvant therapy, but new systemic therapies, such as Vascular endothelial growth factor (VEGF) inhibitors, are showing significant promise. This study aims to determine whether rationale exists for combination therapeutic approaches using VEGF inhibitors and/or immune checkpoint blockade. METHODS: Using fresh specimens from the O.R., we performed flow cytometry on papilloma, normal adjacent tissue, and blood. Papilloma and surrounding tissue were examined for expression of PD-L1, PD-L2, Galectin-9, VEGFR2, and VEGFR3. CD8+ and CD4+ T cells were assayed for expression of PD-1, TIGIT, LAG3, and TIM3. RESULTS: Our data shows that papilloma tissue exhibits significantly higher levels of PD-L1 and PD-L2 compared to adjacent tissue. Elevated levels of the VEGF receptor VEGFR3 were also observed in papilloma tissue. When examining T cells within the papilloma, elevated PD-1 and TIGIT expression was observed on CD8+ T cells, while levels of PD-1, TIGIT, and TIM3 were elevated on CD4+ T cells compared to PBMCs. Heterogenous marker expression was observed between individuals. CONCLUSIONS: Our analysis shows that RRP tissue shows elevated levels of multiple immune check point targets and VEGFR3, with varied patterns unique to each papilloma patient. Some of these immune checkpoint markers already have novel immunotherapies available or in development, providing molecular rationale to offer these systemic treatments to selected patients affected by RRP alongside VEGF inhibitors. Laryngoscope, 134:2819-2825, 2024.

Efficacy of Systemic Bevacizumab for Recurrent Respiratory Papillomatosis with Pulmonary Involvement.

OBJECTIVES: Pulmonary papillomatosis is a rare but severe manifestation of recurrent respiratory papillomatosis (RRP). Efficacy data of systemic bevacizumab for pulmonary RRP are limited. This study's objective was to characterize disease response of pulmonary RRP to systemic bevacizumab. METHODS: A retrospective review was performed to identify patients with pulmonary RRP seen at three medical institutions. Clinical symptoms, CT findings, and disease response were compared before and after initiation of systemic bevacizumab therapy. Disease response was categorized as complete response, partial response, stabilization, or progression for each subsite involved by papilloma. RESULTS: Of the 12 pulmonary RRP patients treated with systemic bevacizumab, 4 (33.3%) were male, and 11 (91.7%) were juvenile-onset RRP patients. All presented with laryngeal, tracheal, and pulmonary RRP. The median (range) age at first bevacizumab infusion was 48.1 (19.5-70.2) years. Progression to pulmonary malignancy was identified in 3 (25.0%) patients, 2 before initiation of and 1 after complete cessation of bevacizumab therapy. Clinical symptoms such as dyspnea (75.0% vs. 25.0%; p = 0.01) and dysphagia and/or odynophagia (33.3 vs. 0.0%; p = 0.03) were significantly decreased following bevacizumab therapy. Compared with pre-treatment baseline, 9 (75.0%) patients experienced a stable-to-partial response in the lungs to systemic bevacizumab, and 10 (83.3%) experienced partial-to-complete responses in the larynx and trachea. CONCLUSION: Systemic bevacizumab is effective in stabilizing progression in even the most severe cases of RRP, with both a dramatic reduction in laryngeal and tracheal disease as well as a stable-to-partial response of pulmonary involvement in a majority of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:577-581, 2024.

Tracheostomy-related durable medical equipment: Insurance coverage, gaps, and barriers.

PURPOSE: Tracheostomy care is supply- and resource-intensive, and airway-related adverse events in community settings have high rates of readmission and mortality. Devices are often implicated in harm, but little is known about insurance coverage, gaps, and barriers to obtaining tracheostomy-related medically necessary durable medical equipment. We aimed to identify barriers patients may encounter in procuring tracheostomy-related durable medical equipment through insurance plan coverage. MATERIALS AND METHODS: Tracheostomy-related durable medical equipment provisions were evaluated across insurers, extracting data via structured telephone interviews and web-based searches. Each insurance company was contacted four times and queried iteratively regarding the range of coverage and co-pay policies. Outcome measures include call duration, consistency of explanation of benefits, and the number of transfers and disconnects. We also identified six qualitative themes from patient interviews. RESULTS: Tracheostomy-related durable medical equipment coverage was offered in some form by 98.1 % (53/54) of plans across 11 insurers studied. Co-pays or deductibles were required in 42.6 % (23/54). There was significant variability in out-of-pocket expenditures. Fixed co-pays ranged from $0-30, and floating co-pays ranged from 0 to 40 %. During phone interviews, mean call duration was 19 ± 10 min, with an average of 2 ± 1 transfers between agents. Repeated calls revealed high information variability (mean score 2.4 ± 1.5). Insurance sites proved challenging to navigate, scoring poorly on usability, literacy, and information quality. CONCLUSIONS: Several factors may limit access to potentially life-saving durable medical equipment for patients with tracheostomy. Barriers include out-of-pocket expenditures, lack of transparency on coverage, and low-quality information. Further research is necessary to evaluate patient outcomes.

Factors Associated with Iatrogenic Laryngeal Injury in Recurrent Respiratory Papillomatosis.

OBJECTIVE: To describe iatrogenic laryngeal injury and identify its risk factors in recurrent respiratory papillomatosis (RRP) patients receiving surgical care. STUDY DESIGN: Case-control. SETTING: Tertiary care academic hospital in a metropolitan area. METHODS: Charts of patients with RRP seen at our institution from January 2002 to December 2022 were reviewed. Patients were separated into 2 cohorts based upon whether they experienced any form of iatrogenic laryngeal injury-including anterior commissure synechiae, vocal cord scar, reduced vocal fold pliability, vocal fold motion impairment, and glottic and/or subglottic stenosis. Adjusted logistic regressions were performed to identify factors associated with iatrogenic laryngeal injury. RESULTS: Of 199 RRP patients, 133 (66.8%) had identifiable iatrogenic laryngeal injury. The most common injuries were anterior commissure synechiae (n = 67; 50.4%) and reduced vocal fold pliability (n = 54; 40.6%). On a multivariate logistic regression, patients with diabetes mellitus (adjusted odds ratio [aOR] [95% confidence interval [CI]]: 2.99 [1.02, 8.79]; P = .04) and who received at least 10 surgeries lifetime (aOR [95% CI]: 14.47 [1.70, 123.19]; P = .01) were at increased risk for iatrogenic laryngeal injury, whereas receiving less than 5 surgeries (aOR [95% CI]: 0.21 [0.09, 0.51]; P < .001) was found to be protective. When treating the lifetime number of surgeries as a continuous variable, a greater number of surgeries was a significant risk factor for iatrogenic laryngeal injury (aOR [95% CI]: 1.32 [1.14, 1.53]; P < .001). CONCLUSION: These results suggest the importance of strict glucose control for diabetic patients receiving RRP surgical care, and emphasize the clinical need to identify medical therapies to decrease RRP surgical frequency for patients.

Factors Associated With Loss of Follow-Up in Transgender Patients Receiving Vocal Therapy.

OBJECTIVES: Optimal vocal care for transgender patients necessitates regular follow-up. Factors associated with loss of follow-up in voice patients have never been investigated. In this study, we report a case series of transgender patients seeking vocal care at our institution and compare those who were and were not lost to follow-up. METHODS: Charts of transgender patients diagnosed with gender dysphoria who sought vocal care at our institution from January 2018 through May 2022 were reviewed. A chronological timeline of each patient's care at our vocal clinic was recorded. Loss of follow-up was defined as instances in which patients were not yet satisfied with their vocal outcomes and expressed interest in scheduling a subsequent visit but had not yet done so. Logistic regressions were performed to identify factors associated with loss of follow-up. RESULTS: Of 73 patients identified, 59 (80.8%) were assigned male at birth, and 72 (98.6%) were non-Hispanic White. Loss of follow-up occurred in 35 (47.9%) patients. Patients who received vocal surgery were significantly less likely to be lost to follow-up (OR: 0.16 (0.03, 0.79); p = 0.03). The availability of telemedicine options for vocal care was protective against loss of follow-up (OR: 0.09 (0.02, 0.44); p = 0.003). Patients who received other non-voice gender-affirming treatments concomitant to their vocal care were more likely to be lost to follow-up (OR: 4.44 (1.35, 14.59); p = 0.01). CONCLUSION: Loss of follow-up in transgender patients receiving vocal care is common. Providing telemedicine options and encouraging patients to complete vocal care prior to or after receiving other non-voice gender-affirming treatments may help increase rates of follow-up. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:3061-3067, 2023.

Interim Results of a Phase 1/2 Open-Label Study of INO-3107 for HPV-6 and/or HPV-11-Associated Recurrent Respiratory Papillomatosis.

OBJECTIVE: To evaluate the safety, immunogenicity, and efficacy of INO-3107, a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). METHODS: Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO-3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post-INO-3107 and cellular immune responses. RESULTS: An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO-3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO-3107 induced durable cellular responses against HPV-6 and HPV-11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. CONCLUSION: The data suggest that INO-3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3087-3093, 2023.

Posterior Glottic Injury Following Prolonged Intubation in COVID-19 Patients.

OBJECTIVE: The objective of this study was to characterize the risk factors for posterior glottic injury (PGI) in patients with coronavirus disease 2019 (COVID-19) who underwent prolonged intubation. STUDY DESIGN: This was a case-control study designed to assess the risk factors associated with development of PGI in COVID-19 patients who underwent prolonged intubation. SETTING: This single-center study was conducted at a tertiary care academic hospital in a metropolitan area. METHODS: We retrospectively reviewed patients who underwent prolonged intubation (≥7 days) for COVID-19 and compared those with PGI to those without. Patient demographics, comorbidities, and intubation characteristics were compared. Factors associated with PGI development among COVID-19 patients were assessed using multivariate regression. RESULTS: We identified 56 patients who presented with PGI following prolonged intubation for COVID-19 and 60 control patients who underwent prolonged intubation for COVID-19 but did not develop PGI. On univariate analyses, the number of reintubations due to failed extubation efforts was significantly associated with development of PGI (odds ratio [OR], 2.9; 95% CI, 1.4-6.2). On multivariate analyses, patients with cardiovascular disease (OR, 3.3; 95% CI, 1.2-9.0); non-COVID-19 respiratory illnesses, which included obstructive sleep apnea and asthma (OR, 5.9; 95% CI, 2.0-17.8); and diabetes mellitus (OR, 11.6; 95% CI, 3.7-36.6) were more likely to develop PGI. CONCLUSION: Our results represent the largest case-control study investigating risk factors for PGI in the setting of prolonged intubation specific to COVID-19. Our study suggests a significant role of comorbidities associated with poor wound healing with development of PGI.