Significant Declines in Juvenile-onset Recurrent Respiratory Papillomatosis Following Human Papillomavirus (HPV) Vaccine Introduction in the United States.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare and serious disease caused by human papillomavirus (HPV) presumably acquired during vaginal delivery. HPV vaccination of females through age 26 years, recommended in the United States since 2006, can prevent HPV transmission. We assessed trends in JORRP cases before and after HPV vaccine introduction in the United States. METHODS: Case-patients were identified from 26 pediatric otolaryngology centers in 23 U.S. states. Demographics and clinical history were abstracted from medical records. Case-patients were grouped by year of birth, and birth-cohort incidences were calculated using number of births from either national or state-level natality data from the 23 states. We calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) in 2-year intervals. RESULTS: We identified 576 U.S. JORRP case-patients born in 2004-2013. Median age at diagnosis was 3.4 years (interquartile range: 1.9, 5.5). Number of identified JORRP case-patients declined from a baseline of 165 born in 2004-2005 to 36 born in 2012-2013. Incidence of JORRP per 100 000 births using national data declined from 2.0 cases in 2004-2005 to 0.5 cases in 2012-2013 (IRR = 0.2, 95% CI = .1-.4); incidence using state-level data declined from 2.9 cases in 2004-2005 to 0.7 cases in 2012-2013 (IRR = 0.2, 95% CI = .1-.4). CONCLUSIONS: Over a decade, numbers of JORRP case-patients and incidences declined significantly. Incidences calculated using national denominator data are likely underestimates; those calculated using state-level denominator data could be overestimates. These declines are most likely due to HPV vaccination. Increasing vaccination uptake could lead to elimination of this HPV-related disease.

An evidence based protocol for managing neonatal middle ear effusions in babies who fail newborn hearing screening.

OBJECTIVES: To evaluate the prevalence of middle ear disease in infants referred for failed newborn hearing screening (NBHS) and to review patient outcomes after intervention in order to propose an evidence-based protocol for management of newborns with otitis media with effusion (OME) who fail NBHS. METHODS: 85 infants with suspected middle ear pathology were retrospectively reviewed after referral for failed NBHS. All subjects underwent a diagnostic microscopic exam with myringotomy with or without placement of a ventilation tube in the presence of a middle ear effusion and had intra-operative auditory brainstem response (ABR) testing or testing at a later date. RESULTS: At the initial office visit, a normal middle ear space bilaterally was documented in 5 babies (6%), 29/85 (34%) had an equivocal exam while 51/85 (60%) had at least a unilateral OME. Myringotomy with or without tube placement due to presence of an effusion was performed on 65/85 (76%) neonates. Normal hearing was established in 17/85 (20%) after intervention, avoiding the need for any further audiologic workup. Bilateral or unilateral sensorineural hearing loss (SNHL) or mixed hearing loss was noted in 54/85 (64%) and these children were referred for amplification. Initially observation with follow up outpatient visits was initiated in 27/85 (32%) however, only 3/27 (11%) resolved with watchful waiting and 24/27 (89%) ultimately required at least unilateral tube placement due to OME and 14/24 (59%) were found to have at least a unilateral mixed or SNHL. CONCLUSIONS: An effective initial management plan for children with suspected middle ear pathology and failed NBHS is diagnostic operative microscopy with placement of a ventilation tube in the presence of a MEE along with either intra-operative ABR or close follow-up ABR. This allows for the identification and treatment of babies with a conductive component due to OME, accurate diagnosing of an underlying SNHL component and for prompt aural rehabilitation.

Rethinking surgical technique and priorities for pediatric tonsillectomy.

The past 100years have witnessed dramatic shifts in the concept of ideal surgical goals and operative technique in tonsil surgery. Surgeons are reviving a technique of intracapsular tonsillectomy with increasing precision thanks to modern technology. With intracapsular tonsillectomy, pediatric patients recover faster, use less pain medication, and have a lower risk of dehydration and hemorrhage. Various considerations will dictate the adoption of this technology in the coming years. This current review explores concepts and controversies surrounding tonsillectomy with a focus on quality improvement.

Intraoperative Use of QuikClot During Adenotonsillectomy: A Prospective Pediatric Trial.

BACKGROUND: Achieving hemostatic control after intracapsular adenotonsillectomy with minimal cauterization may potentially lead to improved outcomes with respect to return to normal diet, normal activity, and less use of narcotic pain medications. METHODS: A prospective, nonrandomized, consecutive series of children with obstructive tonsils and adenoids at a tertiary children's hospital was undertaken. RESULTS: One hundred consecutive children (52 boys/48 girls) ages 0-16 (mean=4.8, SD=3.7, median=4.0) years were recruited with complete data available on all 100. Mean total procedure time was 19.8 (SD=4.3, median=19.5) minutes, including mean total cauterization time of 155.3 (SD=59.7 seconds, median=143.0) (adenoids: mean=60.9, SD=31.5, median=53.0; tonsils: mean=94.5, SD=41.9, median=82.0) minutes. Mean estimated blood loss was 29.4 (SD=40.9, median=25.0) ml. There were no major complications (0/100 episodes of bleeding or dehydration after surgery). Mean return to normal diet was 3.4 (SD=2.2, median=3.0) days; mean return to normal activity was 2.8 (SD=2.1, median=3.0) days, and mean days to no further narcotics was 3.0 (SD=2.3, median=2.0) days. Mean days to complete recovery (normal diet, normal activity, and no narcotics) was 4.5 (SD=2.1, median=4.0, range: 1-10). Total cautery time was significantly correlated with time to complete recovery (P<.05). CONCLUSIONS: Intracapsular microdebrider tonsillectomy with adenoidectomy utilizing QuikClot to enhance the hemostasis results in recovery times better than previously reported for this common operation in children.

Management of patients susceptible to malignant hyperthermia: A surgeon's perspective.

OBJECTIVES: Malignant hyperthermia (MH) susceptibility caries broad implications for the care of pediatric surgical patients. While precautions must often be taken for only a vague family history, two options exist to assess MH-susceptibility. We evaluate the use of MH precautions and susceptibility testing at a freestanding children's hospital. METHODS: This single institution retrospective cohort study identified patients of any age who received general anesthetics utilizing MH precautions over a five-year period. The electronic medical record was further queried for patients diagnosed with MH. The indication for MH precautions and uses of susceptibility testing are assessed. Secondary outcomes included a diagnosis of bona fide MH. RESULTS: A total of 125 patients received 174 anesthetics with MH precautions at a mean age of 114 months (0-363 months). Otolaryngology was the procedural service most frequently involved in the care of the cohort (n = 45; 26%). A reported personal or family history of MH (n = 102; 59%) was the most common indication for precautions, followed by muscular dystrophy (n = 29; 17%). No MH events occurred in the cohort and further review of ICD-9 and -10 diagnosis codes found no MH diagnoses. No study subjects received muscle biopsy and contracture testing and only 5 (4%) underwent genetic testing for genomic variants known to cause MH susceptibility. A case example is given to highlight the implications of a reported MH history. CONCLUSION: Otolaryngologists should maintain a familiarity with the precautions necessary to manage patients at risk for MH and MH-like reactions. Without an accessible test to rule out susceptibility, surgeons must rely on a careful history to appropriately utilize precautions. An inappropriate label of "MH-susceptible" may result in decreased access to care and treatment delays.

Recurrent respiratory papillomatosis: A 2020 perspective.

OBJECTIVE: Despite recent advancement recurrent respiratory papillomatosis (RRP) remains a rare but challenging benign airway neoplasm. In recent years there has been significant shifts in incidence of this disease due to changes in vaccination and prevention for human papilloma virus (HPV) and its related pathology. This review will highlight the epidemiology, prevention and treatment of RRP. METHODS: The PubMed database was searched using relevant MeSH terms including "recurrent respiratory papillomatosis." The titles and abstracts were reviewed to assess relevance and unrelated articles were excluded. A full-text review for select articles was performed, the data and discussions were interpreted and synthesized to create a concise update on the management of RRP. RESULTS: With the increasing utilization of the 9-valent and quadrivalent HPV vaccine in Australia, we have seen a significant decrease in the incidence of RRP. Preliminary data in the US shows a similar trend of decreased incidence after implementation of vaccination. Single dose Gardasil in developing countries has shown sustained immunization for at least 7 years. Preliminary clinical trials and retrospective studies have shown the HPV vaccine may have benefit as a treatment method in addition to prevention for HPV related diseases. Bevacizumab (Avastin), a VEGF monoclonal antibody, has shown promise as a systemic treatment for RRP. The Corona Virus Disease 2019 (COVID-19) pandemic has affected perioperative management of RRP. CONCLUSION: RRP continues to decline in incidence since the implementation of HPV vaccination. Advancement in the medical management including Bevacizumab show promise as an additional option for the management of RRP.

Juvenile-Onset Recurrent Respiratory Papillomatosis in the United States, Epidemiology and HPV Types-2015-2020.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease characterized by the growth of papillomas in the respiratory tract. In the United States, JORRP is not a nationally notifiable condition and current data are limited. METHODS: Children with JORRP aged <18 years were enrolled from 26 pediatric otolaryngology centers in 23 US states from January 2015 through August 2020. Demographic, birth information, and maternal vaccination history were collected from a parent/guardian. Clinical history was abstracted from medical records. Papilloma biopsies were tested for 28 human papillomavirus (HPV) types. Mothers who delivered in 2006 or later were considered age-eligible for HPV vaccination if aged ≤26 years in 2006. We described characteristics of enrolled children and their birth mothers and analyzed disease severity by diagnosis age and HPV type using multiple logistic regression. RESULTS: Among 215 children with JORRP, 88.8% were delivered vaginally; 64.2% were firstborn. Among 190 mothers, the median delivery age was 22 years. Among 114 (60.0%) age-eligible for HPV vaccination, 16 (14.0%) were vaccinated, 1 (0.9%) before delivery. Among 162 specimens tested, 157 (96.9%) had detectable HPV; all 157 had a vaccine-preventable type. Disease severity was associated with younger diagnosis age and HPV 11; adjusted analyses found only younger diagnosis age significant (adjusted odds ratio: 6.1; 95% confidence interval: 2.9, 12.8). CONCLUSIONS: Children with JORRP were commonly firstborn and delivered vaginally to young mothers; most of the mothers reported no HPV vaccination before delivery. Vaccine-preventable HPV was identified in all specimens with detectable HPV. Increasing preexposure HPV vaccination could substantially reduce or eliminate JORRP in the United States.

Management and Outcomes of Button Batteries in the Aerodigestive Tract: A Multi-institutional Study.

OBJECTIVES/HYPOTHESIS: To describe the clinical presentation, management, and complications associated with button battery impaction in the aerodigestive tract in children. STUDY DESIGN: Retrospective case series. METHODS: This multi-institutional study, endorsed by the American Society of Pediatric Otolaryngology research consortium, is a retrospective medical record review, including all children at five tertiary-care institutions presenting with button batteries impacted in the aerodigestive tract between January 2002 and December 2014. Battery type/size, duration and location of impaction, presenting symptoms, treatment, complications, and outcomes were examined. RESULTS: Eighty-one patients were included (64.2% male), with ingestion witnessed in 20 (24.7%). Median age at presentation was 3 years (range, 1 week-14 years). Median time from diagnosis to removal was 2.5 hours (range, 0.4-72 hours). Locations included the esophagus (n = 48), hypopharynx (n = 1), stomach (n = 6), nasal cavity (n = 22), and ear canal (n = 4). Most common symptoms for esophageal/hypopharyngeal impactions included dysphagia (26.5%), nausea/vomiting (26.5%), drooling (24.5%), cough (18.4%), and fever (18.4%). Most common symptoms for nasal impactions included epistaxis (54.6%), rhinorrhea (40.9%), nasal pain (27.3%), and fever (22.7%). Almost all esophageal impactions were from 3-V (89.5%), 20-mm (81.8%) lithium batteries. Severe esophageal complications included stricture (28.6%), perforation (24.5%), tracheoesophageal fistula formation (8.2%), pneumothorax (4.1%), and bilateral true vocal fold paresis (4.1%). Nasal complications included necrosis (59.1%), septal perforation (27.3%), and saddle nose deformity (4.5%). Duration of impaction correlated with an increased likelihood of persistent symptoms only for nasal batteries (P = .049). CONCLUSIONS: Button batteries in the upper pediatric aerodigestive tract or ear canal should be considered a surgical emergency, requiring urgent removal and careful vigilance for complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E298-E306, 2021.

Competency-Based Assessment Tool for Pediatric Esophagoscopy: International Modified Delphi Consensus.

OBJECTIVES/HYPOTHESIS: Create a competency-based assessment tool for pediatric esophagoscopy with foreign body removal. STUDY DESIGN: Blinded modified Delphi consensus process. SETTING: Tertiary care center. METHODS: A list of 25 potential items was sent via the Research Electronic Data Capture database to 66 expert surgeons who perform pediatric esophagoscopy. In the first round, items were rated as "keep" or "remove" and comments were incorporated. In the second round, experts rated the importance of each item on a seven-point Likert scale. Consensus was determined with a goal of 7 to 25 final items. RESULTS: The response rate was 38/64 (59.4%) in the first round and returned questionnaires were 100% complete. Experts wanted to "keep" all items and 172 comments were incorporated. Twenty-four task-specific and 7 previously-validated global rating items were distributed in the second round, and the response rate was 53/64 (82.8%) with questionnaires returned 97.5% complete. Of the task-specific items, 9 reached consensus, 7 were near consensus, and 8 did not achieve consensus. For global rating items that were previously validated, 6 reached consensus and 1 was near consensus. CONCLUSIONS: It is possible to reach consensus about the important steps involved in rigid esophagoscopy with foreign body removal using a modified Delphi consensus technique. These items can now be considered when evaluating trainees during this procedure. This tool may allow trainees to focus on important steps of the procedure and help training programs standardize how trainees are evaluated. LEVEL OF EVIDENCE: 5. Laryngoscope, 131:1168-1174, 2021.

In RRP, serologic response to HPV is frequently absent and slow to develop.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is characterized by repeated formation of papillomas in the respiratory tract and is caused by human papillomavirus (HPV) types 6 and 11. Women with genital HPV infection are slow to develop weak humoral immunity, but respond robustly to the HPV vaccine. We wondered if people with RRP had a similar immune response. METHODS: A convenience cross-sectional sample of patients with RRP were recruited into one of four groups: 1) adults and adolescents with active RRP, 2) children with active RRP, 3) RRP patients who had undergone HPV vaccination prior to enrollment and, 4) people with RRP who were in remission. Anti-HPV6 and HPV11 serology was determined by cLIA on a single blood draw. RESULTS: Of the 70 subjects enrolled, 36, 16, 8, and 10, were in groups 1, 2, 3, and 4, respectively. 47% of participants aged >11 years and 81% aged ≤11 years possessed no antibodies against HPV6 or HPV11 (ie. double seronegative). 61% of patients in remission were double seronegative. All participants who had received HPV vaccine previously were seropositive to at least one of these low risk HPV types (ie none of them were double seronegative). Among patients who had active RRP and never had HPV vaccination (n = 52) there was an association between duration of symptoms and seropositivity. Of those who were seropositive, the geometric mean duration of symptoms was 11 years compared to 4.7 years for those who were seronegative (p = 0.001). CONCLUSION: People with RRP are capable of developing a humoral response to HPV6 and HPV11. That response appears to be robust when initiated by the HPV vaccine, but either nonexistent or slow to develop in response to infection. Most in remission do not have demonstrable antibody levels against HPV6 or HPV11.

Competency-Based Assessment Tool for Pediatric Tracheotomy: International Modified Delphi Consensus.

OBJECTIVES/HYPOTHESIS: Create a competency-based assessment tool for pediatric tracheotomy. STUDY DESIGN: Blinded, modified, Delphi consensus process. METHODS: Using the REDCap database, a list of 31 potential items was circulated to 65 expert surgeons who perform pediatric tracheotomy. In the first round, items were rated as "keep" or "remove," and comments were incorporated. In the second round, experts were asked to rate the importance of each item on a seven-point Likert scale. Consensus criteria were determined a priori with a goal of 7 to 25 final items. RESULTS: The first round achieved a response rate of 39/65 (60.0%), and returned questionnaires were 99.5% complete. All items were rated as "keep," and 137 comments were incorporated. In the second round, 30 task-specific and seven previously validated global rating items were distributed, and the response rate was 44/65 (67.7%), with returned questionnaires being 99.3% complete. Of the Task-Specific Items, 13 reached consensus, 10 were near consensus, and 7 did not achieve consensus. For the 7 previously validated global rating items, 5 reached consensus and two were near consensus. CONCLUSIONS: It is feasible to reach consensus on the important steps involved in pediatric tracheotomy using a modified Delphi consensus process. These items can now be considered to create a competency-based assessment tool for pediatric tracheotomy. Such a tool will hopefully allow trainees to focus on the important aspects of this procedure and help teaching programs standardize how they evaluate trainees during this procedure. LEVEL OF EVIDENCE: 5 Laryngoscope, 130:2700-2707, 2020.

Extracts from The Cochrane Library: intranasal corticosteroids for moderate to severe adenoidal hypertrophy.

The "Cochrane Corner" is a quarterly section in the Journal that highlights systematic reviews relevant to otolaryngology-head and neck surgery, with invited commentary to aid clinical decision making. This installment features a Cochrane Review entitled "Intranasal corticosteroids for nasal airway obstruction in children with moderate to severe adenoidal hypertrophy," which finds limited evidence of a short-term improvement in nasal symptoms with a reduction of adenoid size.

Update on Recurrent Respiratory Papillomatosis.

Recurrent respiratory papillomatosis (RRP) remains a challenging disease afflicting children and adults, resulting in an estimated $120 million per year in United States healthcare-related costs, with annual costs per patient approaching $60,000. Although the prevalence of RRP has declined, RRP remains the most common benign laryngeal neoplasm in children. RRP is unique in its high rate of multisite recurrence, its high burden on patient quality of life, and its high associated healthcare costs. This article summarizes current understanding of the natural history and quality of life burden of RRP, and basic science advancements in prevention and treatment.

Age at diagnosis, but not HPV type, is strongly associated with clinical course in recurrent respiratory papillomatosis.

BACKGROUND: Recurrent Respiratory Papillomatosis (RRP) is a rare disease characterized by the growth of papillomas in the airway and especially the larynx. The clinical course is highly variable among individuals and there is poor understanding of the factors that drive an aggressive vs an indolent course. METHODS: A convenience cohort of 339 affected subjects with papillomas positive for only HPV6 or HPV11 and clinical course data available for 1 year or more, from a large multicenter international study were included. Exploratory data analysis was conducted followed by inferential analyses with frequentist and Bayesian statistics. RESULTS: We examined 339 subjects: 82% were diagnosed prior to the age of 18 years, 65% were infected with HPV6, and 69% had an aggressive clinical course. When comparing age at diagnosis with clinical course, the probability of aggressiveness is high for children under five years of age then drops rapidly. For patients diagnosed after the age of 10 years, an indolent course is more common. After accounting for confounding between HPV11 and young age, HPV type was minimally associated with aggressiveness. Fast and Frugal Trees (FFTs) were utilized to determine which algorithms yield the highest accuracy to classify patients as having an indolent or aggressive clinical course and consistently created a branch for diagnostic age at ~5 years old. There was no reliable strong association between clinical course and socioeconomic or parental factors. CONCLUSION: In the largest cohort of its type, we have identified a critical age at diagnosis which demarcates a more aggressive from less aggressive clinical course.

Recurrent respiratory papillomatosis: update 2018.

PURPOSE OF REVIEW: Recurrent respiratory papillomatosis (RRP) is the most common as well as the costliest benign airway neoplasm in the United States [Ivancic et al. (2018). Laryngoscope Investig Otolaryngol 3:22; Derkay (1995). Arch Otolaryngol Head Neck Surg 121:1386]. In addition, it is potentially deadly, with risk of airway obstruction as well as a 3-7% risk of malignant conversion [Schraff et al. (2004). Arch Otolaryngol Head Neck Surg 130:1039]. This review highlights exciting advancements over the past 1-2 years in scientific understanding of the pathophysiology, epidemiology, natural history, prevention, and treatment of this difficult disease. RECENT FINDINGS: Recent studies have yielded the following findings: The primary quality of life reduction that patients perceive is voice-related; the membranous vocal folds are the most frequently involved anatomic subsite in adult-onset RRP; there may be a correlation between laryngopharyngeal reflux, herpes simplex virus type 2, and adult-onset RRP; there has been a decline in RRP incidence in Australia following the implementation of a national vaccination program; addition of educational audiovisual aids assists in vaccine acceptance rates; preventive vaccination can be used as treatment for pediatric as well as adult RRP patients with demonstrable effects on antibody titers and reoperation rates; calreticulin-linked DNA vaccines show promise in reducing the growth rate of human papilloma virus (HPV)11 E6/E7-expressing tumors in mice; injection of bevacizumab is associated with no adverse tissue affects; systemic bevacizumab is effective as a treatment for severe uncontrolled disease; pegylated interferon treatment is effective in select severe pediatric RRP disease; and finally, increased rates of programed death 1 T-lymphocyte infiltration and programed death-ligand 1 expression are seen on both papilloma and infiltrating immune cells. SUMMARY: RRP is declining in incidence but remains a challenging disease to treat with great costs to patients, families, and the healthcare system. As the disease continues to be better understood, new frontiers are opening in treatment, particularly for severe or poorly controlled disease. Until the disease can be eradicated, it remains a vital area of research to help prevent new cases and treat afflicted patients.

Microdebrider intracapsular tonsillectomy.

With a continued desire to reduce the morbidity of tonsil surgery, otolaryngologists have begun to use powered microdebriders to perform partial intracapsular tonsillectomies. This technique has an advantage over conventional tonsillectomy of leaving a biological dressing or residual tonsillar tissue and capsule to protect the underlying musculature with its vessels and nerves. The literature has shown that partial intracapsular tonsillectomy is equally effective at relieving patient's symptoms of obstruction when compared to conventional tonsillectomy and that it appears to reduce the complications of postoperative pain, dehydration, and bleeding. Patients are able to return to normal activity and diet faster as the healing process is accelerated. This article reviews the published data on microdebrider-assisted partial intracapsular tonsillectomy with a discussion of its advantages, potential limitations and areas of future research.

E-cigarettes: An update on considerations for the otolaryngologist.

PURPOSE: We provide an update in the literature and national regulations regarding electronic cigarettes with special attention to the pediatric population. BACKGROUND: Electronic nicotine delivery systems (ENDS) are handheld battery operated devices that vaporize nicotine-containing liquids for inhalation. Use of these products has dramatically increased over the last several years, particularly among the youth. ENDS are being marketed with advertising techniques and flavors which appeal to the adolescent and young adult population. More reports of accidental pediatric exposures are being documented, as are suicides from abuse of liquid nicotine. Federal regulation has only now become required of these devices. CONCLUSION: Use of e cigarettes among adolescents increases each year. Government oversight is needed to protect our children from the re-normalization of tobacco. Otolaryngologists should be prepared to counsel their patients and families regarding the latest in ENDS use.

Post-tonsillectomy morbidity and quality of life in pediatric patients with obstructive tonsils and adenoid: microdebrider vs electrocautery.

OBJECTIVE: To prospectively compare outcomes in children over age 2 with obstructive adenotonsillar hypertrophy when tonsillectomy is performed utilizing an intracapsular microdebrider technique versus low-wattage electrocautery technique. STUDY DESIGN AND SETTING: Prospective, single-blind, randomized controlled trial at a tertiary care children's hospital. RESULTS: Among the 300 children, those treated with the microdebrider resumed normal activity faster, with a median recovery of 2.5 days, and stopped taking pain medication sooner, with the median time to the last dose of 4 days. The microdebrider group were 3 times more likely to no longer need pain medications at 3 days postoperatively and 2.5 times less likely to be still needing pain medication 7 days postoperatively. They were twice as likely to be at a normal activity level by 3 days postoperatively and were less likely to still not have attained normal activity and normal diet after 7 days. There was no difference between groups in median days to return to normal diet (3.0 to 3.5 days). At 1-month follow-up, children in the microdebrider group were 5 times more likely to have residual tonsil tissue. CONCLUSIONS: Intracapsular tonsillectomy in children with obstructive adenotonsillar hypertrophy results in improved peri-operative outcomes. Residual tonsil tissue is more common with use of the microdebrider; however, the incidence of future obstruction or infection is unknown. EBM RATING: A-1b.

Unique challenges of obtaining regulatory approval for a multicenter protocol to study the genetics of RRP and suggested remedies.

OBJECTIVE: Investigations that seek to generalize findings or to understand uncommon diseases must be conducted at multiple centers. This study describes the process of obtaining regulatory approval for a minimal risk genetic study in a multi-center setting as undertaken by the Recurrent Respiratory Papillomatosis (RRP) Task Force. STUDY DESIGN AND SETTING: Sequential cohort of American children's hospitals. A single protocol was submitted to each Institutional Review Board (IRB). RESULTS: Documentation was prepared for 14 IRBs over 2.5 years. The median time between enlistment and approval at the first 8 sites was 15 months. Institutions varied considerably in their requirements and in the issues that were raised. Protocols were submitted sequentially and accumulated experience was used in the preparation of applications to subsequent IRBs. Nevertheless, there was no correlation between the accumulated experience and the number of issues that were raised. CONCLUSION: Despite uniform federal standards, all local IRBs required unique and individualized submissions. For multicenter studies, investigators should seriously consider the establishment of cooperative authorization agreements. On a simpler level, a standardized format for applications needs to be adopted nationwide. EBM RATING: B-3b.