Estimates of incidence and prevalence for JoRRP have been reported for the Free State province of South Africa and Lesotho, a small country of 1.9 million people geographically situated within South Africa (Seedat 2014). The Free State province has a population of 2.75 million people, and all cases of JoRRP from the Free State and Lesotho are managed at the same referral center. The retrospective study reviewed all cases in patients under the age of 15 years presenting between January 2011 and December 2013. The estimates of incidence and prevalence were calculated based on midyear populations of children aged 0–14 years published by Statistics South Africa and the Lesotho Bureau of Statistics.

During this 3-year period, 31 new cases of JoRRP were diagnosed in the Free State province with an average incidence of 1.34 per 100,000 per year. Year over year, the incidence fluctuated between 0.52 and 2.36 per 100,000 population per year. The average prevalence was 3.88 per 100,000 per year (range, 3.10–4.73 per 100,000 population per year). The median age at diagnosis was 4.3 years, and the male to female ratio was 1:1.21.

In comparison, 10 new cases of JoRRP were referred from Lesotho, indicating an incidence of 0.49 per 100,000 and a prevalence of 1.04 per 100,000 population per year. The median age at diagnosis was slightly lower at 3.8 years, and the male to female ratio was 4:1. The variability in the statistical measures is expected in jurisdictions with relatively small populations. Moreover, the measures of incidence and prevalence are probably an underestimation due to more difficult access to medical care for patients from remote communities and the high rate of poverty in the Free State province and Lesotho. Although not specifically studied, the high prevalence of coinfection with HIV may account for the higher incidence and prevalence rate reported for Africa compared to populations in Europe, Australia, and North America.

Estimates of disease burden have also been reported for academic referral centers in cities in Ghana and Nigeria. In 2012, Baidoo and Kitcher retrospectively reviewed the theater records at the ENT Unit of Korle Bu Teaching Hospital, Accra, Ghana (Baidoo and Kitcher 2012). Over a 10-year period, 69 patients were treated for RRP. The median age of the patients was 8.5 years (range 2–54 years). Forty-eight (70%) of the patients were children 10 years of age or younger. The patients were subjected to a high cumulative rate of tracheostomy of 14.5%. The authors recognized the need to avoid tracheostomy to prevent the distal airway spread of papillomas. However, limitations to accessing medical care in remote communities rendered the need for tracheostomy unavoidable.

A similarly large proportion of pediatric patients were identified in two studies from Nigeria. In Ibadan, Nigeria, 74.4% of RRP patients were children (Nwaorgu et al. 2004). In Enugu, Nigeria, an 11-year review of 54 cases of RRP revealed that 51.8% of patients were children (Mgbor et al. 2005). Epidemiological data from South Africa, Lesotho, Ghana, and Nigeria confirm that RRP has a significant pediatric footprint.

Efforts to estimate the incidence and prevalence of JoRRP in Australia have been spearheaded by Novakovic and Brotherton. In a recently published study, Novakovic and colleagues reported the results of a retrospective review of pediatric RRP cases presenting at three tertiary pediatric hospitals in New South Wales (Novakovic et al. 2016). Cases were identified from hospital records using ICD-10 codes and RRP-related procedure codes. The local epidemiological results were subsequently applied to national hospital separations data to estimate national disease prevalence.

The retrospective review at the three pediatric hospitals in New South Wales identified 30 cases of JoRRP with a median age of onset of 36 months. There was a small female preponderance (57%). The use of ICD-10 codes to identify cases was found to have a very high positive predictive value of 98.1%. Assuming the high positive predictive value was consistent nationally, the local data was applied to national hospital separations data. This exercise revealed a national (estimated) JoRRP prevalence rate of 0.8 per 100,000 children <15 years of age between 2000 and 2013. The peak rate of 1.1 per 100,000 was found in 5- to 9-year-old children.

The limitations of this study design include the need for a consistent positive predictive value of ICD-10 codes across hospitals, the regional distribution of RRP treatment to specialized centers, and missing local data from private hospitals.

Australia has also established an Australian Paediatric Surveillance Unit (APSU) that facilitates the national active surveillance of uncommon diseases of childhood including JoRRP (Deverell et al. 2014). APSU uses standardized case definitions and distributes a report card to 1400 practicing pediatricians and child health specialists every month. Response rates have remained at approximately 90% for the past 20 years. In the 2013 APSU report, there were six confirmed cases and one probable case of JoRRP in 2012 and one confirmed case and two probable cases in 2013. The data suggests there has been a decline in the incidence of JoRRP. This reporting structure has its limitations but may prove useful in the surveillance of JoRRP in the postvaccination era.

JoRRP epidemiological data have been reported for several geographical areas of Europe including Denmark, Norway, the United Kingdom, and France. Robust data have been reported for the Scandinavian countries but is very limited for the rest of Europe.

In 1988, Bomholt identified and analyzed the clinical course of 23 patients treated for RRP in the Copenhagen region during a 4-year period (Bomholt 1988). Although the age range of the patients was 3–67 years (median 18 years), all patients presented with RRP in childhood. Between 1980 and 1983, seven new cases of JoRRP presented out of an at-risk population of 300,000 children aged 0–14 years, indicating an incidence of 0.6 per 100,000 children.

The incidence of JoRRP was calculated for another Danish subpopulation by Lindeberg and Elbrønd in 1990 (Lindeberg and Elbrønd 1990). They calculated the incidence of RRP in patients that lived in Funen or Jutland at first presentation between 1965 and 1984. The population of this area is approximately 2.8 million persons. They classified presentations at 20 years of age or younger as “juvenile.” The observed incidence of JoRRP for patients below 20 years of age was 0.36 per 100,000. Adjustments to include only cases with presentation of JoRRP below 15 years of age resulted in an incidence of 0.48 per 100,000 children.

Omland and colleagues conducted a study to estimate the incidence of juvenile and adult RRP in two Norwegian regions with a combined population of 3.7 million inhabitants (Omland et al. 2012). All patients were treated in three hospitals. Patients were identified with ICD-10 codes, procedure codes, and electronic pathology archives. The search protocol identified 115 patients treated between 1987 and 2009, of which 22 patients had a juvenile onset of disease. JoRRP was defined as disease onset before puberty. The overall incidence of JoRRP was 0.17 per 100,000 children per year. The median age at diagnosis was 4 years with a 3:1 male preponderance. The analysis did not detect a statistically significant change in incidence over the study period.

Estimates of incidence and prevalence of JoRRP have not been reported for other European countries. In the United Kingdom, epidemiological data is limited to a retrospective review of cases treated at Christie Hospital and the Manchester Royal Infirmary, Manchester (Hartley et al. 1994). The study analyzed 59 cases of RRP presenting between 1974 and 1992. Twenty of the 59 patients were children under 16 years of age at disease onset. The study revealed that HPV 11 was more often detected in younger patients and that all seven patients with distal airway disease at presentation were children. In another UK study, consultant members of the British Association of Paediatric Otorhinolaryngology were surveyed regarding the management of patients with RRP (Tasca et al. 2006). Although information regarding 103 patients was elicited, there is no breakdown of data according to the age of the patients. A poignant conclusion of the study was the recognition of the need to establish a centralized national database to which consultants can report cases.

In 2009, an attempt to initiate a database that could serve as a European multicenter epidemiological study was proposed by a group in Lyon, France, under the leadership of Froehlich (Carvalho et al. 2009). This group published a retrospective study of RRP cases in a tertiary care teaching hospital and developed a standardized intake questionnaire. Between January 2005 and July 2007, 72 patients were entered into the RRP database. Of the patients registered, 24 had JoRRP defined as diagnosis before the age of 12 years. The mean age at first treatment was 5 years with a small female preponderance. Although this study represented the first data registry of RRP patients in France and Europe, no further updates have been published by this group.

The first estimates of incidence and prevalence of JoRRP in the United States (and worldwide) were derived from a survey study by Strong and colleagues in 1976 (Strong et al. 1979). The survey was distributed to 4200 practicing otolaryngologists in the United States. Responses were received by 51% of the surgeons identifying 1500 new cases of RRP in all age groups, 56% of which were children 16 years of age or younger. The authors estimated the national incidence of JoRRP at 0.4 per 100,000 children. This value was surprisingly similar to future rates reported for Scandinavian countries and Canada.

In 1995, Derkay championed a second national survey study of otolaryngologists in the United States (Derkay 1995). A three-page survey was administered to all active US members of the American Society of Pediatric Otolaryngology (ASPO) , American Broncho-Esophagological Association (ABEA) , and 1000 board-certified otolaryngologists practicing in the United States through a random mailing list provided by the American Academy of Otolaryngology—Head and Neck Surgery . More than 1300 surveys were mailed out and 315 were returned. The highest response rates were from ASPO members (81%) and surgeons in a full-time academic practice (77%). The survey identified 2354 new pediatric cases over a 12-month period. Based on US census data, the incidence of JoRRP in children 14 years of age and younger was estimated at 4.3 per 100,000 children. The estimated incidence rate is almost tenfold higher than previously reported for the United States and other health jurisdictions. The higher response rate from ASPO members and full-time academics may have skewed the national incidence estimate. The survey also identified 5970 active cases (in the preceding 3 years), requiring 16,597 surgical procedures over a 12-month period at an estimated cost of $109 million (USD). Extralaryngeal spread was identified in 31% of children, 13 children developed squamous cell carcinoma, and 14% required a tracheostomy. Interestingly, there were only four sibling sets identified in this large series of patients.

A meticulous calculation of the incidence of JoRRP in two US cities with a similar population was reported by Armstrong and colleagues in 2000 (Armstrong et al. 2000). The authors recruited the participation of 240 physicians in a 24-county area of Atlanta and an 8-county area of Seattle. The physicians were requested to identify all patients under the age of 18 years treated for JoRRP during the 1996 calendar year. The study protocol identified nine new cases of JoRRP in Atlanta and three cases in Seattle. Using 1990 US Census data, the authors calculated the incidence of JoRRP in Atlanta at 1.11 per 100,000 and in Seattle at 0.36 per 100,000. The prevalence for Atlanta and Seattle was estimated at 2.59 per 100,000 and 1.69 per 100,000, respectively. The study demonstrated that when studied at a smaller scale, there may be regional differences in incidence and prevalence of JoRRP.

A novel approach to estimate the incidence and prevalence of JoRRP in the United States was completed with medical claims insurance databases representing both privately and publicly insured children. The study by Marisco and colleagues was the first to assess differences in epidemiology in large, geographically and socioeconomically diverse source populations (Marisco et al. 2014). Study populations were derived from the two databases using predefined algorithms. Children aged 0–17 years were identified with continuous health plan coverage for at least 90 days (or 30 days if born in 2006) during the 2006 calendar year. ICD and procedure codes were used to identify potential cases followed by chart validation protocols to calculate the positive predictive value (PPV) of the claims-based algorithms. The overall PPV-adjusted incidence of JoRRP in 2006 was 0.51 per 100,000 in privately insured children and 1.03 per 100,000 in publicly insured children. The peak incidence was identified in children aged 0–4 years for both privately and publicly insured children. The PPV-adjusted prevalence of JoRRP in 2006 was 1.45 per 100,000 in privately insured children and 2.93 per 100,000 in publicly insured children. The PPV of the incidence and prevalence algorithms was 34% and 52%, respectively. Nonetheless, the discrepancy in calculated incidence and prevalence between privately and publicly insured children suggests a higher susceptibility and severity of disease in children with lower socioeconomic status.

In Canada, a population-level national database was developed through a JoRRP Working Group that networked all tertiary pediatric referral centers (Campisi et al. 2010). Canada represents an ideal location for a JoRRP database because of the universal health-care system and strict centralization of specialized pediatric care to tertiary centers. In addition, the population is large enough to derive accurate measures of incidence and prevalence but small enough to thoroughly collect population-level data. The Canadian national database was predicated on a well-defined case definition of JoRRP, a strategy to accurately identify cases across the country, a stable JoRRP Working Group membership, a standardized case report form, and a centralized database. Twelve academic pediatric centers contributed to the database. Between 1994 and 2007, 243 cases of JoRRP were identified nationally. Almost 50% of the cases were identified in Ontario and Quebec, the most populous provinces in the country. The 243 children underwent more than 3000 surgical procedures during the time frame of the study, providing approximately 837 patient-years of retrospective observation.

When the incidence and prevalence data was analyzed regionally, the rates of incidence were highly variable year over year. This is not unexpected given the rare occurrence of the condition. This finding demonstrates that a sufficiently large population is required to derive meaningful epidemiological measures. Nationally, the incidence rate was calculated at 0.24 per 100,000 children aged 14 years or younger. The prevalence rate was 1.11 per 100,000 children. These values are actual measures, not estimates. The median age at diagnosis was 4.4 years (range 1 month–14 years) with a slight male preponderance. Patients underwent a median of seven surgical procedures throughout the course of their disease.

The Canadian national database is currently being used as a platform for the surveillance of incident and prevalent cases of JoRRP following the introduction of provincial HPV vaccination strategies introduced in 2007. The ongoing surveillance study will be further addressed later in the chapter.

A thorough understanding of the clinical course of JoRRP is important for patient and family counseling, anticipating disease progression and complications, and the interpretation of therapeutic interventions. The characteristics of the natural history of JoRRP have been pieced together from several studies with large cohorts of patients. For example, the initial results from the US national registry for JoRRP, which analyzed the clinical course of 399 children, revealed that children diagnosed under the age of 3 years were 3.6 times more likely to require more than 4 surgical procedures per year (Armstrong and Derkay 1999). This study also demonstrated that the mean duration of the disease was 4.4 years. This basic information regarding clinical course is very important to prepare the parents of newly diagnosed children to cope with the financial and psychological challenges they are likely to encounter.