Global Epidemiology of HPV-Associated Recurrent Respiratory Papillomatosis and Effect of Vaccination

Keywords:

• developing countries
• epidemiology
• HPV
• papillomavirus vaccines
• recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP), caused by human papillomavirus (HPV), results in the development of papillomas in the respiratory tract [1]. The larynx is the most frequently affected site, with the trachea being the most common site of extralaryngeal involvement [2]. Other extralaryngeal sites that may be involved include the nose, nasopharynx, oral cavity, oropharynx and lungs.

Patients initially present with progressive dysphonia, but stridor and respiratory distress occur as upper respiratory tract obstruction develops [2]. Other symptoms may include chronic cough, recurrent upper respiratory tract infections and hemoptysis.

RRP is classified into two clinical types based on age at diagnosis: juvenile-onset RRP (JoRRP) and adult-onset RRP (AoRRP). JoRRP is believed to be acquired during birth from the mother’s infected genital tract, while AoRRP is believed to be sexually transmitted [1]. RRP has been shown to have a trimodal distribution in the age at diagnosis in Europe, with peaks in the age at diagnosis of 7, 35 and 64 years [3]. However, this trimodal age at diagnosis has not been demonstrated in sub-Saharan Africa, where a bimodal distribution has been found, with peaks in the age at diagnosis at 5 and 45 years, and the overwhelming majority of patients are in the juvenile-onset group [4]. There is no difference in the sex distribution between males and females with JoRRP, while AoRRP occurs more commonly in males.

There is no cure, and treatment consists of repeated microlaryngoscopic procedures to remove the papillomas while attempting to preserve normal laryngeal tissue, until the patient goes into remission [2]. Repeated surgical procedures frequently lead to complications, such as anterior laryngeal synechiae, anterior glottic stenosis, posterior glottic stenosis and granuloma formation. Patients with airway obstruction may require a tracheostomy. Adjuvant treatments that have been used in the treatment of RRP including indole-3-carbinol, vaccination with mumps, MMR or HPV vaccines, IFN-α, cidofovir, programmed cell death protein 1 (PD-1) inhibitors and bevacizumab.

Human papillomavirus

HPVs are DNA viruses that belong to the family Papillomaviridae [5]. The viral genome consists of approximately 8000 base pairs and is divided into three regions, the long control region, early region (E1, E2, E4, E5, E6 and E7) and late region (L1 and L2) [5]. HPVs are classified based on the nucleotide sequence of the L1 gene [6]. The L1 genes of different HPV types have less than 90% similarity. Over 220 HPV types have been identified [7]. RRP is caused mainly by HPV types 6 and 11 [8–13].

Variants of an HPV type have less than 2% similarity in the L1 gene [6]. HPV6 can be classified into two variant lineages, A and B; lineage B can be classified into five B sublineages (B1, B2, B3, B4 and B5) [14]. HPV11 can be classified into two variant lineages, A and B, with lineage A consisting of four sublineages, A1, A2, A3 and A4 [15]. Intratypic variants of HPV6 and HPV11 vary by geographic area but are not as geographically restricted as the high-risk types [14,15]. Variants of high-risk HPV types, such as HPV16 have been found to differ in oncogenic potential [16]. A similar situation may exist with regard to the pathogenic potential of the low-risk HPV types, HPV6 and HPV11. However, although differences have been shown in the functional activity of HPV6 and HPV11 variants in in vitro studies [17,18], differences in clinical disease severity between HPV variants has not been demonstrated [19].

Prevaccination epidemiology of RRP

The prevaccination epidemiology of RRP has been studied mainly in developed countries. In Denmark and Norway an incidence of JoRRP of between 0.17 and 0.6 per 100,000 per year and an AoRRP of between 0.39 and 0.8 per 100,000 have been found [20–23]. North American studies have found an incidence of JoRRP in the USA of between 0.12 and 4.5 per 100,000 per year and an AoRRP of 1.8 per 100,000 [24–26]. The incidence of 4.5 per 100,000 is probably an overestimate as it was based on a survey of pediatric otorhinolaryngologists and thus subject to selection bias, while the incidence found in other studies (0.36–1.11 per 100,000) is similar to European incidence rates. The incidence of JoRRP in Canada was found to be 0.24 per 100,000 per year [27]. Australian studies have reported a prevalence similar to that in European and North American studies of 0.6–1.1 per 100,000 [28,29]. In Korea, the incidence of JoRRP was 0.5 per 100,000 children per year [30]. In developing countries, the incidence rates per 100,000 children per year have been reported to be 0.49 in Lesotho, 1.34 in South Africa and 2.8 in Thailand [4,9,31]. The incidence of AoRRP has been found to be higher in European and North American studies than in South Africa, where an incidence of 0.18 per 100,000 adults per year has been reported.

The incidence and prevalence rates from developing countries are probably an underestimate as developing countries have a shortage of healthcare workers and facilities, and patients may not be presenting as a result of the lack of appropriate healthcare services. This is also reflected in the clinical presentation of patients with RRP. In developed countries, patients with RRP initially present mainly with hoarseness, while in developing countries, upper airway obstruction is a frequent initial clinical presentation [22,27,31,32].

HPV vaccines

HPV vaccine subtypes are differentiated by their antigen content. Currently there are three distinct vaccine subtypes available on the market: HPV2 (the bivalent vaccines against HPV types 16 and 18: Cervarix^® and Cecolin^®), HPV4 (quadrivalent against HPV types 6, 11, 16, 18: Gardasil^®) and HPV9 (nonavalent against HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58: Gardasil-9) [33]. These prophylactic vaccines are composed of viral-like particles based on the L1 gene that are immunogenic but not infective and prevent infection by the specific HPV types. Only the quadrivalent and nonavalent vaccines include the HPV types responsible for causing RRP.

HPV vaccination programs

Approximately 110 countries, corresponding to approximately a third of the target population, have introduced HPV vaccination programs to prevent cervical carcinoma [33]. Unfortunately, vaccination programs have not been introduced in many low- and middle-income countries. These are countries with the highest incidence of cervical carcinoma, where HPV vaccines would be of most benefit. Barriers to the introduction of HPV vaccination programs include supply constraints and price [33].

Effect of HPV vaccination on RRP

The use of HPV vaccines that protect against HPV6 and HPV11 infection in vaccination programs has led to a reduction in the incidence of JoRRP through elimination of the maternal source of infection.

A national HPV vaccination program which included protection against HPV6 and HPV11 was established in Australia for females aged 12–26 years of age in 2007, with males being included in this vaccination program in 2013 [34]. This program subsequently resulted in a significant decline in the incidence of JoRRP from 0.16 per 100,000 in 2012 to 0.022 per 100,000 in 2016 [8]. No new cases of JoRRP were diagnosed in Australia since 2017 [34].

There was also a significant decline in the incidence of JoRRP in the USA following the introduction of the HPV vaccine [35]. The incidence of JORRP declined between 2004–2005 and 2012–2013 from 2.0 to 0.5 cases per 100,000 births (using national birth data), respectively, and from 2.9 to 0.7 cases per 100,000 births (using state-level data), respectively.

It is probable that the use of vaccines that protect against infection by HPV6 and HPV11 may also result in a decline in the incidence of AoRRP. Vaccination programs that do not include protection against HPV6 and HPV11 are unlikely to decrease the incidence of RRP. The use of HPV vaccines that do not protect against HPV6 and HPV11 may be a possible missed opportunity to also prevent RRP [36].

Future perspective

The introduction of HPV vaccination programs has resulted in a significant decline in the incidence of cervical carcinoma. Countries that have used vaccines that include protection against HPV types 6 and 11 that cause most cases of RRP have also seen a significant decline in the incidence of JoRRP. However, RRP is likely to remain a problem that will persist for many years in developing countries, especially those in sub-Saharan Africa, with a probable greater relative burden of the condition, due to the lack of HPV vaccination programs and the use of vaccines that do not protect against HPV6 and HPV11 in vaccination programs. Ultimately all HPV-related diseases can potentially be prevented worldwide through vaccination. Lack of supply, price and political priorities are concerns that need to be addressed by the WHO and governments. It is only through the implementation of appropriate HPV vaccination programs that HPV-induced conditions, including RRP, can be eliminated.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.