Risk Factors for the Development and Severity of Juvenile-Onset Recurrent

International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197

Contents lists available at ScienceDirect

International Journal of Pediatric Otorhinolaryngology

jo urnal homepage: www.elsevier.com/locate/ijporl

Review Article

Risk factors for the development and severity of juvenile-onset

recurrent respiratory papillomatosis: A systematic review

a,b a,c b a,b,

Joseph Niyibizi , Caroline Rodier , Maggy Wassef , Helen Trottier *

Department of Social and Preventive Medicine, University of Montreal, Public Health School 7101, Avenue du Parc, 3rd Floor, Montreal, Quebec H3N 1X9, Canada

Sainte Justine Hospital (CHU Sainte-Justine), 3175 Chemin de la Coˆte Ste-Catherine, Room A-830, Montreal, Quebec H3T 1C5, Canada

Merck Canada Inc., 16711 Route Transcanadienne, Kirkland, Quebec H9H 3L1, Canada

A R T I C L E I N F O A B S T R A C T

Article history: Objectives: Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease

Received 13 November 2013

caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few

Accepted 28 November 2013

develop JoRRP and the clinical course of the disease varies from one child to another. This systematic

Available online 6 December 2013

review seeks to provide an up-to-date understanding of the risk factors for acquisition and severity.

Methods: We conducted a comprehensive literature search in EMBASE, MEDLINE and EBMR databases

Keywords:

using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also

Human papillomavirus

searched Google Scholar and the reference lists of eligible studies. Our search was limited to original

Recurrent respiratory papillomatosis

studies published in French or English between 1995 and July 2012 and to patients under 20 years of age.

Acquisition

Severity Results: Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32

Review studies meeting inclusion criteria. All were observational and together included 2296 JoRRP cases. Risk

factors could be classiﬁed mainly as maternal and birth history, viral genotype, and host factors. A history

of genital warts during pregnancy and delivery was strongly linked to the development of JoRRP.

Depending on ethnicity, speciﬁc human leukocyte antigen class II alleles and immune response factors

were important determinants of JoRRP acquisition and severity. HPV-11 genotype and younger age at

onset of JoRRP were important predictors of severity.

Conclusions: Genetic and immunological proﬁles underlying the acquisition and clinical course are not

readily modiﬁable. Thus, preventing condylomas in women of childbearing age could reduce the burden

of this life-threatening disease.

Contents

1. Introduction ...... 187

2. Methods ...... 187

2.1. Search strategy ...... 187

2.2. Study screening, data collection and quality assessment ...... 187

3. Results ...... 187

3.1. Description of included studies ...... 187

3.2. Socioeconomic status ...... 187

3.3. Age at onset ...... 188

3.4. Birth history and parental HPV status ...... 188

3.5. Host genetic and immune response factors...... 188

3.6. HPV genotype ...... 191

3.7. Affected sites and cell types...... 194

3.8. Comorbidities ...... 194

* Corresponding author at: Sainte Justine Hospital Research Center, Department of Social and Preventive Medicine, University of Montreal, 3175 Chemin de la Coˆte Ste-

Catherine, Room A-830, Montreal, Quebec H3T 1C5, Canada. Tel.: +1 514 345 4931x7152; fax: +1 514 345 4801.

E-mail address: [email protected] (H. Trottier).

J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197 187

4. Discussion ...... 194

5. Conclusions ...... 195

Acknowledgements ...... 195

References ...... 195

1. Introduction 2.2. Study screening, data collection and quality assessment

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a Two of the authors (MW and CR) screened the identiﬁed titles

rare yet aggressive disease caused by the human papillomavirus after removal of duplicates. The same authors then screened the

(HPV). The wart-like growths in the upper airway are mostly due to abstracts and selected which full-text manuscripts to retrieve for

HPV genotypes 6 and 11 [1,2]. Several observational studies have evaluation. Studies conforming to inclusion and exclusion criteria

associated the JoRRP to maternal vaginal condylomas [3–6]. were then classiﬁed according to study objective: acquisition,

The incidence and prevalence of JoRRP vary from one country to severity of disease, or both. Each of these steps was performed

another. The incidence has been estimated at 0.24–4.3 per 100,000 independently and in duplicate. Any discrepancies were resolved

children, the prevalence at 1.11–2.59 per 100,000 children [7–10]. by consensus, with referral to a third author (JN or HT) where

Although the disease is rare, morbidity is notoriously high. necessary.

Recurrent proliferative lesions in the respiratory tract can spread We collected research data on demographics (country, year of

to the trachea, bronchi or pulmonary parenchyma and compromise publication, study population, age of participants), study design,

local function such as vocalization, breathing and swallowing [11– and results of HPV genotyping. For all variables analyzed as

15]. potential determinants of JoRRP acquisition or severity, we noted

The course of the disease can vary from mild to severe. Some relative risks (odds ratio or risk ratio) and conﬁdence intervals (CI)

children experience minor symptoms with spontaneous and when applicable and available. Where the authors provided only p-

complete remission at puberty, while others require multiple values for statistical test results, we reported the p-value and

surgeries throughout childhood [13] at great physical, emotion- direction of the association. We assessed each study for quality,

al, and ﬁnancial burden to the individual, the family, and society according to levels of evidence determined by study design and

[16,17]. In rare yet severe progression, the disease may potential bias [28]. Given the design variability and insufﬁcient

transform into malignant lesions [14], or in 1–3% of cases, similarities in outcome measures of the included studies, we did

may spread to the lower respiratory tract, entailing high not deem it appropriate to extend this review to a meta-analysis

mortality [11]. [29].

Individual studies have analyzed the risk factors associated

with the occurrence and severity of JoRRP but ﬁndings have not

3. Results

been consistently replicable. Various published reviews have

described the clinical manifestations and treatment options

3.1. Description of included studies

[12,16,18–26]. None, however, has focused systematically on

etiology and prognosis. This systematic review, by summarizing

Our initial search identiﬁed 1362 citations. Of these, we

recently published data, seeks to provide an up-to-date under- retrieved 102 unduplicated full-text articles that conformed to

standing of the risk factors for acquisition and severity.

eligibility criteria (Fig. 1). We found 14 additional studies from the

reference lists. We retained 32 studies altogether, of which three

2. Methods [30–32] focused on risk factors for both acquisition and severity of

disease.

2.1. Search strategy All 32 studies were observational and together reported on a

total of 2287 JoRRP cases. Seven studies included both JoRRP and

We conducted a comprehensive systematic review of studies adult-onset recurrent respiratory papillomatosis (AoRRP) cases

investigating risk factors associated with the acquisition and [30,31,33–36,38] (Table 1). Analyzed variables included socio-

severity of JoRRP. We searched EMBASE, MEDLINE and Evidence- demographics, maternal pregnancy history, immune response

Based Medicine Reviews (EBMR) databases using the OvidSP characteristics and genetic proﬁle. Sixteen studies examined HPV

interface with the following combinations of keywords and genotypes [2,7,13,33,35–46], particularly HPV-6.

Boolean operators: (Laryn$ OR respiratory) AND (HPV OR

papilloma or Papillomaviridae OR Papillomavirus Infections) 3.2. Socioeconomic status

AND (Disease* OR lesion* OR infection*) OR (Juvenile onset

recurrent papillomatosis OR JORRP OR Juvenile laryngeal papillo- Only 4 publications [13,17,44,47] examined the link between

ma) AND (cause* OR sever* OR acquisition OR etiology OR Risk JoRRP and socioeconomic factors (Fig. 2). Medicaid coverage (a

factor OR Risk Factors OR agress$). Given the use of new techniques proxy for a low socioeconomic status in the US, as opposed to

for HPV genotyping since the late 1990s, we limited our search to private insurance coverage) was signiﬁcantly associated with

studies published between 1995 and July 2012. We also limited it JoRRP severity in a 10-year prospective study in Alabama, US [13],

to studies investigating patients under 20 years of age, a cut-off but not in a study of 603 cases in 22 tertiary pediatric care centers

proposed by Lindeberg et al. [27]. Only studies published in French (also in the US) [17]. It was thus unclear whether or not the

or English were retained. We conducted an additional search using availability of medical health insurance played a role as a

Google scholar, conference proceedings, and the reference lists of facilitating factor for timely access to care and better prognosis.

all eligible studies and any previous reviews on JoRRP, again Leung et al. conﬁrmed that, in a universal health care setting

eliminating studies of adults only (age 20). In all cases, we (Canada), socioeconomic status was not signiﬁcantly associated

excluded studies analyzing tissues outside the respiratory tract or with JoRRP severity [47]. Similarly, in a multicentre study of 118

investigating less than 5 patients. Case reports, editorials and JoRRP cases in the US and Canada, neither maternal education level

opinion pieces were not considered eligible. nor gross household income was indicative of disease progression

188 J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197

1317 Titles identified 45 Additional titles to a case–control study of 3033 Danish births, the risk of JoRRP

through systematic search from other sources increased 231-fold (OR 231, 95% CI: 135.3–395.9) when the mother

had genital condylomas during pregnancy [3] (Table 2). The risk of

JoRRP increased 3-fold when the mother with condylomas during

pregnancy was not living with newborn’s natural father [3].

Unstable relationships may account for increased vertical trans-

mission by the possibility of newly acquired HPV infection [3,4].

86 Duplicates removed

The risk of JoRRP acquisition doubled when delivery lasted

more than 10 h [3]. Furthermore, there were fewer cesarean births

1276 Titles screened

in JoRRP children than expected by US [4] and Danish [3] national

statistics (Table 2). It is therefore unclear whether cesarean section

992 Titles excluded†

is protective against JoRRP. For disease severity, Wiatrak et al. [13]

and Silverberg et al. [48] both reported a possibly signiﬁcant effect

284 Abstracts screened

of cesarean birth toward greater severity (Table 3).

182 Abstracts excluded† Unlike genital condylomas, other parental HPV presentations

seemed to be risk-free for JoRRP. After a 15-year follow-up, none of

102 Full-text articles assessed for 45 children born to 30 patients (22 mothers and 8 female partners

eligibility of male patients) with AoRRP had developed JoRRP [51].

84 Full-text excluded†

3.5. Host genetic and immune response factors

14 Additional articles Given the high prevalence of HPV carriage in women of

from reference lists

childbearing age [52], many newborns are likely exposed to HPV.

32 Studies included in the review However, few of them develop JoRRP [7–10] and the clinical course

of the disease varies from one child to another [13]. Thus, factors

* Additional search in Google scholar and conference proceedings. other than HPV, such as genetic polymorphisms and immune

† Studies recruiting adult patients only ( 20 years); analyzing tissues outside the respiratory response, may be involved in JoRRP pathogenesis. Seven studies

tract; without a comparison group; with less than 5 patients; case reports; editorials;

revealed a strong relationship between speciﬁc human leukocyte

opinion pieces.

§ Studies focused on: disease acquisition (9), disease severity (20), or both (3). antigen (HLA) class II alleles and HPV infection, ranging from latent

HPV infection to minor and severe JoRRP [30–32,35,53–55]

Fig. 1. Flow diagram of literature search.

(Table 2). Gelder et al. [35] reported a signiﬁcant association

between the DRB1*0301 allele and JoRRP susceptibility. Other HLA

class II alleles (DRB1*0102, DQB1*0201, DQB1*0402, DQB1*050X,

[44]. None of the included studies revealed gender [3,11,13,17, DQA*0102 and DQA*0101) were dominant in severe cases and

34,38,44,48] or ethnic [11,13,17,32] differences as regards JoRRP their effect varied by ethnicity [31,32]. Caucasians were at higher

incidence or severity. risk of developing JoRRP than African Americans if they carried the

DQA*0102 allele (OR 3.04, 95% CI: 1.21–7.64) [32]. Likewise, the

3.3. Age at onset DQB1*050X allele conferred a preferentially increased risk of JoRRP

acquisition to Caucasian as compared to African American children

A number of studies analyzed the effect of age on JoRRP severity (OR 17.46, 95% CI: 0.88–345.68 for Caucasian; OR 4.62, 95% CI:

[2,7,11,13,17,33,34,38,40,44,45,47–50] but few on JoRRP acquisi- 1.44–14.87 for African American). Moreover, the simultaneous

tion. In children with suspected sexual abuse, Sinclair et al. found presence of certain alleles increased the risk of developing severe

that HPV lesions were more prevalent in the younger children [49]. JoRRP. Caucasians were at high risk of severe RRP if they expressed

Furthermore, young children, when affected, were more likely to both DRB1*0301 and DQB1*0201 (OR 2.4, 95% CI: 1.3–4.4)

develop laryngeal papillomatosis than anogenital or oral papillo- [31]. However, other alleles seemed to be protective, such as

mas [49]. DQB1*0402 in African Americans (OR 0.07, 95% CI: 0.004–1.22).

Younger age at onset was consistently linked to severity DQA*0101/0104 was found more frequently in Caucasian children

[7,11,13,17,38,40,44,45,47,48,50] and ranked among the most without JoRRP (OR 0.39, 95% CI: 0.15–0.99), while DBQ1*0602 was

important risk factors for severity. In the 19 studies with data on signiﬁcantly less frequent in severe cases [31].

age, JoRRP patients were a mean of 2–9.4 years old, median 3–5.5 The role of killer cell immunoglobulin-like receptors (KIR) in the

years, at initial diagnosis (Table 1). One study identiﬁed a bimodal acquisition and progression of JoRRP was also investigated. While

distribution for age at diagnosis: approximately 2 years and most KIR genotypes identiﬁed in healthy Caucasian children were

beginning of puberty [38]. Reeves et al. further reported that not detected in JoRRP patients [30], the difference was not

severity (as measured by frequency of surgical procedures) was a statistically signiﬁcant [30]. However, the lack of KIR genes 3DS1

function of age at the time of ﬁrst surgery rather than at the time of and 2DS1 was evident in severe JoRRP as compared to mild-

diagnosis [17]. Buchinsky et al. further noted a positive correlation moderate cases (Table 3) [30]. A signiﬁcant relationship was also

between age at enrolment (current surgery) and the time interval reported between the DRB1/DQB1 alleles and the absence of KIR

elapsed from the previous surgery [44]. 3DS1, 2DS1, 2DS5 receptors in JoRRP cases [30], indicating that

certain allele combinations may be more deleterious than others

3.4. Birth history and parental HPV status (Table 2).

In investigations on compromised immune response (inappro-

Mode of delivery, birth order, and maternal genital HPV status priate or ineffective) against HPV [35,46,50,55,56], a signiﬁcant

were associated with HPV transmission and JoRRP (Table 2). Two relationship was found between low CD4/CD8 ratio and JoRRP [55].

studies using national birth registries reported an association In addition, papilloma tissues from patients with severe JoRRP

between genital condylomas during pregnancy, especially in were more likely to reveal an absence of CD28 co-expression by

young and primiparous women, and JoRRP [3,4] (Fig. 2). According CD8+ in tumor-inﬁltrating lymphocytes [53].

J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197 189

Table 1

Study design and population characteristics.

a b

Author Year, country Study population Study design HPV types (n) Age in years – mean Æ SD; Evidence level

(JoRRP cases) mean (min–max) or median

(min–max)

Gabbott [38] 1997, Australia 46 Retrospective HPV 11 (24) 4.9 Æ 3.8 3b

HPV 6 (19)

Mixed HPV 6/11 (1)

(Genotyped 44)

Rimell [37] 1997, US 24 Retrospective HPV 11 (6) 2 (0–10) 3b

HPV 6 (9)

Mixed HPV 6/11 (4)

(Genotyped 19)

Armstrong [11] 1999, US 399 Retrospective NR 3.8 (0.1–16.3) 2b

Shah [4] 1998, US 138 Cross-sectional NR NR 3b

Penaloza [39] 2000, Mexico 47 Cross-sectional HPV 11 (18) (0–17) 3b

HPV 6 (15)

HPV 16 (39)

HPV 33 (26)

HPV 31 (13)

HPV 39 (7)

Rabah [40] 2001, US 61 Retrospective HPV 11 (32) 3.5 (0–11) 2b

HPV 6 (29)

Snowden [50] 2001, US 15 Case–control NR 7 Æ 3 3b

Gelder [35] 2003, UK 36 Case–control HPV 6 (20) 4.3 (0–13) 3b

HPV 11 (13)

(Genotyped 33)

Gregoire [32] 2003, US 48 Case–control NR NR 3b

Reeves [17] 2003, US 603 Prospective NR Median 3.1 (0–17) 2b

Silverberg [3] 2003, Denmark 57 Retrospective NR Median 5.5 3b

Silverberg [48] 2004, Denmark Prospective NR 1b

Abramson [36] 2004, US 30 Prospective HPV 6 (34) NR 1b

HPV 11 (27)

Bonagura [31] 2004, US 29 Case–control NR NR 3b

Wiatrak [13] 2004, US 73 Prospective HPV 6 (31) 3.8 (0–12) 1b

HPV 11 (23)

Mixed HPV 6/11 (4)

(Genotyped 58)

Vambutas [56] 2004, US 17 Prospective NR NR 1b

Sinclair [49] 2005, US 40 Retrospective NR 4.0 (SD 2.9) 2b

Gerein [34] 2005, Germany 22 Prospective HPV 6 (17) NR 1b

HPV 11 (14) d

(Genotyped 31)

Draganov [42] 2006, Bulgaria 23 Cross-sectional HPV 11 (13) 7.8 (0.5–12) 3b

Mixed HPV 6/11 (5)

Mixed HPV 6/11 (3)

(Genotyped 21)

Gerein [51] 2006, Germany/ (28 exposed Retro/prospective NA NA 4

Russia children 0 JoRRP)

Maloney [43] 2006, US 15 Prospective HPV 11 (4) Median 2.4 (0.5–5.7) 1b

HPV 6 (4)

Mixed HPV 6/11 (7)

Leung [47] 2007, Canada 21 Cross-sectional NR 5.8 3b

Stern [55] 2007, US 20 Prospective NR 9.4 (2–18) 1b

Buchinsky [44] 2008, US/Canada 118 Cross-sectional HPV 11 (47) Median 3 (0.1–13.1) 3b

HPV 6 (71)

Louw (a) [57] 2008, South Africa 10 Case–control NR Range (4–12) 3b

Louw (b) [58] 2008, South Africa Case–control NR 3b

Shehata [45] 2008, US 43 Retrospective HPV 11 (14) Range (0.4–10) 3b

HPV 6 (29)

Carvalho [33] 2009, France 24 Retrospective HPV 11 (7) 5 3b

HPV 6 (12)

(Genotyped 19)

Kovalenko [46] 2009, Russia/Germany 40 Retrospective HPV 11 (24) Range (1.7–20) 2b

HPV 6 (14)

(Genotyped 38)

Bonagura [30] 2010, US 26 Case–control NR NR 3b

Campisi [7] 2010, Canada 243 Retrospective HPV 6 and/or 11 (74) Median 4.4 (0.1–14) 2b

(HPV-positive 77; genotyped 74)

190 J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197

Table 1 (Continued )

a b

Author Year, country Study population Study design HPV types (n) Age in years – mean Æ SD; Evidence level

(JoRRP cases) mean (min–max) or median

(min–max)

Seedat [2] 2010, South Africa 19 Cross-sectional HPV 11 (9) 5.3 (1.4–9.5) 3b

HPV 6 (9)

(Genotyped 18)

Not entire study population was genotyped.

Levels of evidence (according to Phillips et al. [28]: 1b: prospective cohort study with good follow-up (retention > 80%); 2b: individual cohort study (<80% follow-up), retrospective

cohort study; 3b: case–control study, non-consecutive cohort study, or very limited population (n < 50), cross-sectional).

Multiple HPV co-infection.

May include adult cases

Studies focused on both acquisition and severity.

HPV, human papillomavirus; JoRRP, juvenile-onset recurrent respiratory papillomatosis; SD, standard deviation; max, maximum; min, minimum; NA, not applicable; NR, not reported;

UK, United Kingdom; US, United States.

Risk factors tested

Age Socioeconomic status Sex Ethnicity RRP Parental Maternal age Genital HPV history Mode of delivery Firstborn HLA alleles KIR genes Immune response HPV type Cellular fatty acid profiles Fatty acid intake GERD Tissue type

Author [reference ]

Acqu isition

Abramson [36] N

Bonagura [30] N

Bon agura [31] S

Gelder [35] S S

Gerein [51] N

Grego ire [32] N S

Louw (a) [57] S

Louw (b) [58] N

Sha h [4] S S S

Silverberg [3] N N N S S N

Sinclair [49] S S

Stern [55] S

Severit y

Armstron g [11] S N N

Bon agura [31] S

Bon agura [30] S

Buchinsky [44] S N N S

Campisi [7] S

Carvalho [33] N S

Dragano v [42] S

Gabbo tt [38] S N N

Gerein [34] N N S

Grego ire [32] S N

Kov alenko [46] S

Leung [47] S N

Maloney [43] S

Penaloza [39] N

Rabah [40] S S S

Ree ves [17] S N N N

Rimell [37] S

Seeda t [2] N S

Sheha ta [45] S S

Silverberg [48] S N N S S

Sno wden [50] S S

Vambutas [56] S

Wiatrak [13] S S N N N N S S S S N

S Statistically significant (p 0.05) N Not statistically significant (p > 0.05)

Socioecono mic status (medical coverage, household income, and/or mother’s education level); GERD: gastroesophageal reflux

disease; HLA: human leukocyte antigen; HPV: human papillomavirus; KIR: killer cell immunoglobulin-like receptor; RRP:

rec urrent respiratory papillomatosis!

Fig. 2. Risk factors tested for association with juvenile-onset recurrent respiratory papillomatosis.

J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197 191

Table 2

Risk factors for JoRRP acquisition.

Author Risk factors analyzed Determinants of occurrence Relative risk and signiﬁcance

Shah [4] Maternal age Mother < 20 years: 2.6 times more prevalent in JoRRP p < 0.002

cases

Birth order Firstborn: 1.6 times more prevalent in JoRRP cases p < 0.001

Mode of delivery Cesarean section: 4.6 times less prevalent in JoRRP cases p < 0.0001

Silverberg [3] Maternal genital warts History of genital warts in pregnancy RR 231.4 (95% CI: 135.3–395.9)

during pregnancy

Mode of delivery Cesarean section vs. vaginal RR 0.95 (95% CI: 0.34–2.66)

Vaginal delivery duration Vaginal delivery duration > 10 h RR 1.97 (95% CI: 1.11–3.84)

Maternal age Maternal age < 30 years RR 0.76 (95% CI: 0.34–1.54)

Gelder [35] HLA class I/II alleles Presence of:

TNF DRB1*0301 OR 4.30 (95% CI: 2.16–8.58)

DQB1*02 OR 2.46 (95% CI: 1.22–4.95)

A1-B8-DR3DQ2 OR 4.04 (95% CI: 1.92–8.49)

TNF2 OR 2.9 (95% CI: 1.3–6.32)

TNF1 OR 0.26 (95% CI: 0.09–0.76)

Gregoire [32] HLA-DQA alleles Presence of:

HLA-DQB alleles DQB1*050X

Ethnicity Caucasian OR 17.46 (95% CI: 0.88–345.68)

African American OR 4.62 (95% CI: 1.44–14.87)

DQA*0102 (Caucasian) OR 3.04 (95% CI: 1.21–7.64)

DQB1*0402 (African American) OR 0.07 (95% CI: 0.004–1.22)

DQA*0501/DQb1*0102 (Caucasian) OR 9.59 (95% CI: 2.32–39.68)

DQB*0101/0104 (Caucasian) OR 0.39 (95% CI: 0.15–0.99)

Abramson [36] Tissue type No difference between tracheal and laryngeal latent/ p > 0.05

subclinical HPV infection

Bonagura [31] HLA alleles Presence of:

DRB1*0102 (Caucasian) OR 7.0 (95% CI: 2.7–16.2)

DRB1*0301

Caucasian OR 1.9 (95% CI: 1.0–3.5)

African American OR 3.0 (95% CI: 0.6–10.7)

DQB1*02

Caucasian OR 1.8 (95% CI: 1.0–3.2)

African American OR 3.3 (95% CI: 1.0–12.9)

DRB1*0301 and DQB1*0201 (Caucasian) OR 2.4 (95% CI: 1.3–4.4)

Sinclair [49] Age Younger age associated with HPV infection p < 0.001

Anatomical localization In younger children, laryngeal papillomatosis was more p = 0.026

likely than anogenital or oral papillomas

‘Gerein [51] RRP in parents (mothers and fathers) None of the exposed children was diagnosed with JoRRP NA

(clinical nor histological examination)

Stern [55] Serum immunoglobulin levels No signiﬁcant difference in IgG or IgM levels between p = 0.20 and p = 0.23

cases and controls

CD4/CD8 ratio More reduction of CD4/CD8 ratio in JoRRP p = 0.02

Lymphocyte response to mitogen More lymphocyte response to mitogen stimulation in p = 0.037

stimulation JoRRP

Natural killer cell function No signiﬁcant difference in natural killer cell activity p = 0.125

between cases and controls

Louw (a) [57] Fatty acid proﬁles Papilloma biopsies showed signiﬁcantly more variation p < 0.05

in several fatty acid proﬁles then normal biopsies

Louw (b) [58] Fatty acid and micronutrient intake Both cases and controls had excessive linoleic acid NR

intakes

Bonagura [30] KIR and HLA gene combinations JoRRP’s susceptible DRB1/DQB1 alleles were associated

with absence of:

KIR3DS1 p = 0.006

KIR2DS1 p = 0.003

KIR2DS5 p = 0.004

Relative risk: odds ratio (OR) or risk ratio (RR) with corresponding 95% conﬁdence interval (CI), when provided. If only p-value was provided, the direction of the

association or effect is described in the column ‘‘Determinants of occurrence’’; HLA, human leukocyte antigen; HPV, human papillomavirus; JoRRP, juvenile-onset recurrent

respiratory papillomatosis; KIR, killer cell immunoglobulin-like receptors; NA, not applicable; RRP, recurrent respiratory papillomatosis; TNF, tumor necrosis factor; UK,

United Kingdom; US, United States.

3.6. HPV genotype Four studies explored HPV genotype and age [2,33,40,44]. Two

found an association between HPV-11 and disease severity;

HPV-6 and HPV-11 were found in more than 95% of JoRRP cases. patients with HPV-11 were diagnosed at a younger age than

Other high-risk genotypes 16, 31, 33, 35 and 39 explained less than those with HPV-6 [40,44]. HPV-11 was in fact more closely

5% of cases (Fig. 3). Ten studies [2,13,33,34,37,40,42–45] indicated associated to younger age at diagnosis than to severity [44]

a significantly increased risk of JoRRP severity associated with the (Table 3). The other two studies did not find any significant

HPV-11 genotype (Fig. 2). Three other studies, however, did not relationship between HPV-6, HPV-11, and age [2,33].

discern any association between HPV genotype and disease Two studies investigated the association between ethnicity

severity [32,38,39]. and HPV genotype, but results were contradictory. Rabah et al.

192 J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197

Table 3

Risk factors for JoRRP severity.

Author Deﬁnition of severity Risk factors analyzed Determinants of severity Relative risk and

signiﬁcancea

Rimell [37] Tracheotomy HPV genotype HPV 11 more severe p = 0.05

Gabbott [38] 10 excisions with frequency Age Younger age at diagnosis (<4 years) p = 0.001

3 excisions per year associated with severity

Tracheal and/or bronchial HPV genotype No signiﬁcant differences in HPV p = 0.313

and/or lung involvement genotype

Sex No signiﬁcant difference between p = 0.107

males and females

Armstrong [11] >4 procedures Age Younger age at diagnosis (<3 years) p < 0.001

associated with severity

Number of anatomical sites Sex; Race Sex and ethnicity were not associated p = 0.52 and p = 0.19

affected with severity

Penaloza [39] 10 resections HPV genotype No signiﬁcant association between p > 0.05

severity and viral genotype or viral

combination

5 years of evolution

3 resections per year

Rabah [40] 10 procedures HPV genotype HPV-11 associated with severity p = 0.02

3 procedures within Race HPV-11 more common in African- p = 0.001

12 months American patients than Caucasian

Spread of disease distal Age Patients with HPV-11 manifested p = 0.04

to the subglottis clinically at a younger age

Snowden [50] >4 surgical recurrences Age Younger age associated with greater p = 0.002

per year severity

IL-2 IL-2 and IL-2 receptor levels p = 0.035 and

signiﬁcantly lower in severe cases

IL-2 receptor p = 0.025

Reeves [17] Frequency of surgery Age Younger age at diagnosis (<4 years) p < 0.001

associated with severity (mean number

of surgeries: 5.7 per year)

Need for tracheotomy Age at surgery was associated with p < 0.001

severity (mean number of surgeries: 6.9

per year)

Anatomic extent of disease

Ancillary therapy Children receiving adjuvant therapy p < 0.001

had more frequent surgeries

Children receiving adjuvant therapy

were diagnosed at

p < 0.001

Race, sex, Medicaid No differences for sex, race or Medicaid p > 0.05

younger age

Gregoire [32] Active disease versus remission HLA-DQA/DQB alleles DQA*0102 associated with remission in OR 0.21 (95% CI:

(absence of laryngeal symptoms African-Americans 0.05–0.85)

for 1 year with/without negative

results of laryngoscopy)

No association between DQB alleles and NR

disease progression

HPV genotype No association between HPV genotype NR

and HLA-DQA/DQB alleles

Silverberg [48] Surgery rate per person-year Age Younger age (<5 years) associated with p < 0.001

severity in children

Maternal condylomas Maternal condylomas associated with p < 0.001

severity

Mode of delivery Cesarean section associated with p = 0.03 severity

Wiatrak [13] Derkay staging system Severity was associated with:

PSS or PSF Age Younger age at diagnosis (<3 years) p = 0.02 (PSS/PSF)

HPV genotype HPV-11 p = 0.01 (PSS)

p = 0.02 (PSF)

Birth order Firstborn p = 0.02 (PSF)

Mode of delivery Cesarean section p = 0.02(PSF)

Maternal condylomas Maternal condylomas p = 0.006 (PSS)

Medicaid Lack of Medicaid coverage p = 0.02 (PSS)/(PSF)

Maternal age No signiﬁcant association between p > 0.05

severity and

Early childhood Second-hand tobacco/GERD/race/

infection formula feeding/early infection/

maternal age

Race; tobacco;

GERD; formula feeding

J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197 193

Table 3 (Continued )

Author Deﬁnition of severity Risk factors analyzed Determinants of severity Relative risk and

signiﬁcancea

Bonagura [31] Number of sites HLA-a, HLA-b, In Caucasians, presence of:

DRB1, DQB1

Luminal obstruction

Anatomical surface

DRB1*301 OR 2.4 (95% CI: 1.1–5.2)

DRB1*0102 OR 5.8 (95% CI: 1.4–17.6)

DQB1*0602 OR 0.3 (95% CI: 0.1–1.0)

DRB1*301 and DBQ1*0201 OR 3.1 (95% CI: 1.4–6.6)

Vambutas [56] Number of sites TAP1 TAP1 associated with severity p = 0.015

Luminal obstruction

Anatomical surface

Gerein [34] Pulmonary spread HPV genotype HPV-11 associated with pulmonary p = 0.004

spread

Malignant transformation HPV-11 associated with malignant p = 0.012

transformation

Age; Sex Age and sex not signiﬁcantly associated p >0.05

with severity

Dragonov [42] 10 procedures HPV genotype HPV-11 associated with severity p = 0.0265

3 procedures/year

Spread to subglottis

(ﬁrst 6 months)

Maloney [43] Frequency of surgical HPV genotype HPV-11 or HPV-11 co-infection with p = 0.02

interventions HPV-6 were signiﬁcantly associated

with severity

Median number of annual Viral load Neither HPV-6 nor HPV-11 viral loads NR

surgical procedures were associated with markers of

clinical severity

Leung [47] PSF Age Younger age at diagnosis is predictive of p = 0.003 and p = 0.047

worst anatomic score and PSF

Derkay staging system SES No signiﬁcant relationship between SES NR

measures and disease severity

Shehata [45] Frequency of excision Age Younger age at diagnosis (< 24 months) p = 0.0002

or debulking associated with severity

HPV genotype HPV-11 patients showed a more NR

aggressive clinical course than HPV 6

patients

Oncogene E6/E7 HPV-6 patients with severe form p < 0.0002

expression showed higher levels of E6 and E7

oncogenes

Buchinsky [44] >10 surgeries ever Age Younger age associated with HPV-11 p = 0.014

4 surgeries per year Younger age associated with severity p = 0.01

Distal involvement HPV genotype HPV-11 associated with severity (total OR 2.6 (95% CI: 1.0–7.5)

number of surgeries)

Tracheostomy HPV-11 associated with severity (distal OR 3.7 (95% CI: 1.4–9.8)

involvement)

HPV-11 associated with severity OR 3.4 (95% CI: 0.84–16) (tracheostomy)

À7

Time from last to 20% of the variability in the interval p = 4 Â 10

current surgery since the last surgery was a function of

the age at enrollment

Gender; Race; Household No association between gender; race; NR

income; Mother’s household income; mother’s education

education level level and disease course

Carvalho [33] Frequency of endoscopies HPV genotype Higher frequency of endoscopies in p = 0.007

HPV-11 vs. HPV-6

Maximum number of Age No signiﬁcant difference between HPV- NR

endoscopies/year 6 and HPV-11 for age, Derkay score or

remission time

Derkay staging system

Remission time

Kovalenko [46] Number of surgeries Dendritic cell density Increase of CD83+ associated with p = 0.005

severity

No statistically signiﬁcant association p = 0.07

between CD1a+ count and severity

Campisi [7] Maximum annual rate Age Younger age at diagnosis associated p < 0.001

Peak anatomical score with severity

Total number of surgeries

194 J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197

Table 3 (Continued )

Author Deﬁnition of severity Risk factors analyzed Determinants of severity Relative risk and signiﬁcancea

Seedat [2] Derkay staging system Age No signiﬁcant difference in age at p = 0.47

diagnosis between patients with HPV-6

Total procedures and HPV-11

Procedures/year HPV genotype HPV-11 was associated with more p = 0.05

procedures

Bonagura [30] Number of anatomical KIR genes Patients lacking activating KIR genes p = 0.019

sites 3DS1 and 2DS1 were more comparable

to severe than to mild-moderate cases

Luminal obstruction KIR-HLA combinations

Anatomical surface

Relative risk: odds ratio (OR) or risk ratio (RR) with corresponding 95% conﬁdence interval (CI), when provided. If only p-value was provided, the direction of the

association or effect is described in the column ‘‘Determinants of severity’’.

Early childhood infection: history of early (<3 years of age) infectious disease (e.g. chickenpox, meningitis, measles, mumps, pneumonia, tuberculosis).

Derkay staging system: Peak Severity Score (PSS) = Mean of 3 highest anatomical scores; Peak Surgery Frequency (PSF) = Highest number of procedures in 12 months. CI,

conﬁdence interval; GERD, gastroesophageal reﬂux disease; HLA, human leukocyte antigen; HPV, human papillomavirus; IL-2, interleukin-2; JoRRP, juvenile-onset recurrent

respiratory papillomatosis; KIR, killer cell immunoglobulin-like receptors; OR, odds ratio; SES, socioeconomic status (medical coverage/household income/mother’s

education level); TAP1, transporter associated with antigen presentation 1; US, United States.

reported a signiﬁcantly increased likelihood of African-American and clinical course of JoRRP disease [13,57,58]. Louw et al.’s

patients with JoRRP to be infected with HPV-11, as compared to research revealed signiﬁcant increase of fatty acid proﬁles in

Caucasian patients [40]. Wiatrak et al., however, did not ﬁnd any papilloma biopsy samples, suggesting enhanced dietary linoleic

signiﬁcant difference in the prevalence of HPV-11 and HPV-6 in and saturated fatty acid intake [57]. However, despite the fact that

Caucasians vs. African-Americans presenting with JoRRP [13]. these fatty acid proﬁles were apparently favorable to cell

proliferation, there was no difference in dietary intake between

3.7. Affected sites and cell types JoRRP patients and controls [58] (Table 2). Likewise, neither

gastroesophageal reﬂux disease nor early childhood infection was

Only two studies investigated HPV disease presentation and associated with JoRRP severity [13].

progression according to anatomical site and mucosal cell type

[36,49]. The respiratory tract was the preferred lesion site in children 4. Discussion

exposed to HPV, other than the anogenital area [49]. Within the

respiratory tract, the course of infection differed according to HPV JoRRP is a relatively rare disease. Prospective studies are

genotype and mucosal lining, with laryngeal disease much more therefore difﬁcult to undertake. In this comprehensive systematic

prevalent than tracheal. To see whether this difference was due review, we found that most (24/32) of the studies on JoRRP were

primarily to latent infection rates or HPV activation, Abramson et al. indeed retrospective, corresponding to a low-moderate level of

compared clinically normal tissue biopsies from the larynx and evidence as determined by the Oxford Center for Evidence-based

trachea of JoRRP patients [36]; they found no signiﬁcant differences Medicine [28]. Some had limitations such that results had to be

in latent or subclinical HPV infection rates [36]. They surmised that interpreted with caution: some simply described JoRRP cases

cellular factors must be responsible for the regulation of HPV without controls [49,51]; others used a case–control design, but

activation and explained the frequent laryngeal papillomatosis with potential bias in the selection of controls [30,32,35,58].

while maintaining a low rate of tracheal HPV lesions [36]. Nevertheless, over 2000 children with JoRRP were included in this

review. Using thorough methodology, this comprehensive sys-

3.8. Comorbidities tematic review summarizes recent literature and elucidates the

multifactorial interactions in the pathway of pathogenesis from

Other factors beyond immunology, genetics and virology, such HPV exposure to JoRRP acquisition and progression.

as nutrition and tissue irritation, may be involved in pathogenesis We found three categories of major risk factors: maternal

genital HPV and birth history, viral genotype, and host factors. All

HPV-11

42.88% three may act synergistically, with the course of disease inﬂuenced

by other comorbidities as well as by the accessibility to health care.

This review highlights the undeniable evidence that genital warts

during pregnancy and delivery were strongly linked to the

development of JoRRP in the offspring. One large study concluded

that 37% of JoRRP cases were attributable to maternal genital warts

Other HPV genotypes Coinfection HPV 6/11 during pregnancy [3]. In addition, prolonged vaginal delivery

(16,31,33,35,39) 4.49%

3.56% exposed babies to greater abrasion and increased the risk not only

of HPV transmission but also of JoRRP [3]. Because prolonged labor

is more likely in young primiparous mothers [3,4,41], these results

support the clinical triad of risk as outlined by Kashima et al. [59]: a

ﬁrstborn delivered vaginally to a teenage mother. Results also

illustrated the indirect role of socioeconomic status in JoRRP

acquisition. HPV prevalence was higher among mothers living in

HPV-6 insecure socioeconomic conditions and these mothers tended to

49.06%

conceive at a younger age [47,52]. However, when affected

Fig. 3. HPV genotypes identiﬁed in patients with juvenile-onset recurrent children had timely access to health care, the clinical course of

respiratory papillomatosis. JoRRP was generally not inﬂuenced by socioeconomic status [47].

J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197 195

The protective role of cesarean delivery remains controversial The risk factors identiﬁed in this review are not readily

[3,4]. Given the high risk of vertical HPV transmission [60] and modiﬁable, be they age or host genetic and immunological factors.

JoRRP acquisition during a vaginal delivery [3,4], elective cesarean In the absence of modiﬁable risk factors, the best hope for reducing

section ought to be protective. Yet many of the study patients with the development and severity of JoRRP in the near future may lie in

JoRRP had been delivered by cesarean section [26,61]. The fact that reducing the prevalence of HPV through successful public

HPV is found in the amniotic ﬂuid [62], placenta, and cord blood immunization programs for girls and young women. In countries

[63,64] suggests the possibility of transplacental transmission like Australia, where HPV vaccination coverage attains 52–83% of

prior to delivery [65,66]. Although cesarean section was signiﬁ- the targeted population [71], a dramatic decrease in genital warts

cantly linked to increased JoRRP severity in two studies [13,48], has been observed in young women presenting at sexual health

this ﬁnding must be interpreted with caution. First, the association clinics [72]. Fewer than 1% of women under 21 years of age were

was derived from ﬁve or fewer, albeit severe, cases in each of the found to have genital warts in 2011 as compared to 11.5% in 2007

two studies [13,48]. In one study in particular [13], 4 of the 5 (before implementation of the vaccination program) [72]. Only

patients were infected with HPV-11. Severity may thus be 3.1% of women 21–30 years had genital warts in 2011, as compared

attributable to the presence of HPV-11, a commonly virulent to 12.5% in 2004 [72]. These women are now of childbearing age. It

genotype. Second, the medical indication was not speciﬁed: will be interesting to see whether prevention of HPV-6 and 11

compared to an elective cesarean section, a procedure undertaken genotypes by vaccination of future mothers will translate into

after obstetric complications such as prolonged labor would JoRRP’s eradication and/or reduction in the next generation. JoRRP

considerably increase the risk of transmission. Further studies are surveillance programs are currently in place in Australia and

needed to elucidate the role of cesarean section delivery and Canada.

obstetric choices in the acquisition and severity of JoRRP.

Young age at diagnosis and HPV-11 were the most important

5. Conclusions

risk factors for JoRRP severity. Of the more than 100 HPV genotypes

identiﬁed to date, HPV-6 [1] and HPV-11 [2,67,68] were

Many children are exposed to HPV, but few develop JoRRP.

consistently associated with JoRRP with HPV-11 showing the

Maternal genital condylomas during pregnancy and delivery

higher risk for severity [2,13,33,34,37,40,42–45]. Some authors

(vertical transmission) are the major risk factors for JoRRP

have considered age as a possible confounder [44], but this remains

acquisition, while the HPV-11 genotype and younger age at which

undetermined. With age and HPV-11 simultaneously associated

a child develops JoRRP lesions are important determinants of

with severity, one of these variables may act as an intermediate.

severity and prognosis. Genetic and immunological proﬁles play a

HPV-11 may be linked to severity through a higher likelihood of

role in the incidence and aggressiveness of JoRRP. Most of the

rapid proliferation that would necessarily appear at a younger age.

underlying factors for disease acquisition and clinical course are

HPV-11 might develop more easily in young children given the

not readily modiﬁable. Prevention of condylomas in women of

immaturity of immune response mechanisms [35,46,50,55,56,69].

childbearing age would therefore seem to be the most effective

Moreover, the possibility that JoRRP at a young age may be

prong of attack in reducing the burden of this life-threatening

diagnosed as a more severe form of the disease cannot be ruled out: disease.

the narrowness of the airways would require more repeated

surgeries to ensure breathing [44]. If age at diagnosis and HPV-11 Acknowledgements

are indeed prognostic factors, additional research is needed to

explain their relationship and the underlying mechanisms.

The authors are grateful to Danielle Buch, medical writer/editor

The large number of children exposed to HPV contrasts with the

at the Applied Clinical Research Unit of the CHU Sainte-Justine

rarity of JoRRP. Although contact with HPV is necessary for the

Research Center, for critical revision and substantive editing of the

development of JoRRP, it is not sufﬁcient in and of itself [36]. This

manuscript. HT received a salary award from the Fonds de la

review points to the importance of host genetic and immunological

recherche du Que´bec-Sante´.

factors in the development and clinical heterogeneity of JoRRP. Two

HLA class II genes, DQ [32] and DR [31,35,69], affected susceptibility

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