International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
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International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Review Article
Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: A systematic review Joseph Niyibizi a,b, Caroline Rodier a,c, Maggy Wassef b, Helen Trottier a,b,* a Department of Social and Preventive Medicine, University of Montreal, Public Health School 7101, Avenue du Parc, 3rd Floor, Montreal, Quebec H3N 1X9, Canada b Sainte Justine Hospital (CHU Sainte-Justine), 3175 Chemin de la Coˆte Ste-Catherine, Room A-830, Montreal, Quebec H3T 1C5, Canada c 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: Received 13 November 2013 Accepted 28 November 2013 Available online 6 December 2013
Objectives: Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few develop JoRRP and the clinical course of the disease varies from one child to another. This systematic 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 using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also searched Google Scholar and the reference lists of eligible studies. Our search was limited to original studies published in French or English between 1995 and July 2012 and to patients under 20 years of age. Results: Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32 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. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Human papillomavirus Recurrent respiratory papillomatosis Acquisition Severity Review
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Study screening, data collection and quality assessment 2.2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Description of included studies . . . . . . . . . . . . . . . . . . . . 3.1. Socioeconomic status . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Age at onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Birth history and parental HPV status . . . . . . . . . . . . . . . 3.4. Host genetic and immune response factors. . . . . . . . . . . 3.5. HPV genotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Affected sites and cell types . . . . . . . . . . . . . . . . . . . . . . . 3.7. Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.
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* Corresponding author at: Sainte Justine Hospital Research Center, Department of Social and Preventive Medicine, University of Montreal, 3175 Chemin de la Coˆte SteCatherine, 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). 0165-5876/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2013.11.036
J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
4. 5.
Discussion . . . . . . . Conclusions . . . . . . Acknowledgements References . . . . . . .
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1. Introduction
2.2. Study screening, data collection and quality assessment
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by the human papillomavirus (HPV). The wart-like growths in the upper airway are mostly due to HPV genotypes 6 and 11 [1,2]. Several observational studies have associated the JoRRP to maternal vaginal condylomas [3–6]. The incidence and prevalence of JoRRP vary from one country to another. The incidence has been estimated at 0.24–4.3 per 100,000 children, the prevalence at 1.11–2.59 per 100,000 children [7–10]. Although the disease is rare, morbidity is notoriously high. Recurrent proliferative lesions in the respiratory tract can spread to the trachea, bronchi or pulmonary parenchyma and compromise local function such as vocalization, breathing and swallowing [11– 15]. The course of the disease can vary from mild to severe. Some children experience minor symptoms with spontaneous and complete remission at puberty, while others require multiple surgeries throughout childhood [13] at great physical, emotional, and financial burden to the individual, the family, and society [16,17]. In rare yet severe progression, the disease may transform into malignant lesions [14], or in 1–3% of cases, may spread to the lower respiratory tract, entailing high mortality [11]. Individual studies have analyzed the risk factors associated with the occurrence and severity of JoRRP but findings have not been consistently replicable. Various published reviews have described the clinical manifestations and treatment options [12,16,18–26]. None, however, has focused systematically on etiology and prognosis. This systematic review, by summarizing recently published data, seeks to provide an up-to-date understanding of the risk factors for acquisition and severity.
Two of the authors (MW and CR) screened the identified titles after removal of duplicates. The same authors then screened the abstracts and selected which full-text manuscripts to retrieve for evaluation. Studies conforming to inclusion and exclusion criteria were then classified according to study objective: acquisition, severity of disease, or both. Each of these steps was performed independently and in duplicate. Any discrepancies were resolved by consensus, with referral to a third author (JN or HT) where necessary. We collected research data on demographics (country, year of publication, study population, age of participants), study design, and results of HPV genotyping. For all variables analyzed as potential determinants of JoRRP acquisition or severity, we noted relative risks (odds ratio or risk ratio) and confidence intervals (CI) when applicable and available. Where the authors provided only pvalues for statistical test results, we reported the p-value and direction of the association. We assessed each study for quality, according to levels of evidence determined by study design and potential bias [28]. Given the design variability and insufficient similarities in outcome measures of the included studies, we did not deem it appropriate to extend this review to a meta-analysis [29].
2. Methods 2.1. Search strategy We conducted a comprehensive systematic review of studies investigating risk factors associated with the acquisition and severity of JoRRP. We searched EMBASE, MEDLINE and EvidenceBased Medicine Reviews (EBMR) databases using the OvidSP interface with the following combinations of keywords and Boolean operators: (Laryn$ OR respiratory) AND (HPV OR papilloma or Papillomaviridae OR Papillomavirus Infections) AND (Disease* OR lesion* OR infection*) OR (Juvenile onset recurrent papillomatosis OR JORRP OR Juvenile laryngeal papilloma) AND (cause* OR sever* OR acquisition OR etiology OR Risk factor OR Risk Factors OR agress$). Given the use of new techniques for HPV genotyping since the late 1990s, we limited our search to studies published between 1995 and July 2012. We also limited it to studies investigating patients under 20 years of age, a cut-off proposed by Lindeberg et al. [27]. Only studies published in French or English were retained. We conducted an additional search using Google scholar, conference proceedings, and the reference lists of all eligible studies and any previous reviews on JoRRP, again eliminating studies of adults only (age 20). In all cases, we excluded studies analyzing tissues outside the respiratory tract or investigating less than 5 patients. Case reports, editorials and opinion pieces were not considered eligible.
3. Results 3.1. Description of included studies Our initial search identified 1362 citations. Of these, we retrieved 102 unduplicated full-text articles that conformed to eligibility criteria (Fig. 1). We found 14 additional studies from the reference lists. We retained 32 studies altogether, of which three [30–32] focused on risk factors for both acquisition and severity of disease. All 32 studies were observational and together reported on a total of 2287 JoRRP cases. Seven studies included both JoRRP and adult-onset recurrent respiratory papillomatosis (AoRRP) cases [30,31,33–36,38] (Table 1). Analyzed variables included sociodemographics, maternal pregnancy history, immune response characteristics and genetic profile. Sixteen studies examined HPV genotypes [2,7,13,33,35–46], particularly HPV-6. 3.2. Socioeconomic status Only 4 publications [13,17,44,47] examined the link between JoRRP and socioeconomic factors (Fig. 2). Medicaid coverage (a proxy for a low socioeconomic status in the US, as opposed to private insurance coverage) was significantly associated with JoRRP severity in a 10-year prospective study in Alabama, US [13], but not in a study of 603 cases in 22 tertiary pediatric care centers (also in the US) [17]. It was thus unclear whether or not the availability of medical health insurance played a role as a facilitating factor for timely access to care and better prognosis. Leung et al. confirmed that, in a universal health care setting (Canada), socioeconomic status was not significantly associated with JoRRP severity [47]. Similarly, in a multicentre study of 118 JoRRP cases in the US and Canada, neither maternal education level nor gross household income was indicative of disease progression
J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
188
1317 Titles identified through systematic search
45 Additional titles from other sources*
86 Duplicates removed 1276 Titles screened 992 Titles excluded† 284 Abstracts screened 182 Abstracts excluded† 102 Full-text articles assessed for eligibility 84 Full-text excluded†
14 Additional articles from reference lists 32 Studies included in the review
§
* Additional search in Google scholar and conference proceedings. † Studies recruiting adult patients only ( 20 years); analyzing tissues outside the respiratory tract; without a comparison group; with less than 5 patients; case reports; editorials; opinion pieces. § Studies focused on: disease acquisition (9), disease severity (20), or both (3). Fig. 1. Flow diagram of literature search.
[44]. None of the included studies revealed gender [3,11,13,17, 34,38,44,48] or ethnic [11,13,17,32] differences as regards JoRRP incidence or severity. 3.3. Age at onset A number of studies analyzed the effect of age on JoRRP severity [2,7,11,13,17,33,34,38,40,44,45,47–50] but few on JoRRP acquisition. In children with suspected sexual abuse, Sinclair et al. found that HPV lesions were more prevalent in the younger children [49]. Furthermore, young children, when affected, were more likely to develop laryngeal papillomatosis than anogenital or oral papillomas [49]. Younger age at onset was consistently linked to severity [7,11,13,17,38,40,44,45,47,48,50] and ranked among the most important risk factors for severity. In the 19 studies with data on age, JoRRP patients were a mean of 2–9.4 years old, median 3–5.5 years, at initial diagnosis (Table 1). One study identified a bimodal distribution for age at diagnosis: approximately 2 years and beginning of puberty [38]. Reeves et al. further reported that severity (as measured by frequency of surgical procedures) was a function of age at the time of first surgery rather than at the time of diagnosis [17]. Buchinsky et al. further noted a positive correlation between age at enrolment (current surgery) and the time interval elapsed from the previous surgery [44]. 3.4. Birth history and parental HPV status Mode of delivery, birth order, and maternal genital HPV status were associated with HPV transmission and JoRRP (Table 2). Two studies using national birth registries reported an association between genital condylomas during pregnancy, especially in young and primiparous women, and JoRRP [3,4] (Fig. 2). According
to a case–control study of 3033 Danish births, the risk of JoRRP 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 transmission by the possibility of newly acquired HPV infection [3,4]. The risk of JoRRP acquisition doubled when delivery lasted more than 10 h [3]. Furthermore, there were fewer cesarean births in JoRRP children than expected by US [4] and Danish [3] national statistics (Table 2). It is therefore unclear whether cesarean section is protective against JoRRP. For disease severity, Wiatrak et al. [13] and Silverberg et al. [48] both reported a possibly significant effect of cesarean birth toward greater severity (Table 3). Unlike genital condylomas, other parental HPV presentations seemed to be risk-free for JoRRP. After a 15-year follow-up, none of 45 children born to 30 patients (22 mothers and 8 female partners of male patients) with AoRRP had developed JoRRP [51]. 3.5. Host genetic and immune response factors Given the high prevalence of HPV carriage in women of childbearing age [52], many newborns are likely exposed to HPV. However, few of them develop JoRRP [7–10] and the clinical course of the disease varies from one child to another [13]. Thus, factors other than HPV, such as genetic polymorphisms and immune response, may be involved in JoRRP pathogenesis. Seven studies revealed a strong relationship between specific human leukocyte antigen (HLA) class II alleles and HPV infection, ranging from latent HPV infection to minor and severe JoRRP [30–32,35,53–55] (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, DQA*0102 and DQA*0101) were dominant in severe cases and their effect varied by ethnicity [31,32]. Caucasians were at higher 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 DQB1*050X allele conferred a preferentially increased risk of JoRRP acquisition to Caucasian as compared to African American children (OR 17.46, 95% CI: 0.88–345.68 for Caucasian; OR 4.62, 95% CI: 1.44–14.87 for African American). Moreover, the simultaneous presence of certain alleles increased the risk of developing severe JoRRP. Caucasians were at high risk of severe RRP if they expressed both DRB1*0301 and DQB1*0201 (OR 2.4, 95% CI: 1.3–4.4) [31]. However, other alleles seemed to be protective, such as DQB1*0402 in African Americans (OR 0.07, 95% CI: 0.004–1.22). DQA*0101/0104 was found more frequently in Caucasian children without JoRRP (OR 0.39, 95% CI: 0.15–0.99), while DBQ1*0602 was significantly less frequent in severe cases [31]. The role of killer cell immunoglobulin-like receptors (KIR) in the acquisition and progression of JoRRP was also investigated. While most KIR genotypes identified in healthy Caucasian children were not detected in JoRRP patients [30], the difference was not statistically significant [30]. However, the lack of KIR genes 3DS1 and 2DS1 was evident in severe JoRRP as compared to mildmoderate cases (Table 3) [30]. A significant relationship was also reported between the DRB1/DQB1 alleles and the absence of KIR 3DS1, 2DS1, 2DS5 receptors in JoRRP cases [30], indicating that certain allele combinations may be more deleterious than others (Table 2). In investigations on compromised immune response (inappropriate or ineffective) against HPV [35,46,50,55,56], a significant relationship was found between low CD4/CD8 ratio and JoRRP [55]. In addition, papilloma tissues from patients with severe JoRRP were more likely to reveal an absence of CD28 co-expression by CD8+ in tumor-infiltrating lymphocytes [53].
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Table 1 Study design and population characteristics. Author
Year, country
Study population (JoRRP cases)
Study design
HPV types (n)a
Age in years – mean SD; mean (min–max) or median (min–max)
Evidence levelb
Gabbott [38]
1997, Australia
46
Retrospective
HPV 11 (24) HPV 6 (19) Mixed HPV 6/11 (1) (Genotyped 44)
4.9 3.8
3b
Rimell [37]
1997, US
24
Retrospective
HPV 11 (6) HPV 6 (9) Mixed HPV 6/11 (4) (Genotyped 19)
2 (0–10)
3b
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 HPV HPV HPV HPV HPV
(0–17)
3b
Rabah [40]
2001, US
61
Retrospective
HPV 11 (32) HPV 6 (29)
3.5 (0–11)
2b
11 (18)c 6 (15)c 16 (39)c 33 (26)c 31 (13)c 39 (7)c
Snowden [50]
2001, US
15
Case–control
NR
73
3b
Gelder [35]
2003, UK
36
Case–control
HPV 6 (20)d HPV 11 (13)d (Genotyped 33)
4.3 (0–13)
3b
Gregoiree [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 d
Abramson [36]
2004, US
30
Prospective
HPV 6 (34) HPV 11 (27)d
NR
1b
Bonagurae [31]
2004, US
29
Case–control
NR
NR
3b
Wiatrak [13]
2004, US
73
Prospective
HPV 6 (31) HPV 11 (23) Mixed HPV 6/11 (4) (Genotyped 58)
3.8 (0–12)
1b
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)d HPV 11 (14)d (Genotyped 31)d
NR
1b
Draganov [42]
2006, Bulgaria
23
Cross-sectional
HPV 11 (13) Mixed HPV 6/11 (5) Mixed HPV 6/11 (3) (Genotyped 21)
7.8 (0.5–12)
3b
Gerein [51]
2006, Germany/ Russia
(28 exposed children 0 JoRRP)
Retro/prospective
NA
NA
4
Maloney [43]
2006, US
15
Prospective
HPV 11 (4) HPV 6 (4) Mixed HPV 6/11 (7)
Median 2.4 (0.5–5.7)
1b
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) HPV 6 (71)
Median 3 (0.1–13.1)
3b
Louw (a) [57]
2008, South Africa
10
Case–control
NR
Range (4–12)
3b
Louw (b) [58]
2008, South Africa
Case–control
NR
Shehata [45]
2008, US
43
Retrospective
HPV 11 (14) HPV 6 (29)
Range (0.4–10)
3b
Carvalho [33]
2009, France
24
Retrospective
HPV 11 (7) HPV 6 (12) (Genotyped 19)
5
3b
Kovalenko [46]
2009, Russia/Germany
40
Retrospective
HPV 11 (24) HPV 6 (14) (Genotyped 38)
Range (1.7–20)
2b
Bonagurae [30]
2010, US
26
Case–control
NR
NR
3b
Campisi [7]
2010, Canada
243
Retrospective
HPV 6 and/or 11 (74) (HPV-positive 77; genotyped 74)
Median 4.4 (0.1–14)
2b
3b
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190 Table 1 (Continued ) Author
Year, country
Study population (JoRRP cases)
Study design
HPV types (n)a
Age in years – mean SD; mean (min–max) or median (min–max)
Evidence levelb
Seedat [2]
2010, South Africa
19
Cross-sectional
HPV 11 (9) HPV 6 (9) (Genotyped 18)
5.3 (1.4–9.5)
3b
a
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 ( 0.05)
Socioeconomic 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: recurrent respiratory papillomatosis !
Fig. 2. Risk factors tested for association with juvenile-onset recurrent respiratory papillomatosis.
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191
Table 2 Risk factors for JoRRP acquisition. Author
Risk factors analyzed
Determinants of occurrence
Relative risk and significancea
Shah [4]
Maternal age
Mother < 20 years: 2.6 times more prevalent in JoRRP cases Firstborn: 1.6 times more prevalent in JoRRP cases Cesarean section: 4.6 times less prevalent in JoRRP cases
p < 0.002 p < 0.001 p < 0.0001
History of genital warts in pregnancy
RR 231.4 (95% CI: 135.3–395.9)
Cesarean section vs. vaginal Vaginal delivery duration > 10 h Maternal age < 30 years
RR 0.95 (95% CI: 0.34–2.66) RR 1.97 (95% CI: 1.11–3.84) RR 0.76 (95% CI: 0.34–1.54)
HLA class I/II alleles TNF
Presence of: DRB1*0301 DQB1*02 A1-B8-DR3DQ2 TNF2 TNF1
OR OR OR OR OR
4.30 (95% CI: 2.16–8.58) 2.46 (95% CI: 1.22–4.95) 4.04 (95% CI: 1.92–8.49) 2.9 (95% CI: 1.3–6.32) 0.26 (95% CI: 0.09–0.76)
HLA-DQA alleles HLA-DQB alleles Ethnicity
Presence of: DQB1*050X Caucasian African American DQA*0102 (Caucasian) DQB1*0402 (African American) DQA*0501/DQb1*0102 (Caucasian) DQB*0101/0104 (Caucasian)
OR OR OR OR OR OR
17.46 (95% CI: 0.88–345.68) 4.62 (95% CI: 1.44–14.87) 3.04 (95% CI: 1.21–7.64) 0.07 (95% CI: 0.004–1.22) 9.59 (95% CI: 2.32–39.68) 0.39 (95% CI: 0.15–0.99)
Abramson [36]
Tissue type
p > 0.05
Bonagura [31]
HLA alleles
No difference between tracheal and laryngeal latent/ subclinical HPV infection Presence of: DRB1*0102 (Caucasian) DRB1*0301 Caucasian African American DQB1*02 Caucasian African American DRB1*0301 and DQB1*0201 (Caucasian)
Birth order Mode of delivery Silverberg [3]
Gelder [35]
Gregoire [32]
Maternal genital warts during pregnancy Mode of delivery Vaginal delivery duration Maternal age
OR 7.0 (95% CI: 2.7–16.2) OR 1.9 (95% CI: 1.0–3.5) OR 3.0 (95% CI: 0.6–10.7) OR 1.8 (95% CI: 1.0–3.2) OR 3.3 (95% CI: 1.0–12.9) OR 2.4 (95% CI: 1.3–4.4)
Sinclair [49]
Age Anatomical localization
Younger age associated with HPV infection In younger children, laryngeal papillomatosis was more likely than anogenital or oral papillomas
p < 0.001 p = 0.026
‘Gerein [51]
RRP in parents (mothers and fathers)
NA
Stern [55]
Serum immunoglobulin levels
None of the exposed children was diagnosed with JoRRP (clinical nor histological examination) No significant difference in IgG or IgM levels between cases and controls More reduction of CD4/CD8 ratio in JoRRP More lymphocyte response to mitogen stimulation in JoRRP No significant difference in natural killer cell activity between cases and controls
CD4/CD8 ratio Lymphocyte response to mitogen stimulation Natural killer cell function
Louw (a) [57]
Fatty acid profiles
Louw (b) [58]
Fatty acid and micronutrient intake
Bonagura [30]
KIR and HLA gene combinations
Papilloma biopsies showed significantly more variation in several fatty acid profiles then normal biopsies Both cases and controls had excessive linoleic acid intakes JoRRP’s susceptible DRB1/DQB1 alleles were associated with absence of: KIR3DS1 KIR2DS1 KIR2DS5
p = 0.20 and p = 0.23 p = 0.02 p = 0.037 p = 0.125
p < 0.05 NR
p = 0.006 p = 0.003 p = 0.004
a 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 HPV-6 and HPV-11 were found in more than 95% of JoRRP cases. Other high-risk genotypes 16, 31, 33, 35 and 39 explained less than 5% of cases (Fig. 3). Ten studies [2,13,33,34,37,40,42–45] indicated a significantly increased risk of JoRRP severity associated with the HPV-11 genotype (Fig. 2). Three other studies, however, did not discern any association between HPV genotype and disease severity [32,38,39].
Four studies explored HPV genotype and age [2,33,40,44]. Two found an association between HPV-11 and disease severity; patients with HPV-11 were diagnosed at a younger age than those with HPV-6 [40,44]. HPV-11 was in fact more closely associated to younger age at diagnosis than to severity [44] (Table 3). The other two studies did not find any significant relationship between HPV-6, HPV-11, and age [2,33]. Two studies investigated the association between ethnicity and HPV genotype, but results were contradictory. Rabah et al.
J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
192 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 3 excisions per year
Age
Younger age at diagnosis ( 0.05
HPV genotype Race
HPV-11 associated with severity HPV-11 more common in AfricanAmerican patients than Caucasian Patients with HPV-11 manifested clinically at a younger age
p = 0.02 p = 0.001
p = 0.52 and p = 0.19
5 years of evolution 3 resections per year Rabah [40]
Snowden [50]
10 procedures 3 procedures within 12 months Spread of disease distal to the subglottis >4 surgical recurrences per year
Age
Age IL-2
Younger age associated with greater severity IL-2 and IL-2 receptor levels significantly lower in severe cases
IL-2 receptor Reeves [17]
Frequency of surgery
Age
Need for tracheotomy
p = 0.04
p = 0.002 p = 0.035 and p = 0.025
Younger age at diagnosis (0.05
Dragonov [42]
10 procedures 3 procedures/year Spread to subglottis (first 6 months)
HPV genotype
HPV-11 associated with severity
p = 0.0265
Maloney [43]
Frequency of surgical interventions
HPV genotype
HPV-11 or HPV-11 co-infection with HPV-6 were significantly associated with severity
p = 0.02
Median number of annual surgical procedures
Viral load
Neither HPV-6 nor HPV-11 viral loads were associated with markers of clinical severity
NR
PSF
Age
Younger age at diagnosis is predictive of worst anatomic score and PSF
p = 0.003 and p = 0.047
Derkay staging systemc
SES
No significant relationship between SES measures and disease severity
NR
Frequency of excision or debulking
Age
Younger age at diagnosis (< 24 months) associated with severity HPV-11 patients showed a more aggressive clinical course than HPV 6 patients HPV-6 patients with severe form showed higher levels of E6 and E7 oncogenes
p = 0.0002
Leung [47]
Shehata [45]
HPV genotype
Oncogene E6/E7 expression
Buchinsky [44]
>10 surgeries ever 4 surgeries per year Distal involvement
Age HPV genotype
Tracheostomy
Time from last to current surgery Gender; Race; Household income; Mother’s education level Carvalho [33]
Younger age associated with HPV-11 Younger age associated with severity HPV-11 associated with severity (total number of surgeries) HPV-11 associated with severity (distal involvement) HPV-11 associated with severity (tracheostomy) 20% of the variability in the interval since the last surgery was a function of the age at enrollment No association between gender; race; household income; mother’s education level and disease course
NR
p < 0.0002
p = 0.014 p = 0.01 OR 2.6 (95% CI: 1.0–7.5) OR 3.7 (95% CI: 1.4–9.8) OR 3.4 (95% CI: 0.84–16) p = 4 10
NR
Frequency of endoscopies
HPV genotype
Higher frequency of endoscopies in HPV-11 vs. HPV-6
p = 0.007
Maximum number of endoscopies/year
Age
No significant difference between HPV6 and HPV-11 for age, Derkay score or remission time
NR
Dendritic cell density
Increase of CD83+ associated with severity No statistically significant association between CD1a+ count and severity
p = 0.005
Younger age at diagnosis associated with severity
p < 0.001
Derkay staging systemc Remission time Kovalenko [46]
Campisi [7]
Number of surgeries
Maximum annual rate Peak anatomical score Total number of surgeries
Age
p = 0.07
7
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194 Table 3 (Continued ) Author
Definition of severity
Risk factors analyzed
Determinants of severity
Relative risk and significancea
Seedat [2]
Derkay staging systemc
Age
No significant difference in age at diagnosis between patients with HPV-6 and HPV-11
p = 0.47
Procedures/year
HPV genotype
HPV-11 was associated with more procedures
p = 0.05
Number of anatomical sites
KIR genes
Patients lacking activating KIR genes 3DS1 and 2DS1 were more comparable to severe than to mild-moderate cases
p = 0.019
Luminal obstruction Anatomical surface
KIR-HLA combinations
Total procedures
Bonagura [30]
a 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’’. b Early childhood infection: history of early (
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Review Article
Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: A systematic review Joseph Niyibizi a,b, Caroline Rodier a,c, Maggy Wassef b, Helen Trottier a,b,* a Department of Social and Preventive Medicine, University of Montreal, Public Health School 7101, Avenue du Parc, 3rd Floor, Montreal, Quebec H3N 1X9, Canada b Sainte Justine Hospital (CHU Sainte-Justine), 3175 Chemin de la Coˆte Ste-Catherine, Room A-830, Montreal, Quebec H3T 1C5, Canada c 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: Received 13 November 2013 Accepted 28 November 2013 Available online 6 December 2013
Objectives: Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few develop JoRRP and the clinical course of the disease varies from one child to another. This systematic 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 using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also searched Google Scholar and the reference lists of eligible studies. Our search was limited to original studies published in French or English between 1995 and July 2012 and to patients under 20 years of age. Results: Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32 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. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Human papillomavirus Recurrent respiratory papillomatosis Acquisition Severity Review
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Study screening, data collection and quality assessment 2.2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Description of included studies . . . . . . . . . . . . . . . . . . . . 3.1. Socioeconomic status . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Age at onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Birth history and parental HPV status . . . . . . . . . . . . . . . 3.4. Host genetic and immune response factors. . . . . . . . . . . 3.5. HPV genotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Affected sites and cell types . . . . . . . . . . . . . . . . . . . . . . . 3.7. Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8.
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* Corresponding author at: Sainte Justine Hospital Research Center, Department of Social and Preventive Medicine, University of Montreal, 3175 Chemin de la Coˆte SteCatherine, 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). 0165-5876/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2013.11.036
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Discussion . . . . . . . Conclusions . . . . . . Acknowledgements References . . . . . . .
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194 195 195 195
1. Introduction
2.2. Study screening, data collection and quality assessment
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by the human papillomavirus (HPV). The wart-like growths in the upper airway are mostly due to HPV genotypes 6 and 11 [1,2]. Several observational studies have associated the JoRRP to maternal vaginal condylomas [3–6]. The incidence and prevalence of JoRRP vary from one country to another. The incidence has been estimated at 0.24–4.3 per 100,000 children, the prevalence at 1.11–2.59 per 100,000 children [7–10]. Although the disease is rare, morbidity is notoriously high. Recurrent proliferative lesions in the respiratory tract can spread to the trachea, bronchi or pulmonary parenchyma and compromise local function such as vocalization, breathing and swallowing [11– 15]. The course of the disease can vary from mild to severe. Some children experience minor symptoms with spontaneous and complete remission at puberty, while others require multiple surgeries throughout childhood [13] at great physical, emotional, and financial burden to the individual, the family, and society [16,17]. In rare yet severe progression, the disease may transform into malignant lesions [14], or in 1–3% of cases, may spread to the lower respiratory tract, entailing high mortality [11]. Individual studies have analyzed the risk factors associated with the occurrence and severity of JoRRP but findings have not been consistently replicable. Various published reviews have described the clinical manifestations and treatment options [12,16,18–26]. None, however, has focused systematically on etiology and prognosis. This systematic review, by summarizing recently published data, seeks to provide an up-to-date understanding of the risk factors for acquisition and severity.
Two of the authors (MW and CR) screened the identified titles after removal of duplicates. The same authors then screened the abstracts and selected which full-text manuscripts to retrieve for evaluation. Studies conforming to inclusion and exclusion criteria were then classified according to study objective: acquisition, severity of disease, or both. Each of these steps was performed independently and in duplicate. Any discrepancies were resolved by consensus, with referral to a third author (JN or HT) where necessary. We collected research data on demographics (country, year of publication, study population, age of participants), study design, and results of HPV genotyping. For all variables analyzed as potential determinants of JoRRP acquisition or severity, we noted relative risks (odds ratio or risk ratio) and confidence intervals (CI) when applicable and available. Where the authors provided only pvalues for statistical test results, we reported the p-value and direction of the association. We assessed each study for quality, according to levels of evidence determined by study design and potential bias [28]. Given the design variability and insufficient similarities in outcome measures of the included studies, we did not deem it appropriate to extend this review to a meta-analysis [29].
2. Methods 2.1. Search strategy We conducted a comprehensive systematic review of studies investigating risk factors associated with the acquisition and severity of JoRRP. We searched EMBASE, MEDLINE and EvidenceBased Medicine Reviews (EBMR) databases using the OvidSP interface with the following combinations of keywords and Boolean operators: (Laryn$ OR respiratory) AND (HPV OR papilloma or Papillomaviridae OR Papillomavirus Infections) AND (Disease* OR lesion* OR infection*) OR (Juvenile onset recurrent papillomatosis OR JORRP OR Juvenile laryngeal papilloma) AND (cause* OR sever* OR acquisition OR etiology OR Risk factor OR Risk Factors OR agress$). Given the use of new techniques for HPV genotyping since the late 1990s, we limited our search to studies published between 1995 and July 2012. We also limited it to studies investigating patients under 20 years of age, a cut-off proposed by Lindeberg et al. [27]. Only studies published in French or English were retained. We conducted an additional search using Google scholar, conference proceedings, and the reference lists of all eligible studies and any previous reviews on JoRRP, again eliminating studies of adults only (age 20). In all cases, we excluded studies analyzing tissues outside the respiratory tract or investigating less than 5 patients. Case reports, editorials and opinion pieces were not considered eligible.
3. Results 3.1. Description of included studies Our initial search identified 1362 citations. Of these, we retrieved 102 unduplicated full-text articles that conformed to eligibility criteria (Fig. 1). We found 14 additional studies from the reference lists. We retained 32 studies altogether, of which three [30–32] focused on risk factors for both acquisition and severity of disease. All 32 studies were observational and together reported on a total of 2287 JoRRP cases. Seven studies included both JoRRP and adult-onset recurrent respiratory papillomatosis (AoRRP) cases [30,31,33–36,38] (Table 1). Analyzed variables included sociodemographics, maternal pregnancy history, immune response characteristics and genetic profile. Sixteen studies examined HPV genotypes [2,7,13,33,35–46], particularly HPV-6. 3.2. Socioeconomic status Only 4 publications [13,17,44,47] examined the link between JoRRP and socioeconomic factors (Fig. 2). Medicaid coverage (a proxy for a low socioeconomic status in the US, as opposed to private insurance coverage) was significantly associated with JoRRP severity in a 10-year prospective study in Alabama, US [13], but not in a study of 603 cases in 22 tertiary pediatric care centers (also in the US) [17]. It was thus unclear whether or not the availability of medical health insurance played a role as a facilitating factor for timely access to care and better prognosis. Leung et al. confirmed that, in a universal health care setting (Canada), socioeconomic status was not significantly associated with JoRRP severity [47]. Similarly, in a multicentre study of 118 JoRRP cases in the US and Canada, neither maternal education level nor gross household income was indicative of disease progression
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188
1317 Titles identified through systematic search
45 Additional titles from other sources*
86 Duplicates removed 1276 Titles screened 992 Titles excluded† 284 Abstracts screened 182 Abstracts excluded† 102 Full-text articles assessed for eligibility 84 Full-text excluded†
14 Additional articles from reference lists 32 Studies included in the review
§
* Additional search in Google scholar and conference proceedings. † Studies recruiting adult patients only ( 20 years); analyzing tissues outside the respiratory tract; without a comparison group; with less than 5 patients; case reports; editorials; opinion pieces. § Studies focused on: disease acquisition (9), disease severity (20), or both (3). Fig. 1. Flow diagram of literature search.
[44]. None of the included studies revealed gender [3,11,13,17, 34,38,44,48] or ethnic [11,13,17,32] differences as regards JoRRP incidence or severity. 3.3. Age at onset A number of studies analyzed the effect of age on JoRRP severity [2,7,11,13,17,33,34,38,40,44,45,47–50] but few on JoRRP acquisition. In children with suspected sexual abuse, Sinclair et al. found that HPV lesions were more prevalent in the younger children [49]. Furthermore, young children, when affected, were more likely to develop laryngeal papillomatosis than anogenital or oral papillomas [49]. Younger age at onset was consistently linked to severity [7,11,13,17,38,40,44,45,47,48,50] and ranked among the most important risk factors for severity. In the 19 studies with data on age, JoRRP patients were a mean of 2–9.4 years old, median 3–5.5 years, at initial diagnosis (Table 1). One study identified a bimodal distribution for age at diagnosis: approximately 2 years and beginning of puberty [38]. Reeves et al. further reported that severity (as measured by frequency of surgical procedures) was a function of age at the time of first surgery rather than at the time of diagnosis [17]. Buchinsky et al. further noted a positive correlation between age at enrolment (current surgery) and the time interval elapsed from the previous surgery [44]. 3.4. Birth history and parental HPV status Mode of delivery, birth order, and maternal genital HPV status were associated with HPV transmission and JoRRP (Table 2). Two studies using national birth registries reported an association between genital condylomas during pregnancy, especially in young and primiparous women, and JoRRP [3,4] (Fig. 2). According
to a case–control study of 3033 Danish births, the risk of JoRRP 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 transmission by the possibility of newly acquired HPV infection [3,4]. The risk of JoRRP acquisition doubled when delivery lasted more than 10 h [3]. Furthermore, there were fewer cesarean births in JoRRP children than expected by US [4] and Danish [3] national statistics (Table 2). It is therefore unclear whether cesarean section is protective against JoRRP. For disease severity, Wiatrak et al. [13] and Silverberg et al. [48] both reported a possibly significant effect of cesarean birth toward greater severity (Table 3). Unlike genital condylomas, other parental HPV presentations seemed to be risk-free for JoRRP. After a 15-year follow-up, none of 45 children born to 30 patients (22 mothers and 8 female partners of male patients) with AoRRP had developed JoRRP [51]. 3.5. Host genetic and immune response factors Given the high prevalence of HPV carriage in women of childbearing age [52], many newborns are likely exposed to HPV. However, few of them develop JoRRP [7–10] and the clinical course of the disease varies from one child to another [13]. Thus, factors other than HPV, such as genetic polymorphisms and immune response, may be involved in JoRRP pathogenesis. Seven studies revealed a strong relationship between specific human leukocyte antigen (HLA) class II alleles and HPV infection, ranging from latent HPV infection to minor and severe JoRRP [30–32,35,53–55] (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, DQA*0102 and DQA*0101) were dominant in severe cases and their effect varied by ethnicity [31,32]. Caucasians were at higher 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 DQB1*050X allele conferred a preferentially increased risk of JoRRP acquisition to Caucasian as compared to African American children (OR 17.46, 95% CI: 0.88–345.68 for Caucasian; OR 4.62, 95% CI: 1.44–14.87 for African American). Moreover, the simultaneous presence of certain alleles increased the risk of developing severe JoRRP. Caucasians were at high risk of severe RRP if they expressed both DRB1*0301 and DQB1*0201 (OR 2.4, 95% CI: 1.3–4.4) [31]. However, other alleles seemed to be protective, such as DQB1*0402 in African Americans (OR 0.07, 95% CI: 0.004–1.22). DQA*0101/0104 was found more frequently in Caucasian children without JoRRP (OR 0.39, 95% CI: 0.15–0.99), while DBQ1*0602 was significantly less frequent in severe cases [31]. The role of killer cell immunoglobulin-like receptors (KIR) in the acquisition and progression of JoRRP was also investigated. While most KIR genotypes identified in healthy Caucasian children were not detected in JoRRP patients [30], the difference was not statistically significant [30]. However, the lack of KIR genes 3DS1 and 2DS1 was evident in severe JoRRP as compared to mildmoderate cases (Table 3) [30]. A significant relationship was also reported between the DRB1/DQB1 alleles and the absence of KIR 3DS1, 2DS1, 2DS5 receptors in JoRRP cases [30], indicating that certain allele combinations may be more deleterious than others (Table 2). In investigations on compromised immune response (inappropriate or ineffective) against HPV [35,46,50,55,56], a significant relationship was found between low CD4/CD8 ratio and JoRRP [55]. In addition, papilloma tissues from patients with severe JoRRP were more likely to reveal an absence of CD28 co-expression by CD8+ in tumor-infiltrating lymphocytes [53].
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189
Table 1 Study design and population characteristics. Author
Year, country
Study population (JoRRP cases)
Study design
HPV types (n)a
Age in years – mean SD; mean (min–max) or median (min–max)
Evidence levelb
Gabbott [38]
1997, Australia
46
Retrospective
HPV 11 (24) HPV 6 (19) Mixed HPV 6/11 (1) (Genotyped 44)
4.9 3.8
3b
Rimell [37]
1997, US
24
Retrospective
HPV 11 (6) HPV 6 (9) Mixed HPV 6/11 (4) (Genotyped 19)
2 (0–10)
3b
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 HPV HPV HPV HPV HPV
(0–17)
3b
Rabah [40]
2001, US
61
Retrospective
HPV 11 (32) HPV 6 (29)
3.5 (0–11)
2b
11 (18)c 6 (15)c 16 (39)c 33 (26)c 31 (13)c 39 (7)c
Snowden [50]
2001, US
15
Case–control
NR
73
3b
Gelder [35]
2003, UK
36
Case–control
HPV 6 (20)d HPV 11 (13)d (Genotyped 33)
4.3 (0–13)
3b
Gregoiree [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 d
Abramson [36]
2004, US
30
Prospective
HPV 6 (34) HPV 11 (27)d
NR
1b
Bonagurae [31]
2004, US
29
Case–control
NR
NR
3b
Wiatrak [13]
2004, US
73
Prospective
HPV 6 (31) HPV 11 (23) Mixed HPV 6/11 (4) (Genotyped 58)
3.8 (0–12)
1b
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)d HPV 11 (14)d (Genotyped 31)d
NR
1b
Draganov [42]
2006, Bulgaria
23
Cross-sectional
HPV 11 (13) Mixed HPV 6/11 (5) Mixed HPV 6/11 (3) (Genotyped 21)
7.8 (0.5–12)
3b
Gerein [51]
2006, Germany/ Russia
(28 exposed children 0 JoRRP)
Retro/prospective
NA
NA
4
Maloney [43]
2006, US
15
Prospective
HPV 11 (4) HPV 6 (4) Mixed HPV 6/11 (7)
Median 2.4 (0.5–5.7)
1b
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) HPV 6 (71)
Median 3 (0.1–13.1)
3b
Louw (a) [57]
2008, South Africa
10
Case–control
NR
Range (4–12)
3b
Louw (b) [58]
2008, South Africa
Case–control
NR
Shehata [45]
2008, US
43
Retrospective
HPV 11 (14) HPV 6 (29)
Range (0.4–10)
3b
Carvalho [33]
2009, France
24
Retrospective
HPV 11 (7) HPV 6 (12) (Genotyped 19)
5
3b
Kovalenko [46]
2009, Russia/Germany
40
Retrospective
HPV 11 (24) HPV 6 (14) (Genotyped 38)
Range (1.7–20)
2b
Bonagurae [30]
2010, US
26
Case–control
NR
NR
3b
Campisi [7]
2010, Canada
243
Retrospective
HPV 6 and/or 11 (74) (HPV-positive 77; genotyped 74)
Median 4.4 (0.1–14)
2b
3b
J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
190 Table 1 (Continued ) Author
Year, country
Study population (JoRRP cases)
Study design
HPV types (n)a
Age in years – mean SD; mean (min–max) or median (min–max)
Evidence levelb
Seedat [2]
2010, South Africa
19
Cross-sectional
HPV 11 (9) HPV 6 (9) (Genotyped 18)
5.3 (1.4–9.5)
3b
a
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 ( 0.05)
Socioeconomic 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: recurrent 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 significancea
Shah [4]
Maternal age
Mother < 20 years: 2.6 times more prevalent in JoRRP cases Firstborn: 1.6 times more prevalent in JoRRP cases Cesarean section: 4.6 times less prevalent in JoRRP cases
p < 0.002 p < 0.001 p < 0.0001
History of genital warts in pregnancy
RR 231.4 (95% CI: 135.3–395.9)
Cesarean section vs. vaginal Vaginal delivery duration > 10 h Maternal age < 30 years
RR 0.95 (95% CI: 0.34–2.66) RR 1.97 (95% CI: 1.11–3.84) RR 0.76 (95% CI: 0.34–1.54)
HLA class I/II alleles TNF
Presence of: DRB1*0301 DQB1*02 A1-B8-DR3DQ2 TNF2 TNF1
OR OR OR OR OR
4.30 (95% CI: 2.16–8.58) 2.46 (95% CI: 1.22–4.95) 4.04 (95% CI: 1.92–8.49) 2.9 (95% CI: 1.3–6.32) 0.26 (95% CI: 0.09–0.76)
HLA-DQA alleles HLA-DQB alleles Ethnicity
Presence of: DQB1*050X Caucasian African American DQA*0102 (Caucasian) DQB1*0402 (African American) DQA*0501/DQb1*0102 (Caucasian) DQB*0101/0104 (Caucasian)
OR OR OR OR OR OR
17.46 (95% CI: 0.88–345.68) 4.62 (95% CI: 1.44–14.87) 3.04 (95% CI: 1.21–7.64) 0.07 (95% CI: 0.004–1.22) 9.59 (95% CI: 2.32–39.68) 0.39 (95% CI: 0.15–0.99)
Abramson [36]
Tissue type
p > 0.05
Bonagura [31]
HLA alleles
No difference between tracheal and laryngeal latent/ subclinical HPV infection Presence of: DRB1*0102 (Caucasian) DRB1*0301 Caucasian African American DQB1*02 Caucasian African American DRB1*0301 and DQB1*0201 (Caucasian)
Birth order Mode of delivery Silverberg [3]
Gelder [35]
Gregoire [32]
Maternal genital warts during pregnancy Mode of delivery Vaginal delivery duration Maternal age
OR 7.0 (95% CI: 2.7–16.2) OR 1.9 (95% CI: 1.0–3.5) OR 3.0 (95% CI: 0.6–10.7) OR 1.8 (95% CI: 1.0–3.2) OR 3.3 (95% CI: 1.0–12.9) OR 2.4 (95% CI: 1.3–4.4)
Sinclair [49]
Age Anatomical localization
Younger age associated with HPV infection In younger children, laryngeal papillomatosis was more likely than anogenital or oral papillomas
p < 0.001 p = 0.026
‘Gerein [51]
RRP in parents (mothers and fathers)
NA
Stern [55]
Serum immunoglobulin levels
None of the exposed children was diagnosed with JoRRP (clinical nor histological examination) No significant difference in IgG or IgM levels between cases and controls More reduction of CD4/CD8 ratio in JoRRP More lymphocyte response to mitogen stimulation in JoRRP No significant difference in natural killer cell activity between cases and controls
CD4/CD8 ratio Lymphocyte response to mitogen stimulation Natural killer cell function
Louw (a) [57]
Fatty acid profiles
Louw (b) [58]
Fatty acid and micronutrient intake
Bonagura [30]
KIR and HLA gene combinations
Papilloma biopsies showed significantly more variation in several fatty acid profiles then normal biopsies Both cases and controls had excessive linoleic acid intakes JoRRP’s susceptible DRB1/DQB1 alleles were associated with absence of: KIR3DS1 KIR2DS1 KIR2DS5
p = 0.20 and p = 0.23 p = 0.02 p = 0.037 p = 0.125
p < 0.05 NR
p = 0.006 p = 0.003 p = 0.004
a 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 HPV-6 and HPV-11 were found in more than 95% of JoRRP cases. Other high-risk genotypes 16, 31, 33, 35 and 39 explained less than 5% of cases (Fig. 3). Ten studies [2,13,33,34,37,40,42–45] indicated a significantly increased risk of JoRRP severity associated with the HPV-11 genotype (Fig. 2). Three other studies, however, did not discern any association between HPV genotype and disease severity [32,38,39].
Four studies explored HPV genotype and age [2,33,40,44]. Two found an association between HPV-11 and disease severity; patients with HPV-11 were diagnosed at a younger age than those with HPV-6 [40,44]. HPV-11 was in fact more closely associated to younger age at diagnosis than to severity [44] (Table 3). The other two studies did not find any significant relationship between HPV-6, HPV-11, and age [2,33]. Two studies investigated the association between ethnicity and HPV genotype, but results were contradictory. Rabah et al.
J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
192 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 3 excisions per year
Age
Younger age at diagnosis ( 0.05
HPV genotype Race
HPV-11 associated with severity HPV-11 more common in AfricanAmerican patients than Caucasian Patients with HPV-11 manifested clinically at a younger age
p = 0.02 p = 0.001
p = 0.52 and p = 0.19
5 years of evolution 3 resections per year Rabah [40]
Snowden [50]
10 procedures 3 procedures within 12 months Spread of disease distal to the subglottis >4 surgical recurrences per year
Age
Age IL-2
Younger age associated with greater severity IL-2 and IL-2 receptor levels significantly lower in severe cases
IL-2 receptor Reeves [17]
Frequency of surgery
Age
Need for tracheotomy
p = 0.04
p = 0.002 p = 0.035 and p = 0.025
Younger age at diagnosis (0.05
Dragonov [42]
10 procedures 3 procedures/year Spread to subglottis (first 6 months)
HPV genotype
HPV-11 associated with severity
p = 0.0265
Maloney [43]
Frequency of surgical interventions
HPV genotype
HPV-11 or HPV-11 co-infection with HPV-6 were significantly associated with severity
p = 0.02
Median number of annual surgical procedures
Viral load
Neither HPV-6 nor HPV-11 viral loads were associated with markers of clinical severity
NR
PSF
Age
Younger age at diagnosis is predictive of worst anatomic score and PSF
p = 0.003 and p = 0.047
Derkay staging systemc
SES
No significant relationship between SES measures and disease severity
NR
Frequency of excision or debulking
Age
Younger age at diagnosis (< 24 months) associated with severity HPV-11 patients showed a more aggressive clinical course than HPV 6 patients HPV-6 patients with severe form showed higher levels of E6 and E7 oncogenes
p = 0.0002
Leung [47]
Shehata [45]
HPV genotype
Oncogene E6/E7 expression
Buchinsky [44]
>10 surgeries ever 4 surgeries per year Distal involvement
Age HPV genotype
Tracheostomy
Time from last to current surgery Gender; Race; Household income; Mother’s education level Carvalho [33]
Younger age associated with HPV-11 Younger age associated with severity HPV-11 associated with severity (total number of surgeries) HPV-11 associated with severity (distal involvement) HPV-11 associated with severity (tracheostomy) 20% of the variability in the interval since the last surgery was a function of the age at enrollment No association between gender; race; household income; mother’s education level and disease course
NR
p < 0.0002
p = 0.014 p = 0.01 OR 2.6 (95% CI: 1.0–7.5) OR 3.7 (95% CI: 1.4–9.8) OR 3.4 (95% CI: 0.84–16) p = 4 10
NR
Frequency of endoscopies
HPV genotype
Higher frequency of endoscopies in HPV-11 vs. HPV-6
p = 0.007
Maximum number of endoscopies/year
Age
No significant difference between HPV6 and HPV-11 for age, Derkay score or remission time
NR
Dendritic cell density
Increase of CD83+ associated with severity No statistically significant association between CD1a+ count and severity
p = 0.005
Younger age at diagnosis associated with severity
p < 0.001
Derkay staging systemc Remission time Kovalenko [46]
Campisi [7]
Number of surgeries
Maximum annual rate Peak anatomical score Total number of surgeries
Age
p = 0.07
7
J. Niyibizi et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 186–197
194 Table 3 (Continued ) Author
Definition of severity
Risk factors analyzed
Determinants of severity
Relative risk and significancea
Seedat [2]
Derkay staging systemc
Age
No significant difference in age at diagnosis between patients with HPV-6 and HPV-11
p = 0.47
Procedures/year
HPV genotype
HPV-11 was associated with more procedures
p = 0.05
Number of anatomical sites
KIR genes
Patients lacking activating KIR genes 3DS1 and 2DS1 were more comparable to severe than to mild-moderate cases
p = 0.019
Luminal obstruction Anatomical surface
KIR-HLA combinations
Total procedures
Bonagura [30]
a 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’’. b Early childhood infection: history of early (
