Prevalence of human papilloma virus types and their influence on the course of the disease in children suffering from recurrent respiratory papillomatosis

The type of human papilloma virus (HPV) was determined in 26 children aged between 1 year 10 months to 15 years 5 months suffering from recurrent respiratory papillomatosis (RRP). Polymerase chain reaction identified DNA of HPV type 6, 11, 16 and 18. HPV DNA was detected in all the patients including fifteen patients infected with HPV type 11; seven patients infected with HPV type 6; four children infected with HPV type 6 and 11. Types 16 and 18 of HPV were not detected. The analysis of RRP course has found that laryngeal papillomatosis runs a more aggressive course in cases with HPV type 11 infection than in those with HPV type 6.     

人乳头瘤病毒型别与儿童复发性呼吸道乳头状瘤临床病程的相关性

目的　研究人乳头瘤状病毒（human papilloma virus,HPV）型别对儿童复发性呼吸道乳头瘤（juvenile onset recurrent respiratory papillomatosis,JORRP）临床病程的影响。方法　收集38例JORRP患儿新鲜瘤体标本,采用流式荧光杂交法检测HPV型别。将患儿分为HPV6阳性组和HPV11阳性组。量化评分其201例手术,对发病年龄、并发症、临床症状、手术次数、乳头瘤侵袭范围程度等方面进行统计学分析。结果　55.2%（21/38）JORRP患儿感染HPV6,36.8%（14/38）感染HPV11,7.9%（3/38）HPV6/11均阴性。两组患儿在发病年龄、术前临床症状评分、乳头瘤解剖亚区数、Derkay、Dikkers评分方面均有统计学差异。结论　感染HPV11发病年龄更小,侵犯范围更广病灶性状更严重,临床症状更严重,致JORRP临床病程更严重。     

小儿复发性呼吸道乳头状瘤治疗进展

小儿复发性呼吸道乳头状瘤是指发生在呼吸道上下的乳头状瘤病,是一种高度复发性和侵袭性的疾病。患儿可出现声音嘶哑症状,严重时有呼吸困难表现。乳头状瘤疾病常为HPV6和HPV11感染,可由于分娩时患儿经母亲产道感染乳头状瘤病毒所致。手术是治疗的主要的方法,但不能根治,往往因为多次手术给患儿和家属带来巨大的痛苦,故需要其他药物来辅助治疗。本文综述概括了目前各种治疗小儿乳头状瘤的方法。     

Detection of human papillomavirus type 57 in a case of inverted nasal papillomatosis in Japan

Human papillomavirus (HPV) type 57 DNA was detected in recurrent nasal inverted papillomatosis, in a 60-year-old Japanese male, using Southern blot hybridization. HPV types 6, 11, 16 and 18 were not detectable in the papilloma. Previous studies have shown that HPV types 6, 11, 16 and 18 were mainly found in nasal papillomatosis in other laboratories but the actual detection rate of virus was low. We speculate that this low detection rate may be due to the lack of a method for detecting HPV type 57.     

Lower airway papillomatosis in children

Laryngeal papilloma in children is a frequent disease caused by human papilloma virus (HPV) type 6 or type 11. This disease has a tendency to recur and the changes are histologically benign. In some cases papilloma may affect the lower levels of the respiratory tract. In this study, among 90 patients treated for laryngeal papillomatosis, in four children papilloma of trachea, bronchi and lung tissue were detected in endoscopic and radiological examination. This constitutes 4.4% of all patients. Compact nodules and acquired cysts between 5 and 50 mm long were found in chest X-rays and in computerised tomography. These cysts appeared from 4 to 8 years after establishing a diagnosis of laryngeal papilloma, and 1 year after recognising papilloma in the trachea. In all four children the presence of nodules and cysts in the lungs was preceded by recurrent pneumonia, emphysema or atelectasis of the lungs. All children with laryngeal papillomatosis should have a chest X-ray. Detection of acquired cyst-like changes in lung tissue in children with laryngeal papillomatosis is a warning of future papilloma in the trachea and bronchi, with involvement of lung tissue. In differential diagnosis of these changes in the lungs we should take into consideration the presence of papilloma in the bronchi. A prognosis of papillomatosis in the lower airways in children is always serious.     

Risk factors for aggressive recurrent respiratory papillomatosis in Chinese juvenile patients

Abstract

Background: Aggressive juvenile-onset recurrent respiratory papillomatosis (JORRP) threatens patient lives if not receives immediate surgical intervene. Even with surgical intervene, complete remission of this disease is not approachable. Therefore, understanding the factors relevant to disease severity and prognosis will do help to the treatment strategy and health management of this disease.

Objective: This study aimed to explore the clinic, laboratory and socioeconomic characteristics of patients and evaluate the risk factors for aggressive JORRP.

Methods: The information of clinical and socioeconomic status of the patients was reviewed and its association with disease severity was analyzed. Papilloma from JORRP patients undergone surgeries was used to determine HPV subtypes by real-time PCR. The profiles of mRNA expression in the papilloma were assessed using microarray.

Results: Age at diagnosis and socioeconomic status were shown to associate with the severity of JORRP. There was no differential severity considering different HPV subtype. The mRNA expression of nucleotide binding oligomerization domain receptor protein 3 (NLRP3) and Gasdermin B (GSDMB) was reduced in papillomas.

Conclusions: A younger age at diagnosis and low socioeconomic status were associated with the severity of JORRP. mRNA expression of NLRP3 and GSDMB in the papillomas of JORRP patients was significantly reduced.

• Abbreviation: JORRP: Juvenile-onset recurrent respiratory papillomatosis; RRP: Recurrent respiratory papillomatosis; OSAS: Obstructive sleep apnea syndrome; NLRP3: Nucleotide binding oligomerization domain receptor protein 3; GSDMB: Gasdermin B.

     

Is cidofovir a useful adjunctive therapy for recurrent respiratory papillomatosis in children?

OBJECTIVE: To assess the usefulness of cidofovir in treating recurrent respiratory papillomatosis in children. Cidofovir is an acyclic nucleoside phosphonate that has been reported to be effective in the treatment of respiratory papillomatosis in several small series of patients. METHODS: A prospective study was conducted in 11 children (mean, 2.1 years; range, 0.5-3 years at diagnosis) with recurrent respiratory papillomatosis who at the start of the study were requiring debridement of papillomas at least every 6 weeks. After microlaryngoscopy with powered microdebridement of papillomas patients received intralesional injection of cidofovir (5mg/ml). The severity of papillomatosis was rated at each visit using a standardized papilloma severity scoring system. The success of therapy was measured by the trend in the patient's papilloma severity scores before and after cidofovir therapy and by whether the frequency of operative interventions decreased in the period after treatment began. RESULTS: Three patients had impressive improvements in severity scores and a decrease in the frequency of required operative interventions after cidofovir, two patients had a partial response, and for six patients cidofovir was considered ineffective. CONCLUSIONS: Intralesional cidofovir did not decrease the severity or frequency of operative intervention for recurrent respiratory papillomas in the majority of children in this study. The drug did improve papillomatosis in the minority of patients without causing notable morbidity. A large multi-institutional controlled study is needed to better assess the efficacy of this treatment.     

Tracheal, bronchial, and pulmonary papillomatosis in children

OBJECTIVES: To compare the clinical course of tracheal, bronchial, and pulmonary papillomatosis with clinical course of laryngeal papillomatosis in children. STUDY DESIGN: The records of the 448 children with recurrent respiratory papillomatosis treated in St. Vladimir Moscow Children's Hospital between 1988 and 2003 were reviewed. In all cases, the diagnosis was confirmed histologically. Age at onset of symptoms, age at first surgery, number of surgical procedures, mean duration of surgical interval, possible causes, and age at a point of papillomatosis spread in the lower airways and course of the disease were analyzed. SETTING: Academic children's hospital. RESULTS: Papillomas extension down to lower airways was observed in 40 children (8.9%). Among 40 patients with lower airway recurrent respiratory papillomatosis, 8 (20%) demonstrated pulmonary involvement. The basic cause of papilloma extension to lower airways appeared to be tracheotomy performed in children with laryngeal papillomatosis (92.5% of cases). Incidence of satellite pharyngeal and esophageal papillomatosis is significantly higher in patients with lower airways papillomatosis, presenting evidence of lager process extension. The clinical course of lower airways papillomatosis is more aggressive as compared with laryngeal papillomatosis, and treatment efficacy in such children is lower. CONCLUSIONS: All the patients with laryngeal papillomatosis having a history of tracheotomy require a regular endoscopic control and chest radiographs or computed tomography scanning because tracheal or pulmonary papillomatosis may occur in such patients even several years after decannulation. The prognosis for the disease after development of pulmonary papillomatosis is always serious.     

Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis

OBJECTIVES: To measure human papillomavirus (HPV) 6 and 11 viral load and antibody response in longitudinal specimens obtained from children with recurrent respiratory papillomatosis and to examine the association of type-specific viral load with clinical severity of disease. DESIGN: Longitudinal pilot study with a median follow-up of 5.4 months. SUBJECTS: The study included 15 children undergoing therapy for recurrent respiratory papillomatosis at the Egleston Children's Hospital, Atlanta, GA, between January 22, 1999, and June 13, 2000. MAIN OUTCOME MEASURES: The kinetics of HPV-6 and HPV-11 viral load and antibody level were examined over time. Longitudinal HPV-6 and HPV-11 viral loads were analyzed for associations with clinical indicators of disease severity. RESULTS: Four children were infected with HPV-11, 4 were infected with HPV-6, and 7 had mixed infections. The HPV-6 and HPV-11 viral loads were stable over time in most of the children. Among children with mixed infections, HPV-6 viral loads were inversely correlated with those of HPV-11 (r = -0.80, P<.001). The HPV-11 infection was significantly associated with more annual surgical procedures (P=.02). Neither HPV-6 nor HPV-11 viral loads were associated with demographic factors or markers of clinical severity. None of the children had detectable antibodies against HPV-6, and only 3 had detectable antibodies against HPV-11 virallike particles. CONCLUSIONS: Our data support the association of HPV-11 infection with clinical severity. Measures of HPV-6 and HPV-11 viral loads are relatively stable over time in most children with recurrent respiratory papillomatosis, suggesting that multiple samples may not be necessary. Cytobrush samples may substitute for tissue biopsy specimens in HPV detection and typing, but not for absolute viral load determination.     

Combined endolaryngeal videoendoscopic surgery and photodynamic treatment of patients with recurrent laryngeal and tracheal papillomatosis

Two-stage combined treatment of chronic recurrent papillomatosis of the larynx and trachea has been designed and tested in P.A. Herzen Research Cancer Institute. Stage I of the treatment consisted in endolaryngeal videoendoscopic surgery with Nd:YAG-laser destruction, argon-plasma coagulation and electroresection of the papilloma; stage II - postoperative photodynamic therapy (PDT) to prevent recurrence. In 1995-2007 the treatment was given to 32 patients aged 10-66 years with recurrent papillomatosis of the airways with the disease history 5-58 years. In two thirds of the patients papillomatosis involved several parts of the larynx and trachea. Squamous cell papilloma was accompanied with dysplasia of the first-second degree in 10 (31%) patients, dysplasia of the third degree - in 4 (12,5%), cancer in situ - in 3 (9,4%) patients. Human papilloma virus (HPV) was detected by hybridization in situ in 96%. The course of the treatment resulted in a complete regression (CR) of papilloma in 25 of 32 (78%), partial regression in 7 patients. The recurrence-free interval averaged 32 months (maximal 7 years) in 14 of 25 patients with CR. HPV was eradicated in a group of patients with persistent clinical remission. A 6 to 19 month follow-up recorded papilloma recurrence in 11 patients. The recurrence-free period increased 2,5-fold. In patients with dysplasia of degree I-III and cancer in situ (n=17) CR of dysplasia and preinvasive cancer foci was achieved in 15 (88%) patients.     

Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up

OBJECTIVES: The aim of this study was analysis of the results of use of interferon-alpha (IFN-alpha) in patients with recurrent respiratory papillomatosis (RRP) and correlation of the results with human papillomavirus (HPV) type. METHODS: A multicenter prospective series (42 patients from 22 hospitals) yielded 20 years of follow-up of patients with RRP and HPV typing who were treated with IFN-alpha in doses of 3 MU/m2 3 times per week. RESULTS: During long-term follow-up (mean +/- SD, 172 +/- 36.8 months), the rate of event-free survival evaluated by Kaplan-Meier analysis was 42.8%, and the overall survival rate was 82.6%. The HPV typing revealed an association of HPV 11 with a more aggressive disease course (64% of HPV 11 patients versus 24% of HPV 6 patients), a lower incidence of long-term response to IFN-alpha therapy (14% of HPV 11 patients versus 64% of HPV 6 patients), and a higher incidence of malignant transformation and mortality during follow-up (36% and 24%, respectively, of HPV 11 patients versus 0% of HPV 6 patients). CONCLUSIONS: The obtained results revealed maximal effectiveness of IFN-alpha therapy in RRP patients with HPV 6 as compared with HPV 11. The association of HPV 11 with a worse long-term response to IFN-alpha therapy and a higher incidence of malignant transformation and mortality is clinically important and indicates the necessity of HPV typing in RRP patients after the first biopsy.     

Effects of human papilloma virus types on course of juvenile respiratory papillomatosis and effectiveness of interferon therapy in children

Identification of the type of human papilloma virus (HPV) was done by means of polymerase chain reaction in 40 children with juvenile respiratory papillomatosis (JRP). Adjuvant to surgery interferon treatment was carried out in 18 patients (study group) with severe JRP. The rest 22 patients (control group) with less severe papillomatosis received only surgical treatment. The majority of the patients from both the groups had the virus type 6/11 (72.2 and 77.3% for the study and control groups, respectively). The assessment of a relationship between HPV type and effectiveness of interferon treatment in the study group has shown that the share of patients with effective and uneffective interferon therapy in each category (by HPV type) was about the same, i.e. no correlation exists between HPV type and interferon therapy effectiveness.     

喉乳头状瘤临床行为与细胞增殖活性关系的研究

利用ISH方法以及免疫病理手段对不同型的LP组织的标本进行PCNA、P53检测，探讨不同型HPV与LP的发生发展的相关机制，以寻求有效的检测方法帮助临床对LP的预后进行评估。标本选自1994年1月～1995年12月间我院收治的LP共36例。ISH法HPV6b／11阳性率为75％，明显高于HPV16和／或HPV18的表达。10例喉鳞癌各有1例HPV16、18阳性，无HPV6b／11阳性。ABC法行P53检测，36例LP标本中仅1例恶变组织阳性表达Ⅱ级（2．8％）；10例喉鳞癌中9例阳性表达（90．0％），其中Ⅱ级以上阳性表达6例（60．0％）。PCNA阳性表达27／36例（75％）；其中JOP组与AOP组阳性率有显著差异（P＜0．05）。本研究表明LP与HPV感染有极为密切的关系，认为HPV分型的检测在判断LP转归中有意义。PCNA阳性表达程度在预测LP肿瘤的活跃程度方面是一个很有意义的指标。P53蛋白表达在喉鳞癌与LP中有显著差异。     

Current advances in the basic research and clinical management of juvenile-onset recurrent respiratory papillomatosis

Juvenile-onset recurrent respiratory papillomatosis is a relatively uncommon disease that presents clinically with symptoms ranging from hoarseness to severe dyspnea. Human papilloma viruses type 6 and 11 are important in the etiology of the papillomata and are most probably transmitted from mother to child during childbirth. Although spontaneous remission is frequent, a rare fatal course because of pulmonary spread or malignant transformation has occurred. CO₂ laser evaporation of papillomas and adjuvant drug therapy using lymphoblastoid α-interferon are the most common treatment modalities at present. However, several other treatment modalities have been tried with varying success. Recent advances in basic research and different therapeutic approaches are reviewed. Received: 13 October 1999 / Accepted: 3 December 1999     

Carcinoma ex-papilloma: Histologic and virologic studies in whole-organ sections of the larynx

A patient with adult-onset recurrent respiratory papillomatosis (RRP), initially diagnosed at age 28 years, was treated with radiation therapy due to the rapid regrowth of lesions. Following 6 years of apparently inhibited growth, papilloma recurred, and squamous carcinoma was diagnosed from a laryngeal biopsy. A spontaneous laryngocutaneous fistula developed, and laryngectomy was performed 14 years after irradiation. The laryngectomy specimen was snap frozen and representative tissues were stored frozen for viral studies. The larynx was whole-organ sectioned for histologic examinations; residual papilloma, as well as carcinoma, was observed. Koilocytosis and other virus-associated histologic changes were also found. HPV capsid antigen was present in papilloma, carcinoma, and clinically normal epithelium. HPV nucleic acids, conforming to HPV type 6, were present in keratin pearls and dysplastic cells. According to prior reports, carcinoma developing in preexisting papilloma arises from juvenile-onset RRP. Irradiated papilloma develop cancer at about 10 years, and the patients rarely survive. Nonirradiated cases develop cancer after 30 years, and some develop papilloma in the hypopharynx and trachea, but most patients survive. Irradiation is not an obligatory precursor for malignant transformation of cancer; however, until now there have been no case reports of favorable outcome after irradiation of papilloma.     

Mucosal swabs detect HPV in laryngeal papillomatosis patients but not family members

Seven patients, aged 2-7 years, with active recurrent respiratory papillomatosis (RRP) attending the University of Michigan Pediatric Otolaryngology Clinic were studied to determine if human papillomavirus (HPV) is harbored in sites of the upper aerodigestive tract other than in the laryngeal papilloma itself. We also determined if close family members had detectable virus in their oral cavities. Noninvasive swabs of buccal mucosa, posterior pharynx, nasal vestibule, and tonsillar pillar of patients, as well as buccal mucosa and posterior pharyngeal swabs of family members were studied. Swabs of the patients' papillomas served as the positive controls. HPV was detected using polymerase chain reaction (PCR) amplification and Southern hybridization techniques. Six of seven patients had detectable HPV in papilloma and endolaryngeal swabs. Four were HPV type 6, and two were HPV type 11. The patient whose swab was negative for HPV was found to be biopsy negative for papilloma 3 weeks after a single laser excision which was performed 6 months prior to the endolaryngeal swab. HPV types 16, 18 and 31 were not found in any of the patients. No swabs from other sites in patients or family members were HPV positive despite the presence of adequate DNA in the swabbed material for successful amplification of beta-actin sequences. The absence of HPV (other than in the papilloma itself) in the upper aerodigestive tract of patients and caregivers is consistent with the absence of reported cases of horizontal transmission to siblings or other family members. The findings are also consistent with the conventional view that juvenile respiratory HPV is transmitted vertically from vaginal condylomas in the mother.     

The predictive value of serum interleukins in recurrent respiratory papillomatosis: a preliminary study

OBJECTIVE: IL-2 is the primary interleukin responsible for activation of the cell-mediated (Th1) arm of the immune response. Our objective was to determine whether a correlation existed between circulating levels of interleukin-2 as well as its soluble receptor (sIL-2R) and the clinical course of recurrent respiratory papillomatosis. METHODS AND MATERIALS: Fifteen children with a histological diagnosis of RRP were recruited. Age at the time of study, time since first diagnosis, and number of surgical interventions were recorded. The number of surgically treated recurrences per year was then calculated. We obtained serum samples from each of these 15 children and from 10 normal control subjects. We then performed in vitro determination of serum IL-2 and soluble IL-2 receptor levels using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: IL-2 was significantly lower (136.6 vs. 199.9 pg/mL, P =.035) in papilloma patients than in control subjects. IL-2R was also lower in papilloma patients (531.7 vs. 785.8 U/mL, P =.025). There was no statistical age difference between the papilloma and control groups. Among patients with papillomatosis, IL-2 and sIL-2R levels were significantly higher in those with aggressive disease (>4 surgically treated recurrences per year) versus non-aggressive disease (179.2 vs. 99.2 pg/mL, P =.024; and 697 vs. 387 U/mL, P =.022). Age was also significantly lower in the aggressive papilloma group (P =.002). CONCLUSIONS: Levels of interleukin-2 and IL-2 receptor were significantly lower in patients with recurrent respiratory papillomatosis compared with normal children. These data support the presence of an aberrant cell-mediated immune response in children with recurrent respiratory papillomatosis.     

The impact of cidofovir treatment on viral loads in adult recurrent respiratory papillomatosis

Cidofovir is an antiviral agent used in the therapy of recurrent respiratory papillomatosis (RRP). In this study, we hypothesized that cidofovir is effective in decreasing the viral load of human papillomavirus (HPV). We established a type specific real-time PCR and measured HPV DNA loads. The course of viral load of HPV types 6 and 11 after repeated applications of cidofovir intralesionally was compared to the clinical outcome using a modified Derkay score. In 6 of the 8 (75?%) patients, we detected HPV 6. In 2 (25?%) patients, we detected HPV 11. In all of the patients, the viral load and the modified Derkay score decreased significantly during the treatment. We conclude that viral load of HPV can be monitored using the technique described here. Cidofovir in combination with surgical debulking reduces the viral load in patients with RRP. Relapses of the symptoms cannot be avoided but might be delayed.     

Immunocompetency in children with recurrent respiratory papillomatosis: prospective study

OBJECTIVES: We sought to investigate the immunologic status of children with recurrent respiratory papillomatosis and to evaluate possible correlations between the patients' immunocompetency and the clinical course of the disease. METHODS: Twenty children with recurrent respiratory papillomatosis underwent immunologic evaluation every 6 months for determination of complete blood count, serum immunoglobulin levels, lymphocyte subpopulations, lymphocyte response to mitogen stimulation, and natural killer cell function. The patients were observed prospectively (42 to 56 months), and their clinical course was recorded. The findings were compared with those in healthy age-matched controls. RESULTS: The CD4/CD8 ratio and the lymphocyte response to mitogen stimulation were significantly reduced in the study children compared to normal controls. A reduction in lymphocyte response to mitogen stimulation was significantly correlated to a high number of papilloma sites and more frequent recurrences. Abnormal natural killer cell function was significantly correlated to more frequent recurrences. CONCLUSIONS: A compromised cell-mediated immune response may be associated with repeated or persistent human papillomavirus infections, leading to the development of recurrent respiratory papillomatosis. Patients with an aggressive clinical course may have underlying cell-mediated immunodeficiency. Long-term prospective investigations are needed to establish the role of the host immune system in the pathogenesis of recurrent respiratory papillomatosis in children.     

Intersurgical interval increased with use of quadrivalent human papillomavirus vaccine (Gardasil) in a pediatric patient with recurrent respiratory papillomatosis: A case report

This is a case of a 4 year old female with recalcitrant recurrent respiratory papillomatosis with decreasing intersurgical interval that had improvement in clinical course after administration of the quadrivalent HPV vaccine.