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。     

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.     

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.     

Pediatric Respiratory Papillomatosis: Prognostic Role of Viral Typing and Cofactors

Children with recurrent respiratory papillomatosis vary greatly in their clinical disease course. Many have mild disease with eventual remission while others present with an early aggressive airway obstructive course. This study consisted of 24 pediatric patients whose specimens underwent polymerase chain reaction analysis for cytomegalovirus (CMV), herpes simplex virus (HSV), and human papillomavirus (HPV) type. Nineteen of 24 specimens contained enough DNA for this study. None of the specimens were found to contain DNA from HPV-16, -18, -31, -33; CMV; or HSV, which contrasts with our previous findings in adults. Ten patients were infected by HPV-11 and seven of these underwent tracheotomy because of an aggressive tumorigenic clinical course. Nine patients were infected by HPV-6 alone of whom only two required a tracheotomy (P = 0.05, Fisher's Exact Test). The early airway obstructive course associated with HPV-11, however, had no bearing on achieving eventual disease remission, with decannulation achieved in eight of nine children.     

2',5'-Oligoadenylate synthetase activity analysis and human papilloma virus typing as prognostic factors in patients with recurrent respiratory papillomatosis

OBJECTIVE: Determination of early prognostic factors in patients with recurrent respiratory papillomatosis is extremely important, so the major goal of our prospective, multicentre study was to evaluate (1) the feasibility of various factors to determine prognosis of the clinical course, as well as (2) the response to interferon-alpha therapy in recurrent respiratory papillomatosis. METHODS: Forty-two patients with recurrent respiratory papillomatosis were treated with interferon-alpha (3 MU/m(2) three times per week; mean therapy duration was 2.7 +/- 1.8 years) in 1983-1994 and followed-up until 2003. Human papilloma virus (HPV) type, recurrent respiratory papillomatosis severity and 2',5'-oligoadenylate synthetase activity were determined by standard methods and analysed for correlation with the results of long-term clinical outcome. RESULTS AND CONCLUSION: Patients with HPV type 11, a severity score >4, a high number of surgical procedures prior to interferon-alpha therapy and a high basal 2',5'-oligoadenylate synthetase activity should be considered at high risk of an aggressive clinical course, often with spread to lower airway passages, malignant transformation and death. Human papilloma virus type, score for recurrent respiratory papillomatosis severity, number of surgical procedures and 2',5'-oligoadenylate synthetase activity showed significant association with response to interferon-alpha therapy and the long-term clinical course, so these factors have value in predicting prognosis in recurrent respiratory papillomatosis.     

Identification of HPV DNA in patients with juvenile-onset recurrent respiratory papillomatosis using SYBR Green real-time PCR

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm affecting the larynx and upper respiratory tract in children. Human papillomavirus (HPV) has been implicated as the cause of RRP, most commonly types 6 and 11. The present study was undertaken to evaluate the occurrence of HPV types in a group of patients with juvenile-onset RRP (JORRP). METHODS: The study group consists of 23 patients with JORRP. The clinical records of the patients were reviewed, and JORRP was classified as non-aggressive or aggressive. The laryngeal biopsies were taken and investigated for HPV DNA presence using real-time polymerase chain reaction (PCR) with a set of consensus primers (MY09/11). Viral typing was subsequently performed by real-time PCR with type-specific primers for HPV types 6, 11, 16, 18, 31, and 33. RESULTS: HPV presence was detected in all samples with amplifiable DNA. HPV-11 was revealed in 61.9% of the patients and HPV-6 in 23.8%. Double positivity for HPV types 6 and 11 was identified in 14.3%. Our findings suggest that RRP runs a more aggressive clinical course when HPV-11 infection is present (p=0.0265). CONCLUSIONS: Our results suggest a high frequency of HPV infection in the upper respiratory tract of the studied patients. We believe that the routine application of molecular techniques such as PCR for detection and analysis of HPVs in patients with RRP has diagnostic and prognostic significance.     

HPV DNA typing of adult-onset respiratory papillomatosis

Respiratory papillomatosis is a recalcitrant, human papillomavirus-induced disorder of the upper airways. Using in situ hybridization and biotinylated deoxyribonucleic acid (DNA) probes, the type of human papillomavirus (HPV) in nine adults was determined both at presentation and during subsequent recurrences. Fifty-three biopsies obtained from seven men and two women over a 10-year period were examined for HPV 6, 11, 16 and 18. All patients had either type 6 or 11. One dual infection was found. Despite intensive therapy with lasers with or without alpha interferon, no elimination or change in viral type occurred. Despite identical histologies, the amount of HPV DNA present in a given patient's papillomata varied markedly. The results suggest that adult-onset respiratory papillomatosis is due to HPV 6 and/or HPV 11, and that its recurrent nature, despite therapy, is due to persistence of a viral reservoir.     

Prevalence and clinical implications of low-risk human papillomavirus among patients with recurrent respiratory papillomatosis in Rio de Janeiro,Brazil

ObjectiveThe aim of this study was to investigate the presence of human papillomavirus (HPV) in biopsy specimens from juvenile and adult patients with histopathological diagnosis of recurrent respiratory papillomatosis (RRP) treated in two public hospitals in Rio de Janeiro, Brazil.MethodsWe performed the detection and genotyping of HPV by PCR technique for the types 6, 11, 16, and 18 in biopsy specimens from 41 RRP patients.ResultsThe juvenile onset RRP (JoRRP) corresponded to 61% and the adult onset RRP (AoRRP) corresponded to 39% of the study group. Prevalence of males was observed in both the adult (81.3%) and the juvenile (56%) groups. Lesions in the larynx were more frequent in the glottis (46%). Genotyping analysis only revealed patients with HPV-6 (34.1%), HPV-11(17.1%), and co-infection HPV-6 and -11 (48.8%). RRP severity was significantly associated with the JoRRP (p < 0.001), with extralaryngeal disease and more surgeries. However, no significant association between RRP severity and HPV types was found. One co-infected patient in the JoRRP died due to the evolution of the disease with lung involvement.ConclusionThese results show the strong association of HPV-6 and/or HPV-11 types with RRP and could complement the diagnosis, prognosis, and therapies for these patients. In addition, the HPV vaccination should be encouraged to prevent the disease.     

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.     

Laryngeal papillomatosis: clinical, histopathologic and molecular studies

The clinical course and pathology of 57 patients with laryngeal papillomatosis were reviewed. Tissues from 26 patients were analyzed for human papillomavirus (HPV) DNA by Southern blot hybridization. Histopathologic evaluation of the papillomas showed no correlation with age of onset or clinical pattern of remission and recurrence. The pathology was characterized by abnormal squamous maturation with parakeratosis, retardation of superficial cell maturation, papillomatosis, and basal hyperplasia. HPV DNA was present in all lesions, with 92% containing either HPV-6 or 11. Latent HPV DNA was detected in clinically uninvolved tissues of 11 of 14 (78.5%) patients studied. There was no correlation between HPV type, histopathology and/or clinical pattern. Despite homogeneity of pathology, the clinical expression of laryngeal HPV infection varied widely. A mechanism for the pathogenesis of laryngeal papillomatosis, based on the concept of maturational arrest, is proposed.     

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.     

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.     

HPV types causing juvenile recurrent laryngeal papillomatosis in South Africa

Objectives

To identify human papillomavirus (HPV) types associated with juvenile onset recurrent laryngeal papillomatosis (RLP) in southern Africa, to determine if there is a correlation between HPV type and disease aggressiveness and to determine the diagnostic and prognostic value of rapid molecular techniques for detection and typing of HPV using laryngeal biopsies.

Methods

Laryngeal biopsies from patients undergoing surgery for RLP were screened for HPV using conventional and real-time PCR techniques. Amplicons were sequenced to determine the HPV type involved. Clinical features were correlated with HPV type.

Results

HPV was identified in papillomata from 18 out of 19 patients. Only HPV-6 and HPV-11 were identified, with no co-infections. There was 100% concordance between conventional and real-time PCR techniques. Patients with HPV-11 disease required more procedures and tended to have higher Derkay scores than those with HPV-6 disease. The HPV types identified in our patients were genetically similar to HPV types from geographically distinct regions.

Conclusions

RLP in our patient population appears to be exclusively due to HPV-6 or HPV-11. HPV-11 disease appears to be more aggressive than HPV-6 disease. Identification of the HPV types provides motivation for inclusion of vaccines against these types in vaccination programs to protect women against infection and subsequently reduce the incidence of RLP.     

幼年型复发性呼吸道乳头状瘤病患儿外周血T细胞初探

目的分析幼年型复发性呼吸道乳头状瘤病(juvenile-onset recurrent respiratory papillomatosis,Jo-RRP)外周血T淋巴细胞免疫状态及其与病情间的相关性,探讨更合适的治疗方案。方法采用流式细胞仪检测19例Jo-RRP患儿外周血T淋巴细胞亚群,按照《复发性呼吸道乳头状瘤病病情严重度评分表》对其病情进行严重度评分,分析外周血T淋巴细胞亚群功能及与病情的相关性。结果Jo-RRP患儿CD3~ 、CD4~ 、CD4~ / CD8~ T细胞以及Th1FFh2均低于正常儿童(P<0.05)。除Th1细胞(P<0.05)外,其余免疫指标与Jo-RRP患儿临床严重度评分间均无明显相关性。结论Jo-RRP患儿可能存在T细胞介导的免疫功能障碍,其紊乱的免疫功能与疾病的发生、发展可能存在相互促进作用,需进一步完善手术切除肿瘤之外的免疫调节等辅助治疗手段。     

复发性呼吸道乳头状瘤病

本文结合一组63例复发性乳头状瘤的基础及临床研究资料进行分析，其中16例的瘤组织以Slotblot和Southernblot杂交技术检测HPV－DNA，其阳性率：HPV6b为87.5％，HPV11为93．7％，HPV16为81．2％。本文就病因学、感染途径、复发部位与上皮组织特性及治疗选择进行讨论。     

Association of human papillomavirus subtype and clinical course in respiratory papillomatosis

The relationship of human papillomavirus type 6 (HPV-6) subtypes to the clinical manifestations of respiratory papillomatosis was investigated. DNA was isolated from biopsy specimens of 21 patients and the viral genome analyzed by molecular hybridization. Four subtypes, designated HPV-6c through HPV-6f, were distinguishable by restriction endonuclease cleavage patterns of the viral genome. Patient records were reviewed to identify associations between viral subtype and sex, race, age at onset of papilloma, duration of disease, frequency of operations, history of tracheotomy and anatomical extension of papilloma. HPV-6c was present in 13 cases which were characterized by extensive anatomical spread of disease, higher frequency of operations, and a need for tracheotomy. HPV-6d occurred in 4 black patients with juvenile onset papilloma. HPV-6e was found in 2 white patients — 1 with juvenile onset and 1 with adult onset papilloma. HPV-6f was identified in 2 white patients with adult onset disease.     

Detection of human papillomavirus infection in diseased and nondiseased sites of the respiratory tract in recurrent respiratory papillomatosis patients by DNA hybridization.

We examined 12 recurrent respiratory papillomatosis patients, who were undergoing treatment for recurrence of their disease, for the presence of human papillomavirus (HPV). Biopsies were obtained from their respiratory papillomas and nondiseased sites (NDS) of the respiratory tract: the nasopharynx, posterior tonsillar pillar, aryepiglottic fold, cervical trachea, intrathoracic trachea, and bronchi. The presence of HPV DNA was determined by using the ViraPap/ViraType DNA hybridization procedure. Two thirds of the patients were infected with HPV 6/11 in either the diseased papilloma or NDS: 50% of patients with papilloma specimens typed positive (6 of 12), and 40% of the patients typed HPV-positive in one or more biopsies from the NDS (4 of 10). No single NDS was more likely to be infected with HPV than any other. No oncogenic HPV types 16/18 or 31/33/35 were detected in the papillomas or NDS of these patients. Only patients with multiple, and not isolated, papilloma involvement were found to harbor HPV DNA in NDS; and 80% of those with infected NDS, compared to 20% of those without infected NDS, required a shorter (no more than 3 months) surgical treatment interval. Our results show that HPV infection frequently persists in adjacent, clinically normal sites, and suggest that the extent of NDS involvement may predict both the extent of disease and the likelihood of recurrence.     

Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: A systematic review

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.