人类乳头状瘤病毒疫苗在复发性呼吸道乳头状瘤中的作用及进展

复发性呼吸道乳头状瘤（recurrent respiratorypapillomatosis,RRP）是指发生于上下呼吸道的乳头状瘤病,是一种具有高度复发性及侵袭性的疾病,与人类乳头状瘤病毒（human papillomavirus,HPV）感染有关。喉乳头状瘤的大量研究及累积的分子学和临床证据表明,HPV感染是RRP发病中的主要因素。手术治疗仍为RRP主要治疗手段,但不能根治,常需辅助治疗。本文对近几年有关HPV疫苗在RRP病例中应用研究做一综述。     

无呼吸道乳头状瘤儿童上呼吸道乳头状瘤病毒的检测

目的 检测儿童扁桃体和腺样体手术标本中的人乳头状瘤病毒(human papillomavirus,HPV)DNA,以了解无复发性呼吸道乳头状瘤(juvenile-onset recurrent respiratory papillomatosis,JORRP)儿童的上呼吸道HPV感染情况.方法 前瞻性研究2008年2月至2009年1月因扁桃体肥大或炎症以及腺样体肥大手术的患儿241例,均确诊为无JORRP或其他已知HPV相关疾病.共取得新鲜的扁桃体标本177个和腺样体标本195个.为验证本研究实验方法的可靠性,取同期17例喉乳头状瘤患儿的新鲜乳头状瘤标本作阳性对照.所有标本采用荧光定量聚合酶链反应法检测HPV DNA并分型.结果 17例乳头状瘤标本HPV-DNA均阳性,均为HPV6或HPV11感染.241例患儿的372个标本中,仅2例扁桃体阳性,分别为HPV6和HPV11感染.再次追问这2例患儿的个人病史和家族史,未发现有HPV感染相关疾病,扁桃体切除样本的病理检查结果均显示淋巴组织增生,无HPV感染的特征病变,也未见恶性肿瘤迹象.本组中上呼吸道HPV感染率为0.8％ (2/241).结论 无JORRP儿童的上呼吸道也存在HPV感染,仅有HPV感染可能不足以引发JORRP.     

小儿喉乳头状瘤患者的免疫状态调查和局部注射5-氟脲嘧啶的疗效观察

喉乳头状瘤由人乳头状瘤病毒 (HPV)引起 ,以HPV6、1 1型多见。小儿患者发病年龄小 ,病变范围广 ,常侵及喉外组织 ,摘除后易复发 ,而成人患者则易发生癌变。复发性喉乳头状瘤的患儿多伴有体液或细胞免疫功能低下 ,抗病毒能力较差 ,病变范围广且容易侵及下呼吸道 ,使治疗变得尤为困难。 2 0 0 0～ 2 0 0 2年我们收治 9例小儿喉乳头状瘤患者 ,行手术摘除肿瘤后局部注射 5 氟脲嘧啶 ( 5 FU) ,并与 7例不注射 5 FU的对照组进行比较 ,以探讨小儿的免疫状态与肿瘤发生的相关性及局部注射 5 FU的治疗效果。1　资料与方法小儿喉乳头状瘤患者…     

复发性呼吸道乳头状瘤研究进展

人类乳头状瘤病毒 (HPV)是一类在脊椎动物中广泛存在的病毒 ,与人类肿瘤的发生密切相关。复发性呼吸道乳头状瘤是喉部常见的肿瘤 ,已知其与 HPV感染有极密切的关系 ,故本文就 HPV特性、研究手段以及与复发性呼吸道乳头状瘤的相关研究做一综述     

复发性呼吸道乳头状瘤研究进展(综述)

人类乳头状瘤病毒(HPV)是一类在脊椎动物中广泛存在的病毒，与人类肿瘤的发生密切相关.复发性呼吸道乳头状瘤是喉部常见的肿瘤，已知其与HPV感染有极密切的关系，故本文就HPV特性、研究手段以及与复发性呼吸道乳头状瘤的相关研究做一综述.     

微RNA与人乳头状瘤病毒相关疾病发病机制研究

微RNA（microRNA,miRNA）是一种非编码RNA,在转录后阶段对基因的表达进行调控,在细胞中参与多个生物学过程。人乳头状瘤病毒（human papillomaviruse,HPV）可引起多种疾病,包括复发性呼吸道乳头状瘤病和宫颈癌等。HPV感染人体细胞后可以通过多种方式引起miRNA的异常表达,从而参与这些疾病的发生和进展。本文就miRNA在HPV相关疾病中的研究进展进行综述,为研究该类疾病的发病机制提供新的思路和视角。     

儿童喉乳头状瘤研究进展[综述]

喉乳头状瘤是儿童最常见的呼吸道良性肿瘤,主要临床表现为声嘶、喘鸣和呼吸困难,严重者可出现完全性喉梗阻导致窒息。儿童喉乳头状瘤的病原体主要为人乳头状瘤病毒（human papilloma virus,HPV）,且主要为低危型HPV6、11型,HPV11型感染和发病年龄早更容易导致不良预后。目前认为幼儿HPV感染途径主要为宫内感染、经阴道接触感染,但母体感染HPV并不是终止妊娠和剖宫产指征。手术是目前主要的治疗方式,疫苗接种等辅助治疗日益发挥作用。     

人乳头状瘤病毒感染与儿童复发性呼吸道乳头状瘤病

复发性呼吸道乳头状瘤病是儿童最常见的呼吸道良性肿瘤,反复手术切除是主要的治疗手段,但是不能防止肿瘤复发.而各种药物治疗也尚未取得满意的疗效,给患儿的家庭及社会带来沉重的经济负担.人乳头状瘤病毒6和11被认为是儿童复发性呼吸道乳头状瘤病发生的主要致病原.     

复发性呼吸道乳头状瘤病的免疫逃逸机制

目的分析复发性呼吸道乳头状瘤与声带息肉免疫相关基因的差异表达,探讨免疫机制在复发性呼吸道乳头状瘤发病中的作用。方法利用mRNA平行扩增和人全基因组芯片分析比较分析3组（6例样本）成人声带息肉与喉乳头状瘤病组织基因表达谱的差异,研究分析与HPV感染致RRP的相关免疫基因。结果涉及免疫监视多个环节的共26个相关基因发生异常,其中21个基因表达下调,5个基因表达上调,表达异常的基因涉及免疫应答的全过程。结论HPV逃逸机体免疫监视是HPV感染机体的重要因素。     

支撑喉镜下射频治疗小儿喉乳头状瘤20例

小儿喉乳头状瘤是小儿喉部常见的良性肿瘤,多数与人类乳头状瘤病毒(Human Papilloma Virus,HPV)感染有关。临床上具有生长迅速、多病灶、易复发、生物行为不确定性,易向下呼吸道蔓延等特点[1]。80%发病于7岁前,随着年龄增长有自限趋势,目前最有效的治疗方法为手术治疗[2]。本病     

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.     

Recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis is a relatively rare disease caused by members of the human papilloma virus family. Lesions may occur anywhere throughout the respiratory tract but show a predilection for squamo-columnar epithelial junctions, frequently leading to hoarseness and upper airway obstruction. Rarely, it can progress to squamous cell carcinoma. The impact of recurrent respiratory papillomatosis on patients, their families, and the health care system is considerable. Unfortunately, despite extensive investigational studies, no cure is available for the disease. This article reviews the aetiology of and therapeutic options for recurrent respiratory papillomatosis.     

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.     

Four mutations in Epidermodysplasia verruciformis 1 (EVER1) gene are not contributors to susceptibility in RRP

OBJECTIVE: Epidermodysplasia verruciformis is a skin disease characterized by abnormal susceptibility to human papilloma viruses. Recently four mutations in the Epidermodysplasia verruciformis 1 gene (EVER1, also known as TMC6) have been associated with the disease. Because of the phenotypic similarity between Epidermodysplasia verruciformis and recurrent respiratory papillomatosis, we decided to investigate whether any of these mutations accounts for the susceptibility to human papilloma viruses in subjects with recurrent respiratory papillomatosis (RRP). METHODS: Allele-specific PCR and restriction fragment length polymorphisms (RFLPs) were employed for genotyping a cohort of 101 patients with recurrent respiratory papillomatosis. RESULTS: None of these four mutations were found in the studied subjects. CONCLUSION: The absence of these mutations in RRP patients might indicate that EVER 1 alleles are not associated with susceptibility to RRP, or that other, as yet unidentified, mutations in the Epidermodysplasia verruciformis 1 gene, might account for the susceptibility to RRP.     

An epigenetically derived monoclonal origin for recurrent respiratory papillomatosis

OBJECTIVE: To investigate the contribution of promoter methylation-mediated epigenetic events in recurrent respiratory papillomatosis tumorigenesis. DESIGN: Archival tissue DNA, extracted from microdissected papilloma lesions, was interrogated for methylation status by means of the novel, multigene methylation-specific multiplex ligation-dependent probe amplification assay. SUBJECTS: Fifteen subjects with recurrent respiratory papillomatosis, 3 females and 12 males, all with adult onset of illness (age range, 23-73 years) except for 1 female patient with juvenile onset (1 year old). RESULTS: Promoter hypermethylation was recorded in 14 of 15 cases, and 19 of 22 unique methylation-prone cancer genes in the multigene panel had altered DNA methylation in at least 1 laryngeal papilloma biopsy specimen. Identical abnormally methylated genes were found in 5 of 15 recurrent cases, of which the CDKN2B gene was hypermethylated in all 5 cases. Dissimilar epigenetic events were noted in the remaining cases. CONCLUSIONS: A clonal origin was derived for 5 of 15 recurrent respiratory papillomatosis biopsy specimens based on identical epigenetic events. The high frequency of epigenetic events, characterized by consistent promoter hypermethylation of multiple tumor suppressor genes, points to the use of gene silencing mechanisms in the pathogenesis of recurrent respiratory papillomatosis.     

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.     

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.     

Prevention of recurrent respiratory papillomatosis: role of HPV vaccination

Recurrent respiratory papillomatosis is a rare, but devastating, cause of airway lesions in children and adults. This disease is caused by human papilloma virus subtypes 6 and 11. At this time there are two vaccines in late stages of development seeking Food and Drug Administration (FDA) approval to prevent cervical cancer, which is also caused by human papilloma virus. One of these vaccines has been developed to stimulate immunity to the most common subtypes that cause cervical cancer but also includes those responsible for recurrent respiratory papillomatosis. With the possibility this could drastically reduce the incidence of RRP, the otolaryngology community should advocate for implementation of a vaccine program that provides effective prevention of HPV infection with subtypes 6 and 11.     

儿童复发性呼吸道乳头状瘤病临床研究

OBJECTIVE: To study the clinical behavior of juvenile-onset recurrent respiratory papillomatosis in order to find some factors correlated to the development of this disease, and to sum up the significance and experience of CO2 laser surgery. METHOD: Sixty patients with juvenile-onset recurrent respiratory papillomatosis from September 1995 to December 1998 were retrospectively analyzed. RESULTS: The age of onset in 50 cases (83.3%) was below 4 years, and the peak-age was 2 years. The rates of recurrence were 72.0% and 45.7% (chi 2 = 4.71, P < 0.05) below and over 2 years, respectively. The rates of aggressive disease were 88.0% and 54.3% (chi 2 = 7.66, P < 0.01) below and over 2 years, respectively. The predominant sites of the disease were the vocal cords, the false vocal cords, the laryngeal ventricle, the laryngeal surface of the epiglottis and the subglottic region. Tracheostomy induced the development of tracheal papilloma, therefore should be avoided as possible. Laryngeal papilloma might be divided into four types on the basis of the growth manner and surface form corresponding to clinical behaviors. Five patients were followed-up for 1.5 years without recurrence, 18 patients had fewer recurrences following treatment, 33 patients were under treatment, and 3 patients died. Nineteen patients lost follow-up. The major complications included laryngeal and tracheal stenosis. CONCLUSION: Clinical behaviors of juvenile-onset recurrent respiratory papillomatosis were relevant to the age, growth form and tracheotomy. CO2 laser was an ideal instrument for ablation of the laryngeal papillomas with the following advantages: simple management, less bleeding, preservation of laryngeal structure and avoidance of tracheostomy.     

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