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。     

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.     

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.     

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.     

Velocardiofacial syndrome: incidence of immune cytopenias

BACKGROUND: Velocardiofacial syndrome (VCFS) is associated with a broad clinical spectrum that frequently overlaps the DiGeorge syndrome. Both have been linked to chromosomal microdeletions of chromosome 22 (22q11.2). DiGeorge syndrome is associated with T-cell dysfunction. What is the incidence of immune cytopenias in children with VCFS? OBJECTIVES: To (1) identify, (2) characterize, (3) quantify, and (4) follow up the immunologic deficits in children initially seen in our institution with VCFS. DESIGN: Prospective clinical evaluation of patients with the features of VCFS. PATIENTS: Twenty consecutive children with the clinical diagnoses of VCFS. SETTING: Tertiary care children's hospital. MAIN OUTCOME MEASURES: All 20 children had genetics evaluation with chromosomal analysis. Immunologic evaluations included serum immunoglobulin concentrations, lymphocyte studies, and mitogen and antigen stimulation studies. RESULTS: Five (25%) of 20 children were noted to have T-cell dysfunction with a clinical presentation marked by recurrent upper respiratory tract infections. Three of these 5 children had resolution of the T-cell dysfunction over a 2-year period. The 2 children with persistent cytopenias combined with immunoglobulin dysfunction required intravenous IgG infusions to control their infections. CONCLUSIONS: Velocardiofacial syndrome is associated with an increased incidence of immune cytopenias and, thus, warrants evaluation in any child with the clinical diagnosis of VCFS. This immune deficit may be transient and depends on the age of the evaluation of the child.     

Is immune system influenced by adenotonsillectomy in children?

OBJECTIVE: Tonsils and adenoids are lymphoid tissues that are located in the pharynx and play an important role against invading antigens of the upper respiratory tract. The present study analyses serum immunoglobulin levels and peripheral blood (PB) lymphocyte subsets in children, 24-48 h prior to and 4-6 weeks after adenotonsillectomy, in order to determine early effects of adenotonsillectomy on the immune system. METHODS: The study population consists of 15 children (aged 4-10 years) who underwent adenotonsillectomy because of adenoidal hypertrophy and chronic tonsillitis and 15 age-matched healthy children without a history of adenotonsillectomy. Serum IgG, IgA and IgM levels were measured by nephelometry. PB lymphocyte subsets were analysed by using monoclonal antibodies and flow cytometry. RESULTS: Children with chronic tonsillitis have increased levels of CD19+ B lymphocytes compared to healthy controls in the pre-operative period. The percentage of B lymphocytes bearing CD23 was found to be significantly higher in patients, most likely representing in vivo B lymphocyte activation due to chronic antigenic stimulation. After the adenotonsillectomy, despite ongoing B lymphocyte activation, CD8+ T lymphocyte levels increased and B cell levels returned to normal. A slight decrease in serum IgG, IgA and IgM levels was detected in the post-operative period compared to prior levels. CONCLUSION: Adenotonsillectomy performed in children leads to alterations that may reflect a compensatory response of the developing immune system after the removal of the lymphoid tissue in the setting of chronic antigenic stimulation. However, these changes do not cause significant immune deficiency.     

小儿复发性呼吸道乳头状瘤病38例临床分析

目的 :探讨小儿复发性呼吸道乳头状瘤病 (JORRP)的临床特点。方法 :回顾分折 1986年 6月～ 2 0 0 0年 6月收治的 JORRP 38例资料。结果 :平均发病年龄 2 .9岁 ,首次诊断平均年龄 3.5岁 ,平均手术 3.45次 ,术后并发喉功能障碍 8例 (2 1.0 5 % ) ,气管切开 19例 (5 0 .0 % ) ,6例气管造口有乳头状瘤传播 (31.5 8% )。结论 :JORRP是儿童最常见的喉部肿瘤 ,由于易复发 ,常需多次手术 ;手术应注意保存喉部正常组织 ;气管切开要慎重 ,以防病变局部接种和邻近器官传播     

Airway reconstruction in children with recurrent respiratory papillomatosis

OBJECTIVE: To determine if children with recurrent respiratory papillomatosis were at increased risk of complications due to their disease following major airway reconstruction. METHODS: We retrospectively reviewed our airway surgery database and the medical records of all children diagnosed with recurrent respiratory papillomatosis who were evaluated at Cincinnati Children's Hospital Medical Center between January 1998 and August 2003. All patients with active airway papillomas or a history of recurrent respiratory papillomatosis who underwent open airway reconstruction at our institution were included in the study. RESULTS: Seven children with recurrent respiratory papillomatosis underwent major airway reconstruction. Six children had tracheotomies and five are now decannulated following their airway reconstruction. Five children had active papillomas at the time of surgery and none had significant worsening of their papillomas following their procedures. Two patients in remission underwent airway reconstruction without recurrence of their papillomas. CONCLUSIONS: Major airway reconstruction can be safely performed in children with recurrent respiratory papillomatosis.     

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.     

Initial experience using propranolol as an adjunctive treatment in children with aggressive recurrent respiratory papillomatosis

We performed a retrospective chart review with a 6-month follow-up to examine the initial use of propranolol as an adjunctive treatment in children with severe recurrent respiratory papillomatosis. This is the first such report. Two of 3 children with severe recurrent respiratory papillomatosis demonstrated a response to oral propranolol therapy, as evidenced by an improved voice and by an increased time between surgical interventions. One child demonstrated no response to propranolol, and medication was halted. Both children who demonstrated a response had undergone more than 10 surgical interventions in the previous year, along with prior treatment including surgical excision and adjuvant therapy. Both children more than doubled the interval between treatments after propranolol administration, and the parents of both children noted marked improvement of the child's voice as measured by their Pediatric Voice-Related Quality of Life score (from 40 to 67.5 in one child and from 27 to 60 in the other child). No child experienced hypoglycemia or blood pressure abnormalities. We conclude that initial use of propranolol as an adjunctive measure in severe recurrent respiratory papillomatosis shows it to have some efficacy in delaying surgical intervention and improving voice. Previous reports have demonstrated relatively safe use of propranolol in children with hemangiomas. Further studies are needed to determine the long-term effectiveness, dosing strategies, and side-effect profile of propranolol for treatment of 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.     

Clinical course of recurrent respiratory papillomatosis in Danish children

OBJECTIVE: To evaluate the clinical course of juvenile-onset recurrent respiratory papillomatosis (RP) with respect to age, disease duration, and maternal condylomas. DESIGN: Inception cohort study. SETTING: All ear, nose, and throat departments in public Danish hospitals. PATIENTS: Fifty-seven Danish children diagnosed with RP and born between 1974 and 1993 were observed for an average of 14 years after diagnosis. MAIN OUTCOME MEASURE: Removal of respiratory papillomas by knife biopsy, laser surgery, or cryotherapy. RESULTS: Children younger than 5 years diagnosed with RP underwent an average of 4.1 surgeries in the first year of disease, the highest rate among all our patients. The overall surgery rate decreased over time after initial diagnosis but remained significantly higher for children with a younger age of onset for the first 4 years of disease (P <.001) and for children with a maternal history of condylomas in pregnancy for years 4 to 10 of the disease (P <.001). We also observed an independent and statistically significant (P <.001) decreasing surgery rate with increasing age and time from initial diagnosis. The trend for children with recurrent disease was a decreasing rate of surgical procedures (28 of 42 patients with recurrent disease); however, a third of patients (14/42) demonstrated a constant or increasing rate of surgical procedures over time. CONCLUSIONS: The clinical course of RP is characterized by a high frequency of surgeries soon after diagnosis that diminishes over time and with increasing age. Additional studies are warranted to identify factors associated with cases that do not conform to the usual disease course.     

Recurrent respiratory papillomatosis of the larynx: current diagnosis and treatment

Treating children with recurrent respiratory papillomatosis can be very rewarding as more information is learned about human papillomavirus. The future goals are reducing the morbidity and mortality of this disease process. The establishment of the national recurrent respiratory papillomatosis patient registry and coordinated efforts between basic scientists involved in human papillomavirus research and clinicians involved in the treatment of recurrent respiratory papillomatosis should aid the endeavor.     

Safe use of systemic bevacizumab for respiratory recurrent papillomatosis in two children

Recurrent respiratory papillomatosis can be a devastating condition for a child, with severe consequences. Currently, there is no proven successful medical treatment. We describe the use of systemic bevacizumab to treat two children affected by aggressive recurrent respiratory papillomatosis. Respiratory symptoms and quality of life improved dramatically in both patients, without observing any toxicity. The only complication was mild proteinuria. Systemic bevacizumab is a promising adjuvant treatment in aggressive recurrent respiratory papillomatosis in children. It is effective and well tolerated. Further studies are needed to establish the optimal dosing frequency and duration of therapy. Laryngoscope, 129:1001–1004, 2019     

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。     

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.     

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。     

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.     

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.     

Histologic review of cidofovir-treated recurrent respiratory papillomatosis

OBJECTIVES: Recurrent respiratory papillomatosis is currently the most common lesion of the larynx in children. The course of the disease is variable and often requires repetitive surgical interventions to maintain the airway. The predominant concern for disease progression is the possibility of spread to the tracheobronchial tree, as this increases the rates of morbidity and mortality. Cidofovir is an antiviral drug with activity against members of the DNA virus family. Development of local malignant change secondary to use of cidofovir has been a concern. The histopathologic findings from biopsy specimens from children treated with cidofovir have not been previously reported. METHODS: We performed a retrospective review of pediatric operative histologic biopsies and charts of patients treated with intralesional cidofovir and untreated study controls from January 1, 1995, through November 1, 2001. RESULTS: Ninety-six specimens were evaluated by 2 blinded pathologists. No cases of dysplasia were identified. The most commonly identified finding was an increased nucleus-to-cytoplasm ratio in 8 of 95 cases (8.4%). No cases of abnormal mitoses, prominent nucleoli, or cellular or nuclear enlargement were found. CONCLUSIONS: This is the first report of pathologically evaluated recurrent respiratory papillomatosis specimens taken before and after treatment with intralesional cidofovir. No dysplasia was identified, and there were no significant dysplastic changes in the specimens analyzed.