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New Guidelines for Treating Childhood-Onset RRP Editor's Note: Craig Derkay, MD has headed a task force created by the American Society of Pediatric Otolaryngology Board consisting of pediatric otolaryngologists and their research nurses from 22 academic sites throughout the United States and representatives from the Centers of Disease Control in Atlanta. GA. The 22 sites have collectively registered nearly 600 children with RRP and more than 10,000 surgical procedures in a database created at the CDC. From its collective experience with this frustrating disease, the task force has established guidelines for the diagnosis and management of children with RRP. The task force has authorized the Academy to make available the guidelines in this Bulletin, in/brining the members of new recommendations regarding the current treatments and issues related to childhood RRP. Parents incur justifiable anxiety when their child undergoes even a one-time surgical procedure requiring general anesthesia. Now imagine the never-ending apprehension of a family with a 12-year-old needing 80 operations in ten years, or a young couple whose lives are on hold while their two-year old daughter has laser
surgery ever)' seven to ten days just so she can breathe. Both of these children suffer from Recurrent Respiratory Papillomatosis (RRP), a disease of viral etiology, caused by human papillomavirus types 6 and 11, associated with exophytic lesions of the airway.
Although it is a benign disease, RRP has potentially morbid consequences because of its involvement of the airway and the risk of malignant conversion. Dr. Derkay, immediate past chair of the Academy's Pediatric Otolaryngology Committee and Professor of Pediatric Otolaryngology at Eastern Virginia School of Medicine, has studied this insidious disease. In
Bailey's Third Edition, Head & Neck Surger3, Otolaryngology, he writes that, in most pediatric series, RRP is diagnosed between two and tour years of age with a delay in diagnosis from the time of onset of symptoms averaging about one year. Seventy-five percent of the children have been diagnosed before their fifth birthday. It is estimated that between
1,500 and 2,500 new cases of childhood-onset RRP occur in the United States each year. The incidence among children in the United States is estimated at 4.3 per 100,000 children, translating into more than 15,000 surgical procedures at a total cost of more than $100 million per year. Anecdotal observations suggest that most patients are first-born, have
young, first time mothers, and come from families of low socioeconomic status. The clinical course is unpredictable, with malignant transformation possible in chronic invasive Papillomatosis. Children can require surgical removal of papillomas as often as every seven to ten days or as little as once a year to maintain adequate airway function. This aggressive disease is highly individual, which
makes prognosis and estimation of lifetime surgeries difficult. "In an 'orphan disease' such as RRP, where most clinicians have only a handful of these difficult patients, it is essential that we pool our resources and expertise in order to help our colleagues manage
these children," says Dr. Derkay. "Projects such as the RRP Registry at CDC and these practice guidelines are attempts at meeting these goals." Diagnosis and work-up History: Persistent or progressive stridor and dysphonia, with the possible development of respirator)' distress, characterizes the child with newly diagnosed RRP. A maternal or paternal history of genital papilloma or abnormal pap should be sought. Associated symptoms such as feeding
difficulties, 'allergic symptoms, vocal abuse, and a history of choking or aspiration of foreign bodies may help to distinguish RRP from other diagnoses. Physical exam: Findings are dependent upon site and size of papilloma. Clinicians should note the quality of voice, presence of stridor, level of respiratory distress, use of accessory muscles of
respiration, and the resting oxygen saturation. The presence of congenital anomalies such as cutaneous hemangiomas may help to distinguish RRP from other diagnoses. Imaging: Airway fluoroscopy with barium may be helpful to role out other diagnoses such as FB, GERD, laryngomalacia, and vascular ring. There is no role for CT or MRI in initial diagnosis but it may be helpful to follow for pulmonary, extension of disease. Endoscopy: Flexible fiberoptic laryngoscopy (FFL) (or indirect laryngoscopy in an older child) is essential to make the diagnosis outside of the OR. If not technically feasible or the child is in such
distress that you fear that instrumenting the airway outside of the OR would be hazardous, then operative endoscopy with a rigid telescope/ventilating bronchoscope or FFL in the OR would be the alternative. Making the diagnosis (or strongly suspecting the diagnosis) before the operative procedure is desirable for facilitating the education/expectations of
the family and the preparation of the anesthesiologist, surgeon, and OR nursing personnel. Other considerations: Children newly diagnosed with RRP warrant a substantial time commitment on the part of the otolaryngologist to engage the family in a frank and open
discussion of the disease and its management. Support groups such as the Recurrent Respiratory Papilloma Foundation (609-530-1443) can be a vital resource for information and support. RRP patients require frequent office visits and endoscopic procedures at the outset to establish the aggressiveness of their disease. They are encouraged to return to the
office or call as often as necessary while family members and the health care team become familiar with the child's symptoms and level of distress. While infant home intercom-type monitors are often recommended, apnea bradycardia monitors and pulse oximetry are generally not necessary. Speech and language therapy is offered early in the course of the
disease. Control of other medical factors such as reflux and asthma is also aggressively pursued. Surgical management Preparation: Room should be set up in advance and the equipment checked by the surgical team to ensure that appropriate-sized bronchoscopes and telescopes
are available, suctions are of proper length to fit through bronchoscopes, video equipment is functioning (desirable for education of families and to allow anesthesia and OR team to follow the progress of the surgery), and microlaryngoscopes, light cables, and light sources are all available. The procedure should not be performed in a facility without the
necessary complement of equipment to safely instrument a child's airway. CO2 laser (when utilized) should be tested before the child enters the room to make sure it is functioning properly. Informed consent from the family should include discussion of possible scarring, airway edema, and airway fire with the use of the laser (at least on first visit to the
OR). Anesthesia technique: A number of acceptable techniques range from ventilation via a laser safe tube with a FiO2 of <30%, to insufflations techniques using Propafol with intermittent intubation if
needed, to jet-ventilation (either supraglottic or subglottic). The key is good communication between surgeon and anesthesiologist before and during the procedure so that the approach is coordinated. An additional key is to utilize an experienced anesthesiologist comfortable with managing obstructed pediatric airways. If no such individual is available, then
the Otolaryngologist should consider delaying the procedure or transferring the child to a facility where one is available. Surgical technique: A number of acceptable techniques are available to the surgeon including use of the CO2 laser, KTP/ND, Yag laser, microlaryngoscopy forceps, and powerized laryngeal shavers. New
technologies that are just coming available with limited long-term follow-ups that may ultimately prove superior to standard techniques include use of the micro-debriders, flash pump dye and 585-mm pulse dye lasers, argon plasma coagulation, and phonomicrosurgical resection techniques. Since there is currently no therapeutic regimen that reliably eradicates the HPV, when there is a question about whether papilloma is an area that needs to be removed, it is prudent to accept some residual
papilloma rather than risk damage to normal tissue and produce excessive scarring. Even with the removal of all clinically evident papilloma, latent virus may remain in adjacent tissue, which may explain the recurrent nature of RRP. Therefore, the aim of therapy in extensive disease should be to reduce the tumor burden, decrease the spread of disease, create a safe and patent airway, improve voice quality, and increase the time interval
between surgical procedures. Staged papilloma removal for disease in the anterior commissure is appropriate to prevent the apposition of two raw mucosal surfaces. The surgeon who is not aware of injury to deeper tissue layers with injudicious laser usage may encounter unacceptable scarring and subsequent abnormal vocal fold function. Inappropriate and
aggressive use of the laser may also cause injury to nonaffected tissues and create an environment suitable for implantation of viral particles. Biopsy: There is controversy among clinicians regarding the need to send a tissue biopsy with each papilloma surgery. It is our recommendation that a biopsy specimen be sent at the time of the initial diagnosis of RRP. HPV-typing may be performed at that time, though its value in terms
of predicting prognosis is currently limited. Subsequent surgeries should have specimens sent for monitoring of progression to atypia and malignant transformation to SCCA. Additional HPV-typing would only seem to be needed if there is a significant clinical change (surgical interval shortens substantially, new onset of spread to an extra-laryngeal site). In
children who require frequent surgeries, it would seem reasonable to send specimens with every other or every third surgery. An additional benefit that may be derived from serial biopsies is the opportunity to study the archival tissue in the future for clues to prognosis using techniques or markers not currently available. Documentation: It is highly desirable to have a consistent staging and severity scale to follow progression of RRP disease. A computerized tracking system
developed by Coltrera and soon to be available in CD-ROM format via an ASPO grant should simplify this problem by standardizing the nomenclature for describing RRP. This system is ideally suited for tracking results of clinical trials of adjuvant therapies and for physician-to-physician communications. Follow-up: Individualized follow-up needs to be arranged between the families and their doctors. Circumstances that would influence the timing and location of this follow-up would include the travel distance to the
medical center, the reliability of the family and the reliability of their transportation, the rapidity at which the papillomas recur, and the degree of airway compromise caused by the papillomas. An acceptable regimen might include monthly follow-up in the office in the first year of disease diagnosis with FFL performed every other month and whenever the
clinical situation warrants with follow-up extended to every two to four months in subsequent years in a local child with stable disease with reliable transportation and guardians. Surgical intervention would then be planned according to clinical needs. In contrast, a family that lives quite a distance from the hospital might be scheduled for interval
operating room exams once a pattern of recurrence has been established with use of email or phone contact between the surgeon and the family to monitor the clinical situation between surgeries. Adjuvant therapy: The decision to embark upon adjuvant therapy should also be individualized and based upon the frequency of surgical interventions, the morbidity of frequent surgeries, and the
recurrence pattern of the papillomas. A basic rule of thumb would suggest the need for adjuvant therapies if surgery were being required more frequently than four times a year for two years or if the papillomas begin spreading outside of the endolarynx. Additionally, children who present with disease in their trachea should have early consideration for
adjuvant therapy. Choice of therapy depends upon informed consent and evidence-based research. Ideally, patients should be enrolled in clinical studies whenever possible. Adjuvant therapies currently recommended would include: Recombinant Interferon alpha-N2 administered initially at 5 million units per meter squared body surface area by subcutaneous injection daily for 30 days and then three times weekly for at least a six-month
trial. The dose can be reduced to 3 million units/m two to three times a week if side effects are severe. Weaning should be slow to prevent a rebound effect. Reinstitution of therapy after discontinuation has been shown to be effective. Children under the age of one year should be monitored for the possibility of spastic diplegia and should have a baseline
neurologic exam. Children on chronic Interferon therapy need to have their liver enzymes and leukocytes monitored on at least a quarterly basis. Indole-3-carhinol, a derivative of cruciferous vegetables has been shown to alter the growth of papilloma in mice by altering estrogen metabolism. The National Toxicology Program at the National Institute of Environmental Health Sciences has recently embarked upon a toxicology-testing program to certify its safety. A large-scale multiinstitutional trial based at the University of Pittsburgh is still enrolling new patients utilizing chemically pure [3C. Photodynamic therapy is currently being investigated at LIJ in a study headed by Abramson and Shikowitz. Preliminary studies using DHE showed promise in reducing surgical intervals, but photosensitivity limited
its usefulness. The present study utilizing Foscan has shown early promise with minimal tissue damage and less photosensitivity. Cidofovir (Vistide) has demonstrated promise in clinical series from San Diego and Belgium in adults and children with aggressive RRP disease. This drug, which is approved for use in HIV patients with CMV
retinitis, is designed to be injected into the papilloma bed after debulking surgery. This has prompted interest in pursuing a multi-institutional open trial. The protocol for the open trial is being formulated currently and will likely include an arm for children with severe disease as well as a randomized, placebo-controlled arm for children with newly
diagnosed papilloma. An ASPO grant and support from the Gilead Pharmaceutical Company are being sought to administer the study. A multi-institutional safety study is also in the process of development. Reflux: Preliminary data from Bowman Gray (Cummins and Koufman) and Great Britain (Harcourt et al.) suggest that achieving optimal control of gastroesophageal reflux disease may have significant benefits in children with laryngeal papillomas. It would seem prudent to investigate and
control reflux in RRP patients while this relationship is studied further. Tissue bank: Through the National Registry established at the CDC, it may be possible to create a potential tissue bank of RRP specimens that could be utilized by RRP
researchers to correlate histopathology with clinical histories of papilloma progression. Confidentiality and logistic issues would need to be worked out to make this a reality. |
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