Rose Stavinoha and Farrel Joel Buchinsky
Recurrent respiratory papillomatosis (RRP) is an uncommon disease caused by two common viruses: human papillomavirus (HPV) 6 and HPV 11. The disease is a tremendous burden to affected children and their families because of dysphonia, airway obstruction, and the need for repeated surgery. Papillomas (warts) may be present at any point along the upper aerodigestive tract but the vocal folds are the predominant site of the lesions and hence dysphonia is typically the first symptom. Notwithstanding the fact that voice is a quintessential human characteristic, abnormalities in a young child's voice often receive little attention. If left unchecked, the papillomas can grow to obstruct the airway and lead to dyspnea and stridor. The primary goal of management is symptomatic relief by removing papillomas but even with aggressive surgical treatment, recurrence is the norm.
Clinical Course
Normal phonation is dependent on the vocal folds being able to vibrate freely in response to positive subglottic pressure. The presence of these wart-like lesions or papillomas impedes the motion of the mucosal wave that should occur on the vocal folds (Figs. 13.1 and 13.2). The corollary is true—papilloma may be present in the larynx or the airway, but as long as it is not located where it would interfere with voice production, the voice may be normal. The unsuspecting clinician may initially manage children with RRP as chronic cough, recurrent pneumonia, upper respiratory infections, croup, asthma, or allergies. Since RRP is rare, there is often a delay of many months between the onset of symptoms and diagnosis of RRP. For children with RRP, the median age at diagnosis is 3.1 years and, on average, they undergo more than 20 surgeries for RRP during their lifetime.1
Figure 13.1 Laryngeal papilloma affecting the true vocal folds with minimal airway obstruction.
Image courtesy: R. Donald Moe, M.D.
At any one point in time, an individual may have a disease that spans the spectrum from mild to severe. The most widely used method to document the instantaneous severity is the Derkay-Coltrera staging system. The scheme assigns a numerical score to describe the type of lesion (surface lesion vs. raised lesion vs. bulky lesion) according to the subsites affected with a final numerical score defining the overall current extent of disease.2
Figure 13.2A, B Laryngeal papilloma affecting the larynx with severe airway obstruction.
Image courtesy: Juan Bonilla, M.D.
The natural course and duration of RRP is highly variable. In essence, RRP is a benign neoplasm but may cause significant morbidity and even death in severe cases. One patient may have an aggressive course, requiring surgical excision of papilloma every few days or weeks, and such a patient is often a candidate for adjuvant therapies. Others may require only periodic surgical interventions every several months or years. “Aggressiveness” is a label often attached to those with a greater frequency of surgeries or a greater number of lifetime surgeries or distal spread to the trachea (Fig. 13.3), bronchi, and pulmonary parenchyma or those who ever undergo tracheostomy for RRP. The average child with active RRP requires 5.1 procedures per year with a range from 0.4 to 22 procedures per year, according to a 2003 report from the RRP task force national registry.1 Eventually most children with RRP go into remission. Among 165 pediatric cases followed-up for a median period of 1.7 years (range, 0.01 to 4.6), 22% went into remission.3 By 3.6 years following diagnosis, 44% had gone into remission. Even with remission, dysphonia seldom resolves and there is always the possibility of recurrence of RRP.4,5
Figure 13.3 Papillomata in a case of recurrent respiratory pappillomatosis with distal spread to the trachea.
Image courtesy: David E. Tunkel, M.D.
The variable behavior of RRP is poorly understood. Epidemiological data indicate that younger patients tend to have a more aggressive disease1,6 and decreased likelihood of remission. Remission aside, even for those still with active disease, most children require less surgery over time7,8 (Fig. 13.4). In the more ominous cases, the disease may progress to include pulmonary lesions9 (1%) or even malignant transformation. Reported malignancy rates have ranged from 2% of 244 cases10 to 13% of 38 cases in those enrolled in an interferon trial.11 Malignancy was almost always associated with HPV 11 and not with HPV 6, occurred many years after diagnosis,12 and commonly occurred in the setting of pulmonary RRP.
Figure 13.4 The Hospital for Sick Children in Toronto chronicled the number of surgical interventions in their cohort of patients. Adjuvant pharmacologic therapy (interferon or cidofovir) was used in less than one-fifth of cases. A locally smoothed estimate shows how, as a group, patients who still had recurrent respiratory pappillomatosis had a decelerating rate of surgeries over time.
Adapted from: Hawkes M, Campisi P, Zafar R, et al. Time course of juvenile onset recurrent respiratory papillomatosis caused by human papillomavirus. Pediatr Infect Dis J 2008;27(2):149–154.
Epidemiology and Virology
Two population-based systematic studies have calculated the incidence in North America at 0.2 to 1.1 per 100,000 people younger than 18 years. The prevalence of the disease is roughly four to five times the incidence.13,14 In 2010, Campisi and colleagues created a national database in Canada for RRP affecting children younger than 14 years of age to follow incidence over time. A study published in 1995, estimated a higher incidence of 4.3 per 100,000 children in the United States.5 This estimate relied on a survey of board-certified otolaryngologists and may be less accurate than the more recent population-based studies.
HPV is a double-stranded DNA capsid virus categorized into more than 180 identified genotypes which have different tissue preferences and clinical manifestations. HPV 6 and 11 account for the overwhelming majority of RRP cases.15 HPV 6 and 11 confer a low risk for malignant transformation compared with HPV 16 and 18. For many years, investigators have noted an association between aggressive clinical course and HPV 11 (rather than HPV 6) and young age (rather than older children). Buchinsky et al analyzed the relevant strength of the association between HPV type, age, and course.6Age was more strongly associated with clinical course than was HPV type.
Epidemiological analysis has led to the presumption that RRP in children is caused by vertical transmission of HPV from the maternal genital tract to the fetus at the time of birth. The virus then remains dormant for months or years. While millions of women have genital HPV 6 and 11, relatively few children develop RRP. Even in the setting of vaginal delivery with visible condyloma acuminata the probability of subsequent RRP is low (1 in 144 being the highest risk reported).16 Cesarean section (C-section) is associated with a lower incidence but it is not absolutely protective. C-section has been considered as a preventative strategy but has not been adopted because of the morbidity, mortality, and economic cost of C-section in the light of low RRP incidence. Further, the majority of cases of RRP occur in the absence of maternal condyloma. Exposure to HPV is necessary but is not sufficient. An underlying genetic susceptibility may explain the different clinical courses and exact mode of transmission. Further research is needed regarding factors affecting the development and clinical course of RRP.17,18
Management
No cure exists. Initial treatment involves surgical intervention where the aim is to improve voice, prevent airway obstruction, and avoid iatrogenic complications while awaiting remission. Many agents have been used over the years as an adjuvant to surgery but surgical removal has been the mainstay of treatment.
Surgical
Papillomas are debulked via endoscopic surgical excision or ablation with microlaryngoscopy. Ideally the surrounding normal tissue should be preserved as much as possible while debriding just the obstructing lesions. Injury to surrounding tissues causes scarring or stenosis, which may lead to permanent dysphonia and/or airway compromise. A biopsy should initially be obtained to confirm the diagnosis. During subsequent surgeries, periodic pathologic surveillance can monitor for atypia and malignant transformation.
There are several methods to debulk the papillomas. The original method involves the use of microlaryngeal instruments such as a pair of cupped biopsy forceps. If the forceps were wielded with little precision, the surrounding normal tissue could have been avulsed, which could have lead to scar formation. Seeking greater precision, surgeons have used laser ablation, using both line of sight and fiber-delivered CO2 lasers. Laser risks include airway fire and injury from the laser beam. HPV DNA can be found in the laser plume of smoke, and in one in vivo experiment, bovine papillomavirus in the laser plume was able to establish disease in calves.19 Thus concern about contagion of surgical workers exists, and safety precautions are advised.
In the past 10 years, powered microdebriders with laryngeal blades have become the most commonly used device for excision of laryngotracheal papilloma. One study of microdebrider use for RRP showed reduced operative and anesthesia time, and avoidance of thermal injury to surrounding tissues when compared with the CO2 laser.20 An American Society of Pediatric Otolaryngology survey in 2004 documented that the microdebrider had supplanted the CO2 laser as the most widely used device for RRP treatment.21 It must be noted however that there have not been any randomized, controlled studies to compare treatment outcomes of CO2 laser ablation or microdebrider excision of laryngeal papillomas. Holler and colleagues published a prospective cohort study in 2009 which compared the voice outcomes of 11 children with RRP treated with CO2 laser or microdebrider.22 The objective acoustic evaluations performed between each group demonstrated that microdebrider resulted in better acoustic results.
Other ablative angiolytic lasers have also been used recently, including, the 585-nm pulsed dye laser and the 532-nm pulsed potassium-titanyl-phosphate laser. Both lasers are absorbed by hemoglobin and selectively target the vascular papilloma lesions. These lasers allow for in-office treatment in older children and adults. A prospective, longitudinal study by Hartnick et al involving 23 pediatric patients found the 585-nm pulsed dye laser may allow more aggressive surgical excision of papillomas at the anterior commissure disease as epithelial damage is reduced with this device.23
Tracheotomy is occasionally undertaken for children with life-threatening airway obstruction from aggressive RRP. Surgeons are reluctant to place a tracheotomy as it has been suggested that the chronic irritation may activate or contribute to the spread of disease to the lower respiratory tract. If tracheotomy is performed, then early decannulation is advised when the disease can be managed by endoscopic techniques alone.
Adjuvants
Numerous adjuvant therapies have been used to treat RRP. The most widely accepted indications for use of adjuvants include surgical frequency more than four per year, rapid regrowth of papilloma with airway compromise, and distal spread of disease to multiple sites. A comprehensive review article by Gallagher and Derkay24 describe multiple adjuvants that have been tried to treat RRP including acyclovir, ribavirin, indole-3-carbinol, cyclooxygenase-2 inhibitors, retinoids, and zinc. The two adjuvants probably most widely used and studied are interferon and cidofovir.
Interferon has been the subject of two randomized trials.25,26 Both studies demonstrated some improvement when the drug was administered to treat aggressive disease. Unfortunately the improvement was found to be only temporary or required the ongoing administration of a drug with bothersome and toxic adverse effects such as fever, flu-like symptoms, seizures, decrease in growth rate, and leukopenia.
There has been wide adoption of cidofovir therapy for RRP most commonly as an intralesional injection or less commonly as an intravenous systemic treatment. The drug is a cytosine nucleotide analog and suppresses DNA replication through selective uptake by the viral DNA polymerase. While that mechanism holds against cytomegalovirus (the original indication for the drug), the same mechanism of action does not apply as well for HPV since HPV does not encode its own DNA polymerase. Pharmacology aside, there have been promising outcomes documented in multiple small case series but there has only been one randomized, double-blind, placebo-controlled trial. McMurray et al27 found significant improvements, such as reduced Derkay severity score, over time in those receiving cidofovir. However, even those who received placebo improved over time. A major weakness of the study was that concerns about toxicity resulted in regulatory approval only being granted for a cidofovir intralesional injection concentration of 0.3 mg/mL—well below what most practitioners were using. Only much later were the investigators permitted to use the concentration of 5 mg/mL. Concerns over the oncogenic potential of cidofovir led the RRP task force in 2005 to recommend limiting the use of adjuvant cidofovir to severely recalcitrant RRP cases.28,29 In contrast to these previous recommendations, a recent study of histologic specimens of RRP patients over time found no worsening of dysplastic progression and recommended additional investigation.30
Control of gastroesophageal reflux has been found to correlate with decreased rate of recurrence of RRP in several case reports. A small series of children with RRP studied by McKenna and Brodsky in 200531 found that control of extraesophageal reflux disease improved control of RRP resistant to earlier therapies. Although further study is needed, it may be worthwhile to treat patients with antireflux medication if they have aggressive disease.
Numerous adjuvants have strong support, with plausible mechanisms of action and anecdotal reports of clinical success. The small number of patients, the variable and unpredictable natural history, and the lack of controlled randomized studies make the support for most of these adjuvants quite problematic.
The most tangible hope for prevention of RRP lies in vaccination. A quadrivalent HPV vaccine has been developed which protects against HPV types 6, 11, 16, and 18. It is currently approved by the U.S. Food and Drug Administration for the prevention of cervical carcinoma, dysplasia, and genital warts. Widespread vaccination with this particular vaccine could potentially reduce newborn exposure to HPV 6 and HPV 11 by eliminating the maternal and paternal reservoir and theoretically prevent RRP. However, the reasonable expectation may be possible only if there is high penetration of the quadrivalent vaccine in the world population, a goal that may not be possible due to cost, competition, or the perception by some of unpalatable moral ramifications. Additionally, such potential benefits would take years to manifest, and affected RRP patients would not benefit.
Quality of Life and Psychosocial Considerations
RRP is frequently extremely burdensome and life altering to both patients and their families as they deal emotionally and physically with RRP and its treatment.
RRP places a large economic burden on individual patients, their families, and society. In the United States, the average lifetime cost to treat one patient with RRP has been estimated between $ 43,267 and $ 218,067.32 see erratum A cross-sectional study by Chadha and colleagues used validated measures of health utility (a measure of where someone feels that they are on the spectrum between death and perfect health), voice-related quality of life, and psychosocial impact to assess the burden of RRP on children and families.13 The study found that the impact of RRP on health utility was comparable to many other chronic diseases of childhood such as cystic fibrosis. Voice disturbance is the predominant factor affecting quality of life. Interestingly, it was also found that health utility and voice-related quality of life outcomes did not correlate well with the Derkay-Coltrera severity score. In terms of family burden, the contributing factors include the need for multiple hospital visits, social stigma of the disease, and parental anxiety about the health of the affected child and unaffected siblings. The co-occurrence of RRP in siblings is rare but has been observed.5
Parents of children with RRP often experience shame and embarrassment as they come to terms with the fact that their child probably contracted the etiologic agent from the mother's genital tract.
There are currently two groups available to assist patients and families with the psychological and social issues surrounding RRP as well as the current research and information about the disease: the Recurrent Respiratory Papillomatosis Foundation in Lawrenceville, New Jersey, and the International RRP Information, Support and Advocacy Center based in Bellingham, Washington.
References
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