HPV is a small DNA-containing, nonenveloped icosahedral (20-sided) capsid virus with a double-stranded circular deoxyribonucleic acid 7,900 base pairs long. Until the 1990s, HPV had been suspected but not confirmed as the causative agent in RRP. This uncertainty developed from an inability to culture the virus in vitro, and from the failure to demonstrate viral particles consistently in papilloma lesions using electron microscopy or HPV antibodies. Today, with the use of viral probes, HPV DNA has been identified in virtually every papilloma lesion studied. The
most common types identified in the airway are HPV 6 and HPV 11, the same types responsible for genital warts. Specific viral subtypes may be correlated with disease severity and clinical course. Children infected with HPV 11 appear to have a more obstructive airway course early in the disease and a greater need for tracheotomy (9,10).

HPVs are grouped on the basis of genetic homology, with viruses that exhibit less than 90% identity in specific regions of the viral genome being defined numerically as separate types. On this basis, nearly 100 different HPV types have been identified. These groupings correlate with tissue preference as well as similarities in pathophysiology. Groups associated with mucosal lesions in the aerodigestive and genital tracts include HPV types 6 and 11 with a low malignant potential; HPV 16 and 18 with a much higher malignant potential; and HPV 31 and 33 with a malignant potential that lies somewhere in between. At least 90 different types of HPV have been identified and are designated by numbers (i.e., HPV 6). The closer the numbers, the more similar the viral subtypes are in their clinical manifestations.

The induction of cellular proliferation is a fundamental property of HPV though its mechanism of action remains unclear. The present understanding is that HPV establishes itself in the basal layer, where viral DNA enters the cell and is transcribed into RNA which is then translated into viral proteins. The genome consists of three regions: an upstream regulatory region and the two regions named according to the phase of infection in which they are expressed, the early (E) and late (L) regions. The E region genes are involved in potent oncogenes that are responsible for the replication of the viral genome, interaction with host cell intermediate filaments, and transforming activities. The L region genes encode the viral structural proteins (11). Several factors are involved in the regulation of cell proliferation.

It is likely that the host immune system plays an important role in the pathogenesis of HPV-induced lesions. Both humoral and cellular immune responses may be compromised in children with RRP and a patient’s immunocompetence may also influence the clinical course of disease. The role of cytokines such as interleukin-2, interleukin-4, and interleukin-10 and expression of the major histocompatibility complex antigens in the malfunction of the cell-mediated immune response in children with RRP have been demonstrated (12). Papillomas with a reduced expression of these antigens may evade immune surveillance and allow the disease to progress more rapidly.

HPV is thought to infect stem cells within the basal layer of epithelium (13,14,15). Following infection of the stem cells, the viral DNA can either be actively expressed, or it can exist as a latent infection in epithelium that remains clinically and histologically normal. During latency, there is very little viral RNA present. In fact, HPV DNA can be detected in normal-appearing mucosa in RRP patients who have been in remission for years, explaining why reactivation and clinical recurrence can occur following many years of remission (16,17,18). Thus, reactivation of viral expression can occur any time following establishment of a latent infection. Adult-onset respiratory papillomas could reflect either activation of virus present since birth or an infection acquired in adolescence or adult life. Gene products of early genes E6 and E7, and possibly E5, are required for papilloma induction, but the details of the mechanism of HPV activation are unknown. In order to “cure” RRP, it is necessary to modulate the host response to the virus and, ideally, eliminate the latent infection.

The universality of HPV in the lower genital tract rivals that of any other sexually transmitted disease in humans. It is estimated that at least 1 million cases of genital papillomas occur per year in the United States, affecting about 1% of the population (19). These most often manifest as condylomata acuminata involving the cervix, vulva, or other anogenital sites in women or the penis of male sexual partners of affected women. In addition, it is estimated that colposcopic (subclinical) changes affect nearly 5 million US women. An additional 14 million women, or about 10% of the female population of child-bearing age, are DNA positive but have no visible lesions while more than 80 million women, or 60% of the at-risk population, are HPV antibody positive but DNA negative. The incidence of HPV infections in sexually active young college women is high, with a cumulative incidence of 43% over a 36-month period in a recent study (20). Clinically apparent HPV infection has been noted in 1.5% to 5% of pregnant women in the United States (21). As in RRP, HPV 6 and 11 are the most common subtypes identified in cervical condylomata.

Histologically, RRP appears as pedunculated masses with fingerlike projections of nonkeratinized stratified squamous epithelium supported by a core of highly vascularized connective tissue stroma (Fig. 94.1). The basal layer may be either normal or hyperplastic, and mitotic figures are generally limited to this layer. Cellular differentiation appears to be abnormal, with altered expression and production of keratins. The degree of atypia may be a sign of premalignant tendency.

RRP lesions occur most often at anatomic sites in which ciliated and squamous epithelium are juxtaposed (22). The most common sites for RRP are the limen vestibuli, the nasopharyngeal surface of the soft palate, the midline of the laryngeal surface of the epiglottis, the upper and lower margins of the ventricle, the undersurface of the vocal folds, the carina, and at bronchial spurs (6). In tracheotomized patients, RRP is often encountered at the stoma and in the mid-thoracic trachea, areas that might be considered iatrogenic squamociliary junctions. Papilloma lesions may be sessile or pedunculated and often occur in irregular exophytic clusters (Fig. 94.2). Typically, the lesions are pinkish to white in coloration. Iatrogenic implantation of papilloma may be preventable
by avoiding injury to nondiseased squamous or ciliated epithelium adjacent to areas of frank papilloma. Ciliated epithelium undergoes squamous metaplasia when exposed to repeated trauma and is replaced with nonciliated epithelium that creates an iatrogenic squamociliary junction. This may also explain the observation that RRP flourishes in the presence of uncontrolled gastroesophageal reflux with an increased incidence of laryngeal scarring (23).

The precise mode of HPV transmission remains unclear. Several studies have convincingly linked childhood-onset RRP to mothers with genital HPV infections, whereas circumstantial evidence suggests that adult disease may be associated with oral-genital contact. Retrospective and recent prospective studies have confirmed that HPV may be passed by vertical transmission from mother to child (32,33,34). Silverberg showed that children born to mothers with active condylomata had a 231-fold increased risk of developing RRP when compared to children born to disease-free mothers (35). In addition, they showed that children born to women with active condylomata had a twofold higher risk of developing RRP if labor lasted more than 10 hours. Kashima found that childhood-onset RRP patients were more likely to be first born and vaginally delivered than were control patients of similar age (36). The authors hypothesized that primagravid mothers are more likely to have a long second stage of labor and that the prolonged exposure to HPV in the birth canal leads to a higher risk of infection in the first born child. They also suggested that newly acquired genital HPV lesions are more likely to shed virus than long-standing lesions. This would explain the higher incidence of RRP observed among the offspring of young mothers of low socioeconomic status—the same group that is more likely to acquire sexually transmitted infections such as HPV.

Hallden showed that 54% of JORPP patients were born to mothers with a history of vulvar condylomata at the time of delivery (37). Despite this apparent close association, few children exposed to genital warts at birth actually develop clinical disease (38). It is not well understood why RRP develops in so few children whose mothers have condylomata. Although HPV could be recovered from the nasopharyngeal secretions of 30% of infants exposed to HPV in the birth canal the number of infants expected to manifest evidence of RRP is only a small fraction of this (39). Based on these data, it appears that secondary factors including patient immunity; timing, length, and volume of virus exposure; and local traumas (intubation, extraesophageal reflux) must be important in the development of RRP. Reports of neonatal papillomatosis suggest that, in at least some cases, development of the disease may occur in utero. Because caesarean section does not seem to prevent the development of RRP in all cases, a better understanding of the risk factors associated with RRP is needed before the efficacy of caesarean delivery in preventing papilloma disease can be fully assessed (40).

A case-control study found that patients with AORRP had more lifetime sexual partners and a higher frequency of oral sex than matched controls (36). This data would suggest patients with AORRP are exposed later in life than patients with JORRP. However, HPV has the disturbing capability to form latent infections in the basal cell layer of otherwise healthy appearing mucosa (16,17,18). It has been suggested that AORRP may represent a reactivation of HPV infection acquired during birth instead of a de novo exposure during adulthood.

Viral DNA has been detected in areas of “normal appearing mucosa” adjacent to papilloma lesions, suggesting a possible explanation for the recurrence of the disease following thorough surgical removal (18,38). Brandsma reported finding HPV DNA in 4% of random, clinically normal biopsies of the airway (41). AORRP, thus, could reflect either activation of virus present since birth or an infection acquired in adolescence or adult life. Nosocomial acquisition of virus by patients in the operating room
(OR) also may result theoretically from improper equipment sterilization or room preparation. However, current Occupational Safety and Health Administration recommendations have virtually eliminated this risk.

Although any site along the upper aerodigestive tract can be affected, HPV shows a predilection to infect sites where ciliated columnar and squamous epithelia are juxtaposed (8). This explains the frequent involvement of the false vocal folds, the upper and lower margins of the ventricle, and the undersurface of the true vocal folds. In tracheotomized patients, papillomas often are encountered at the stoma and in the mid-thoracic trachea, which are areas where iatrogenic trauma to ciliated epithelium often induces squamous metaplasia (see Fig. 94.3). It is postulated that an eddying flow of the mucous blanket at squamociliary junctions may concentrate infectious viral particles at these sites. Children with bronchopulmonary dysplasia who require prolonged endotracheal intubation also may be at increased risk for development of RRP. An endotracheal tube may play the same role in the mechanical dissemination or implantation of papilloma virus as a tracheotomy in this setting, through the interruption of the continuous respiratory mucosal surface. Gastroesophageal reflux disease (GERD) also has been identified as a potential risk factor for disease persistence, although additional research is necessary to verify this anecdotal observation.

Persistent or progressive stridor and dysphonia, with the possible development of respiratory distress, are the most consistent signs and symptoms of RRP in children (Table 94.1). In the absence of severe respiratory distress, a careful history should be obtained. Information regarding the time of onset of symptoms, possible airway trauma including a history of previous intubation, and characteristics of the cry are obviously important. Hoarseness, although a common and often benign clinical complaint in young children, always indicates some abnormality of structure or function. Because of the precision of laryngeal mechanics, hoarseness may result from a remarkably small lesion and thus be an early sign in the course of a disease process. On the other hand, if the lesion’s origin is remote from the vocal cords, hoarseness may present as a late sign. Although histologically the same lesion, a papilloma that produces hoarseness in one patient may produce stridor and obstruction in another, depending on the size and location of the lesion. The quality of the voice change may give only limited clues to its etiology, whereas other characteristics such as age of onset, rate of progression, associated infection, history of trauma or surgery, and the presence of respiratory or cardiac distress may be of much greater significance. A low-pitched, coarse, fluttering voice suggests a subglottic lesion, whereas a high-pitched, cracking voice, aphonia, or a breathy voice suggests a glottic lesion. Associated high-pitched stridor also suggests a glottic or subglottic lesion. Although stridor that has been present since birth is more often associated with laryngomalacia, subglottic stenosis, vocal cord paralysis, or a vascular ring, it should be realized that neonates also can present with papillomatosis.

Associated symptoms such as feeding difficulties, allergic symptoms, vocal abuse, and the presence of hereditary congenital anomalies may help distinguish RRP from alternative diagnoses, including vocal fold nodules, vocal fold paralysis, subglottic cysts, subglottic hemangioma, and subglottic stenosis. In the absence of any history suggesting these lesions, review of the perinatal period may reveal a history of maternal or paternal condylomata. If the onset of stridor and dysphonia is gradual and progressive over weeks or months, then neoplastic growth compromising the airway must be considered and investigated.

Certainly not every child with a hoarse voice or cry merits investigation beyond an assessment of the symptom. However, in the presence of hoarseness with respiratory distress, tachypnea, decreased air entry, tachycardia, cyanosis, dysphagia, chronic cough, failure to thrive, recurrent pneumonia, or dysphagia, the larynx must be visualized and a firm diagnosis of the cause of hoarseness must be made. Any child with slowly progressive hoarseness merits investigation and the clinician should not wait until total aphonia or airway problems occur.