Age at diagnosis, but not HPV type, is strongly associated with clinical course in recurrent respiratory papillomatosis

Abstract

Background: Recurrent Respiratory Papillomatosis (RRP) is a rare disease characterized by the growth of papillomas in the airway and especially the larynx. The clinical course is highly variable among individuals and there is poor understanding of the factors that drive an aggressive vs an indolent course.

Methods: A convenience cohort of 339 affected subjects with papillomas positive for only HPV6 or HPV11 and clinical course data available for 1 year or more, from a large multicenter international study were included. Exploratory data analysis was conducted followed by inferential analyses with frequentist and Bayesian statistics.

Results: We examined 339 subjects: 82% were diagnosed prior to the age of 18 years, 65% were infected with HPV6, and 69% had an aggressive clinical course. When comparing age at diagnosis with clinical course, the probability of aggressiveness is high for children under five years of age then drops rapidly. For patients diagnosed after the age of 10 years, an indolent course is more common. After accounting for confounding between HPV11 and young age, HPV type was minimally associated with aggressiveness. Fast and Frugal Trees (FFTs) were utilized to determine which algorithms yield the highest accuracy to classify patients as having an indolent or aggressive clinical course and consistently created a branch for diagnostic age at ~5 years old. There was no reliable strong association between clinical course and socioeconomic or parental factors.

Conclusion: In the largest cohort of its type, we have identified a critical age at diagnosis which demarcates a more aggressive from less aggressive clinical course.

Fig 1. Relationship between clinical course and type of HPV in patients across the spectrum of age at diagnosis.

Fig 2. The relationship between age at diagnosis and clinical course.

Proportion of patients with an indolent versus aggressive clinical course in relation to the age at which each patient was diagnosed with RRP. Each bar represents one twelfth of the subjects (duo-decile) ranked by age at diagnosis.

Fig 3. FFT for predicting the clinical course of RRP.

A stepwise decision tree using age at diagnosis (dxage), country, and HPV type best predict the clinical course of RRP. An age at diagnosis of < 5.2 years, residence in the countries of USA, South Africa, and Netherlands, and HPV11 are the best variables to predict an aggressive clinical course of RRP. “p” is for probability. “! =“ is notation for “not equal to”. Colors: green = correct, red = false. Shapes: triangle = aggressive, circles = indolent (see bottom left 2x2 box).