This document summarizes juvenile respiratory papillomatosis (JORRP), a potentially life-threatening disease caused by human papillomavirus (HPV) types 6 and 11. It affects the respiratory tract from the nose to the bronchi. The main treatment is surgical debulking, while adjuvant therapies like interferon alpha, cidofovir and bevacizumab may help control disease between surgeries. While most cases resolve spontaneously, some children develop uncontrolled disease that can rarely spread to the lungs and become fatal, including potential malignant transformation of the papillomas.

1. SCOTT BROWN
LEARNING 2020- JORRP
VOLUME-2
CHAPTER-32
PAGE-367 to 376
Dr.MONISHA RM

2. KEY POINTS
• Juvenile respiratory papillomatosis can affect any part of the respiratory
tract.
• uncommon condition-major surgical burden to the otolaryngologist.
• The mainstay of treatment is by surgical debulking.
• The role of adjuvant therapy is uncertain but supported by level 3 evidence.
• In the majority of cases, the disease goes into spontaneous remission.
• Some children develop uncontrolled disease, which in rare cases may be
fatal.

3. INTRODUCTION
• Recurrent respiratory papillomatosis (RRP) is a potentially life-threatening disease
characterized by the development of papillomata anywhere in the respiratory tract from the
nasal vestibules to the terminal bronchi.
• Predominant sites are where there is a change of epithelium (e.g. from squamous to ciliated)
tonsillar pillars
uvula
vocal folds and laryngeal commissure.
• Bimodal age distribution - juvenile-onset peak occurring at 3–4 years of age
- adult-onset peak occurring at 20–30 years of age.
• Boys and girls appear to be nearly equally affected in juvenile-onset RRP (JORRP)
• Adult-onset RRP, which is a disease transmitted via sexual contact or via indirect contact
with anogenital lesions, preferentially affecting men by a ratio of approximately 3 : 2.

4. HISTORY
• First described by Morrell Mackenzie in 1880
• By 1923, Ullmann had demonstrated an infective aetiology by injecting
homogenized papilloma from a child’s larynx into his own forearm and
inducing local growth of papillomas.

5. AETIOLOGY
• Direct evidence of the association between human papilloma virus (HPV)
and RRP came from the identification of HPV DNA within laryngeal
papillomas by Southern blot hybridization and the subsequent recognition in
papillomas of HPV types 6 and 11
• Human papillomavirus is a naked, double-stranded, icosahedrally shaped
virus with circular supercoiled double-stranded DNA genome surrounded by
an outer capsid of protein that belongs to papovavirus family
• HPV types 6 and 11 are also associated with condyloma acuminata (genital
warts). Types 16 and 18 have been implicated in carcinogenesis, particularly
in the uterine cervix and in squamous cell carcinoma of the head and neck.

6. • HPV is thought to first enter traumatized epithelium and reside in the basal
layer of the mucous membrane, where it replicates by a process known as
episomal maintenance.
• This replication interferes with the normal process of cell maturation,
causing epithelial proliferation and neovascularization.
• Conversely, the virus may lie dormant, causing subclinical infection, and can
often be recovered from apparently normal tissue adjacent to papillomas.
• Viral protein, DNA synthesis and virion assembly only takes place in the
granular and cornified layers of the terminally differentiated epithelium

7. EPIDEMIOLOGY
• Prevalence of only 4 in 100 000 children.
• The oft-quoted triad of susceptibility factors for JORRP – young
mother,vaginal delivery and low maternal socioeconomic status–is of limited
predictive usefulness
• HPV DNA has been found in one-third to one-half of aerodigestive tract
swabs of children born to affected mothers.
• However, the majority of these children do not develop disease.
• Only 1 in 400 infants delivered to women with genital warts subsequently
develops JORRP. This relative risk is much lower than that for sexually
transmitted diseases.

8. • A large retrospective study has shown that children born to mothers with
genital warts carry a 231× relative risk of developing JORRP.
• A prolonged delivery time (exceeding 10 hours) conferred a twofold increased
risk but delivery by Caesarean section did not appear to reduce that risk
• Variation in the susceptibility of the host to viral infection may be associated
with specific HLA polymorphisms,several of which have been reported.
• Two recent, large independent studies have shown an association between
HLA-DRB1*0301 and severe disease

9. DIAGNOSIS
• The clinical diagnosis should be established with awake fibre-optic
nasolaryngoscopy (using an infant 2.2 mm or 2.7 mm endoscope)
• The preferred anaesthetic technique is that of spontaneous respiration
without endotracheal intubation.
• General anaesthesia is induced either by intravenous propofol or by
inhalation of sevoflurane in oxygen.
• The larynx is topically anaesthetized with 2% lidocaine and anaesthesia
maintained by sevoflurane in oxygen

10. • Meticulous haemostasis is therefore required during the procedure using
topical epinephrine (1 : 10 000)
• Pre-operative dexamethasone to reduce laryngeal oedema but some surgeons
feel that anti-inflammatory agents are best avoided during active
manipulation of papilloma tissue.
• Laryngopharyngeal exposure to gastric acid is increasingly being recognized
as a cause of laryngeal pathology particularly in the immediate post op
period
• Prophylaxis against gastro-oesophgeal reflux with an H2-antagonist or a
proton pump inhibitor for 48 hours after all laryngeal surgery, including
surgery for JORRP

11. • Macroscopically, papillomas can be pedunculated or sessile, spread over the
mucosal surface of the larynx.
• They tend not to be friable and can be grasped using microlaryngeal
instruments and excised for histological examination.
• Microscopically, the papillomas appear as exophytic projections of
keratinized squamous epithelium overlying a fibrovascular core, with
varying degrees of dyskeratosis, parakeratosis and dysplasia.
• Koilocytes (vacuolated cells with clear cytoplasmic inclusions)are often seen
indicating viral infection.

12. STAGING
• Proposed and modified by Derkay-based on a combination of the anatomical
distribution and extent of lesions and their clinical effects on voice and the
child’s airway.
• Enables the comparison of results between
centres and facilitates multicentre trials, particularly
of adjuvant treatments

13. TREATMENT
• The aim of surgical treatment is the removal of papillomas and restoration
of a safe and patent airway while minimizing trauma to the mucosa and
vocal cords.
• Risk of scarring and webbing can be reduced by the avoidance of two
opposing raw surfaces, especially at the anterior commissure.
• In children requiring repeated extirpations of extensive papillomas,
especially if they predominantly occur in the larynx, it may be ultimately
impossible to achieve normal voice.

14. SURGICAL TREATMENTS
POWERED MICRODEBRIDER
• Gold standard for papilloma removal in the larynx
• A non-serrated laryngeal blade is used with a setting of 300–700 rpm which
allows the papillomas to be suctioned into the debrider with minimal cutting
trauma to surrounding normal tissues.
• allows gentle but comprehensive removal of papillomas with minimal
contamination of the lower respiratory tract with blood or papillomas.
• compared with the CO2 laser,patients undergoing laryngeal papilloma
debridement have good disease clearance, require a shorter procedureand
experience less post-operative pain.

16. COLD STEEL SURGERY
• Advocates of papilloma removal using microlaryngeal instruments claim
that the use of a microflap technique minimizes trauma to the vocal fold
while satisfying disease clearance.
• Thermal damage to neighbouring tissue is also avoided, as is the vapour
plume
• Disadvantage-no direct haemostasis when dealing with a very vascular
lesion

17. CO2, KTP,ND:YAG,PULSED DYE LASER
• Treatment of choice for many surgeons because of its ability to ablate the
papillomas with minimal bleeding and its ease of use with a microscope and
micromanipulator.
• Frequency of late soft tissue complications, such as vocal fold fibrosis,
interarytenoid fibrosis and stenosis, glottic webbing and arytenoid fixation,
has been reported to be 13–45%
• Two-stage procedure whereby the bulk of the papillomas are removed at the
first operation, which is then followed by a repeat endoscopy and laser
ablation 10 days later, by which time the coagulum and carbonized tissue
have resolved, allowing a more precise laser clearance of residual papillomas

18. • KTP laser and the Nd:YAG laser are as effective as the CO2 laser in
papilloma ablation and haemostasis but, in addition, can be delivered
through an optical fibre.
• Fibre-guidance system with a bendable distal tip developed for the Nd:YAG
laser achieves a 50° range of directional manoeuvrability with minimal
power loss.
• The delivery of pulsed-dye laser through a flexible bronchoscope can render
it an outpatient procedure

19. • Advantages:
fibre-delivered
minimal vocal-fold fibrosis
minimal voice damage.
• 585 nm pulsed-dye laser is a vascular laser which causes photoangiolysis of
sublesional microcirculation, denaturation of epithelial basement membrane
linking proteins, and cellular destruction.
• Therefore, it is less effective against large exophytic lesions and can be used
as an adjunct to surgery either before or after the laser application.

20. PHOTODYNAMIC THERAPY
• Rapidly proliferating tissue selectively takes up a number of
photosensitizing agents when administered intravenously, and that these
agents release tumouricidal oxygen derivatives when activated by laser light
of the appropriate wavelength.
• Patients on the higher dose of DHE (4.25 mg/kg body weight) were reported
to show a significantly larger decrease in papilloma growth rate but, despite
that, only approximately half of the 48 patients receiving DHE showed a
response, and no response was seen in patients previously treated with PDT

21. COBLATION
• Minimally invasive low-heat technology that delivers a plasma layer to
dissolute target tissue while maintaining the integrity of surrounding
tissues
• The wands are designed to function at temperatures as low as 40–70 degrees
Celsius (°C), thus minimizing rapid heating, charring or burning.

22. ADJUVANT THERAPY
Adjuvant medical therapies can be broadly divided into antiviral therapies and
drugs with antiproliferative or immunomodulatory properties.
• Interferon alpha
• Bevacizumab
• Cidofovir
• Ribavirin
• Indole 3 carbinol
• cimetidine

23. INTERFERON ALPHA
• Interferons are naturally produced by human leucocytes although, as a
pharmaceutical, interferon is now produced via recombinant DNA
technology.
• Interferon-α can claim to have antiviral, antiproliferative and
immunomodulatory properties.
• Antiviral action by interfering with normal host cell translation mechanisms
and by inducing synthesis of intracellular enzymes that act to control viral
growth
• Increases the length of their multiplication cycle, thereby slowing target cell
growth.

24. • It is administered systemically by subcutaneous injection at a dose of 2–5
MU/m2 of body surface area.
• many serious, idiosyncratic and unpredictable side effects including
pancytopenia, hepatorenal failure and cardiac dysfunction preventing the
more widespread use

25. BEVACIZUMAB (AVASTIN)
• Bevacizumab (Avastin) is a recombinant monoclonal antibody that inhibits
angiogenesis (VEGF-A)
• Administered at a concentration of 2.5 mg/mL for three consecutive
injections at 2–3 week intervals, it can be used in conjunction with cidofovir
and/or the KTP laser.
• Improved voice quality of life when using the Paediatric Voice-related
Quality of Life (PVRQOL)score

26. CIDOFOVIR
• Cidofovir is an acyclic nucleoside phosphonate which is active against a
broad spectrum of DNA viruses including cytomegalovirus, Epstein–Barr
virus and HPV.
• Its mechanism of action is by inhibition of viral DNA polymerases essential
for viral replication.
• Intralesional injections of cidofovir at a concentration of 1 mg/mL. Injections
were given at 2-weekly intervals for four treatments and then the interval
between treatments extended by 1 week after each and every subsequent
treatment.
• Concomitant laser surgery was reserved for bulky lesions.

27. • The RRP Task Force recommended that intralesional cidofovir should be
considered in patients with RRP that require surgery at less than 3-month
intervals, with regular biopsies.
• Administration should remain below the established safe dose of 3 mg/kg.

28. RIBAVIRIN
• Ribavirin is a synthetic nucleoside which has activity against a broad
spectrum of viruses, but which is principally used as an aerosol in the
treatment of respiratory syncytial virus pneumonia and systemically in the
treatment of hepatitis C.
• There have been reports of its use both as an aerosol and systemically.
• However, these remain anecdotal reports and ribavirin is not widely used as
an adjuvant treatment of JORRP.

29. ACYCLOVIR
• Acyclovir is a nucleoside analogue,which inhibits thymidine kinase, which is
present in herpes simplex viruses (HSV) but not HPV.
• Molecular evidence of coinfection with other viruses,particularly HSV, which
may have a potentiating effect on HPV. It has been suggested that the
mechanism of action of acyclovir is to eradicate HSV, thus removing this
synergism
• Side effects are rare and include nausea, vomiting,diarrhoea, fatigue and
headache.

30. INDOLE-3-CARBINOL
• Indole-3-carbinol is a substance derived from cruciferous vegetables (e.g.
cabbage, broccoli, cauliflower, brussels,sprouts), which has been shown to
alter growth patterns of JORRP cell cultures in vitro.
• It affects oestrogen metabolism,shifting production to antiproliferative
oestrogen.

31. CIMETIDINE
• Cimetidine – a histamine receptor type 2 (H2) antagonist–has been reported
as a useful treatment for cutaneous warts.
• There is a single case report of very advanced JORRP with tracheobronchial-
pulmonary involvement being treated successfully with adjuvant cimetidine
at a dose of 40 mg/kg for 4 months with remarkable

32. TRACHEOBRONCHIAL DISEASE
• Extralaryngeal spread of JORRP beyond the larynx occurs in approximately
one third of patients, with spread to the trachea in approximately one
quarter of patients.
• cobble-stoning of the mucosa coupled with the presence of papillomas
• Factors predisposing to tracheal spread include the presence of subglottic
papillomas, presence of a tracheostomy and a long duration of disease
• Patients may develop cavitary pulmonary lesions leading to fever, sepsis and
pulmonary atelectasis.
• Radiographically, these lesions may appear as solid or cystic pulmonary
masses
• A high index of suspicion must be maintained for malignant degeneration of
bronchopulmonary lesions

34. TRACHEOSTOMY???
• Tracheostomy essentially constitutes an iatrogenic squamociliary junction
and may present an additional area of predilection for papillomas
• Tracheostomy may promote extensive tracheobronchial ‘seeding’ of disease
• Tracheostomy is very much a last resort but in patients with severe disease
it may be life-saving.
• It may also facilitate a longer interval between debulking procedures to
restore some normality to the child’s life

35. MALIGNANCY
• Malignant degeneration of papillomas is a rare but devastating sequel. It is
universally fatal.
• There is a higher incidence of invasive carcinoma ex-papilloma in children
with a younger age of onset (2 vs 6 years old; P = 0.009) and those with
tracheal involvement.
• Risk factors including tobacco use and long-standing disease.
• Malignant transformation appears to be more likely with HPV 16, an
unusual cause of JORRP, but HPV 6 and HPV 11 have been shown to
oncogenically transform cell culture lines in vitro.
• In adults, malignant degeneration usually involves the larynx, unlike
children where cancer usually develops in the bronchopulmonary tree.

36. • HPV types 6 and 11 produce transforming oncoproteins E6 and E7 that have
been implicated in growth dysregulation through their ability to inactivate
the tumour suppressor proteins p53 and the retinoblastoma tumour-
suppressor gene product (pRb).
• The inactivation of the tumour suppressor genes results in a loss of control
over proliferation and cell division and contributes to the development of the
malignant phenotype.

37. VOICE MORBIDITY
• Well-recognized voice assessment scales include the GRBAS (grade,
roughness, breathiness,asthenia and strain) scale, the Voice Handicap
Index(VHI), Short-Form 36-Item Health Survey (SF-36)
• When comparing post-op acoustic voice parameters, patients treated with
the microdebrider appeared to have lower scores for jitter, shimmer and
perceptual scores, thus indicating a better voice outcome with the
microdebrider when compared to the CO2 laser.
• Increased frequency of interventions using the CO2 laser is associated with
poorer voice quality.

38. VACCINATION
• Currently two HPV vaccines, CervarixR and GardasilR.
• These vaccines contain no live virions and are thus incapable of causing an
infection, but they are designed to induce an antibody response.
• CervarixR is bivalent vaccine against HPV 16 and 18.
• GardasilR is a quadrivalent vaccine against HPV 6, 11, 16 and 18 containing
virus-like particles of the L1 protein of the four strains.

39. SCHEDULE
• The vaccination schedule comprises three intramuscular injections: the
initial dose, 2 months later, and finally 6 months after the initial injection.
• More recently, GardasilR has been enhanced to a nonavalent vaccine (HPV
6, 11, 16, 18, 31, 33, 45, 52 and 58).
• Ideally, the vaccine should be given to young boys and girls, from the age of 9
years old, prior to them becoming sexually active, thus reducing the spread
of HPV and its sequelae in the general population.

40. THANK U