OLAF YOU MUST HAVE A TALK AT MT

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2 OLAF YOU MUST HAVE A TALK AT MT ME..

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4 SEVERE HPV INFECTION - RESPIRATORY PAPILLOMATOSIS. A CONTINUOS DILEMMA. Paula Sánchez-Moreno Pediatric Immunology, Reumatology and Infectious Diseases Unit Hospital Virgen del Rocío (Sevilla)

5 2013- MY FIRST RRP PATIENT

6 MACKENZIE (1800) AIRWAY PAPILLOMA MY MY FIRST FIRST RRP RRP PATIENT PATIENT

7 MACKENZIE (1800) AIRWAY PAPILLOMA ULLMAN (1923) INFECTIOUS ETIOLOGY MY FIRST RRP PATIENT

8 MACKENZIE (1800) C. JACKSON (1940S) AIRWAY JUVENILE LARYNGEAL PAPILLOMA PAPILLOMATOSIS MY FIRST RRP ULLMAN (1923) PATIENT INFECTIOUS ETIOLOGY

9 MACKENZIE (1800) C. JACKSON (1940S) AIRWAY JUVENILE LARYNGEAL PAPILLOMA ULLMAN (1923) INFECTIOUS ETIOLOGY PAPILLOMATOSIS 1980/5- HPV DNA HPV 6 Y 11 MY FIRST RRP PATIENT

10 MACKENZIE (1800) C. JACKSON (1940S) AIRWAY JUVENILE LARYNGEAL PAPILLOMA ULLMAN (1923) INFECTIOUS ETIOLOGY PAPILLOMATOSIS 1980/5- HPV DNA HPV 6 Y 11 MY FIRST RRP PATIENT MODERN TRENDS

11 MACKENZIE (1800) C. JACKSON (1940S) AIRWAY JUVENILE LARYNGEAL PAPILLOMA ULLMAN (1923) INFECTIOUS ETIOLOGY PAPILLOMATOSIS 1980/5- HPV DNA HPV 6 Y 11 MY FIRST RRP PATIENT MODERN TRENDS

12 HUMAN PAPILLOMA VIRUS DNA VIRUS >180 SUBTYPES EPITHELIAL CELLS HIGH RISK SUBTYPES - 16, 18 - CERVIX CANCER LOW RISK - 6, 11 - WARTS

13 HUMAN PAPILLOMA VIRUS

14 HUMAN PAPILLOMA VIRUS

15 HUMAN PAPILLOMA VIRUS

16 HPV AND RRP DEVELOPING

17 HPV AND RRP DEVELOPING BECAUSE NOT EVERY EXPOSED CHILD DEVELOPS THE DISEASE

18 HPV AND RRP DEVELOPING BECAUSE NOT EVERY EXPOSED CHILD DEVELOPS THE DISEASE OF EXPOSED CHILDREN, ONLY 1 WILL SUFFER A HPV INFECTION

19 HPV AND RRP DEVELOPING BECAUSE NOT EVERY EXPOSED CHILD DEVELOPS THE DISEASE OF 400 EXPOSED CHILDREN, ONLY 1 WILL SUFFER A HPV INFECTION INCIDENCE 4: * UNK? *DERKAY CS ET AL. 1995

20 HPV AND RRP DEVELOPING OF 400 SHOTS, ONLY 1 WILL BE A GOAL

21 HPV AND RRP DEVELOPING RISK FACTORS HOST ENVIRONMENT MICROBE

22 HPV AND RRP DEVELOPING RISK FACTORS/Environment - MATERNAL ANOGENITAL WARTS (x231) - PROLONGED DELIVERY (>10H) (x2) - NEWLY ACQUIRED HPV INFECTIONS > CHRONIC INFECTIONS - LOW SOCIOECONOMIC STATUS? (YOUNGER MOTHERS, HPV MORE PREVALENT)

23 HPV AND RRP DEVELOPING RISK FACTORS/Environment - MATERNAL ANOGENITAL WARTS (x231) - PROLONGED DELIVERY (>10H) (x2) - NEWLY ACQUIRED HPV INFECTIONS > CHRONIC INFECTIONS - LOW SOCIOECONOMIC STATUS? (YOUNGER MOTHERS, HPV MORE PREVALENT) IS CAESAREAN SECTION PROTECTIVE?

24 HPV AND RRP DEVELOPING RISK FACTORS/Environment - MATERNAL ANOGENITAL WARTS (x231) - PROLONGED DELIVERY (>10H) (x2) - NEWLY ACQUIRED HPV INFECTIONS > CHRONIC INFECTIONS - LOW SOCIOECONOMIC STATUS? (YOUNGER MOTHERS, HPV MORE PREVALENT) IS CAESAREAN SECTION PROTECTIVE? IF INTACT AMNIOTIC SAC, RISK BUT UP TO 30% TRANSMISSION BEFORE BIRTH

25 HPV AND RRP DEVELOPING - HPV 6 AND 11 (>90%) RISK FACTORS/Microbe - HPV 11. MORE AGRESSIVE, YOUNGER, WORST RESPONSE - CO-INFECTIONS (HSV): MORE SEVERE Niyibizi et al

26 HPV AND RRP DEVELOPING RISK FACTORS/Host - YOUNGER AGE: MORE AGRESSIVE - GENETIC FACTORS:. HLA II DQ/DR POLYMORPHISM: SUSCEPTIBILITY ALLELES AND SEVERITY ALLELES (EFFECT VARIED BY ETHNICITY). KIR (KILLER CELL IMMUNOGLOBULINS RECEPTOR) RECEPTORS: LACK OF 3DS1, 2DS1, 2DS5 (SEVERITY) - MICROTRAUMAS: INTUBATION, GERD, TRACHEOSTOMY? Niyibizi et al

27 HPV AND RRP DEVELOPING RISK FACTORS/Immune response - DEFECTIVE IMMUNE RESPONSE:. ALTERED T CD8 SUBSETS. TH1/TH2 DISBALANCE: IL10, IFN? Venkatesan. EXPRESSION TAP-1 > MHC I EXPRESSION et al. 2013

28 HPV AND RRP DEVELOPING RISK FACTORS Niyibizi et al

29 HPV AND RRP DEVELOPING RISK FACTORS Niyibizi et al

30 RRP SYMPTOMATOLOGY

31 RRP SYMPTOMATOLOGY TYPICAL SYMPTOMS: HOARSENESS, STRIDOR, BREATHING DIFFICULTY SEVERE CASES: AIRWAY OBSTRUCTION IF DISTAL SPREAD: PNEUMONIA, ATELECTASIS, HEMOPTYSIS NON SPECIFIC SYMPTOMS DIAGNOSIS DELAY (1Y)

32 RRP SYMPTOMATOLOGY TYPICAL SYMPTOMS: HOARSENESS, STRIDOR, BREATHING DIFFICULTY SEVERE CASES: AIRWAY OBSTRUCTION IF DISTAL SPREAD: PNEUMONIA, ATELECTASIS, HEMOPTYSIS Juvenile Form NON SPECIFIC SYMPTOMS DIAGNOSIS DELAY (1Y) BIMODAL DISTRIBUTION Adult Form 2-5 Y Y Female = Male Multiple lesions Male Solitary lesion +++ symtomps + symtomps Recurrence Congenital Not recurrence Reactivation/Oral sex

33 RRP COURSE SPONTANEUS REMISSION LESIONS GROWTH RECURRENCES LESIONS SPREAD MALIGNANT CONVERSION (<1%) ADJUVANT THERAPY MULTIPLE SURGERIES Economic impact (60, ,000$/patient) Morbidity

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35 RRP TREATMENT

36 RRP TREATMENT ADJUVANT THERAPY SURGERY PREVENT RECURRENCES REDUCE SURGERIES REDUCE LOCAL COMPLICATIONS PREVENT TO REDUCE LESION SPREAD SECURE AIRWAY QUALITY OF VOICE

37 RRP TREATMENT ADJUVANT THERAPY SURGERY TO CURE PREVENT RECURRENCES REDUCE SURGERIES REDUCE LOCAL COMPLICATIONS PREVENT TO REDUCE LESION SPREAD SECURE AIRWAY QUALITY OF VOICE

38 RRP TREATMENT S? 3. A IMMUNOMODULATORY TREATMENTS: - INTERFERON - HPV VACCINE - MUMPS VACCINE Adjuvant therapy TO BE CONSIDERED WHEN: 1. More than 4 surgical procedures per year 2. Rapid regrowth of papilloma with airway compromise Distal multisite spread of disease OTHER: - HSPE7 - CELECOXIB - BEVAMIZUMAB - GERD CONTROL - PHTOTHERAPY - INDOLE-3-CARBINOL - CIS-RETINOIC ACID ANTIVIRAL THERAPIES: - CIDOFOVIR - RIBAVIRINE - ACICLOVIR

39 RRP TREATMENT S A Adjuvant therapy Tasca et al IMMUNOMODULATORY TREATMENTS: - INTERFERON - HPV VACCINE - MUMPS VACCINE OTHER: - HSPE7 - CELECOXIB - BEVAMIZUMAB - GERD CONTROL - PHTOTHERAPY - INDOLE-3-CARBINOL - CIS-RETINOIC ACID ANTIVIRAL THERAPIES: - CIDOFOVIR - RIBAVIRINE - ACICLOVIR

40 RRP TREATMENT S A Adjuvant therapy Tasca et al IMMUNOMODULATORY TREATMENTS: - INTERFERON - HPV VACCINE - MUMPS VACCINE OTHER: - HSPE7 - CELECOXIB - BEVACIZUMAB - GERD CONTROL - PHOTOTHERAPY - INDOLE-3-CARBINOL - CIS-RETINOIC ACID ANTIVIRAL THERAPIES: - CIDOFOVIR - RIBAVIRINE - ACICLOVIR

41 RRP TREATMENT S A Adjuvant therapy Tasca et al IMMUNOMODULATORY TREATMENTS: - INTERFERON - HPV VACCINE - MUMPS VACCINE OTHER: - HSPE7 - CELECOXIB - BEVACIZUMAB - GERD CONTROL - PHOTOTHERAPY - INDOLE-3-CARBINOL - CIS-RETINOIC ACID ANTIVIRAL THERAPIES: - CIDOFOVIR - RIBAVIRINE - ACICLOVIR

42 RRP TREATMENT Antiviral treatment Intralesional cidofovir ( n = 158) Antiviral treatment Controlled studies Yes (4 patients - 3 controls) Efficacy 90 (57%) complete resolution a (within the follow-up periods) 55 patients (35%) a partial response 13 patients (8%) no improvement Security Safe. BUT teratogenic? Sistemic cidofovir (n = 2) No? (Used in combination with other agents) Nephrotoxicity. Neutropenia. Teratogenic? Ribavirine (n = 5) No? (Follow up < 6 m) Decrease Hb with reticulocytosis. Headache and fatigue. Aciclovir (n = 21) No If co-infection Safe Nebulized cidofovir* (n=2) No? Haemoptisis *Ksiazek J et al. Otolaryngol Head Neck Giles Bl et al. Paediatr Respir Rev Chadha et al. 2007

43 RRP TREATMENT Intralesional cidofovir ARTICLES. 504 PATIENTS (APROX 50% PEDIATRIC PATIENTS)

44 RRP TREATMENT Intralesional cidofovir ARTICLES. 504 PATIENTS (APROX 50% PEDIATRIC PATIENTS) No clear regimen Concentration 5-7,5 mg/ml Volume up to 5ml Frequency and dose??

45 RRP TREATMENT Immunomodulatory treatment: IFN First adjuvant therapy used Decrease number of recurrences and surgeries Systemic toxicity Long term efficacy?

46 RRP TREATMENT Immunomodulatory treatment: IFN Long term efficacy? N=38 Gerein et al

47 RRP TREATMENT Immunomodulatory treatment: IFN DOSAGE 3MUI/m2/dose, 3/week If partial response: 5MUI/m2/dosis, 3/week 5MUI/m2/dose, 3/week IF NOT EFFECTIVE IN FIRST 6 MONTHS, DISCONTINUED IT

48 RRP TREATMENT Immunomodulatory treatment: HPV VACCINE 16,18 6,11,16,18 THERAPEUTIC USE!!!

49 RRP TREATMENT Immunomodulatory treatment: HPV VACCINE 16,18 6,11,16,18 THERAPEUTIC USE!!!

50 RRP TREATMENT Immunomodulatory treatment: HPV VACCINE Tjon P et al. 2016

51 RRP TREATMENT Young et al Tjon P et al Retro/ Prospec tive R R Population Study 17 pt. Adult and Children n = 6 Adult and children Other adjuvant therapy YES Follow-up 12M Results IBS CR 40% PR 25% yes 4Y IBS Chirila et al P n = 13 Adult and children YES 1Y CR n=2 Sato et al P n = 9 Children NO 1Y NS IBS Hocevar- Boltežar P n = 11 Adult and Children NO 12-50M IBS CR n=1

52 RRP TREATMENT Young et al Tjon P et al Chirila et al Sato et al Hocevar- Boltežar Retro/ Prospec tive R R P P P Population Study 17 pt. Adult and Children n = 6 Adult and children n = 13 Adult and children Other adjuvant therapy YES PROMISING RESULTS n = 11 Adult and Children BUT CONFOUDING FACTORS n = 9AND Children SHORTS FOLLOW-UP Follow-up 12M Results IBS CR 40% PR 25% yes 4Y IBS YES 1Y CR n=2 NO 1Y NS IBS NO 12-50M IBS CR n=1 Treatment With Quadrivalent Human Papillomavirus Vaccine for Juvenile-Onset Recurrent Respiratory Papillomatosis: Case Report and Review of the Literature.

53 RRP TREATMENT Bevacizumab

54 RRP TREATMENT Bevacizumab CASES REPORTS INCREASE THE TIME INTERVAL BETWEEN SURGICAL PROCEDURES REDUCTION IN NUMBER OF PROCEDURES REQUIRED PER YEAR IMPROVEMENTS IN VOICE QUALITY

55 RRP TREATMENT Bevacizumab CASES REPORTS INCREASE THE TIME INTERVAL BETWEEN SURGICAL PROCEDURES REDUCTION IN NUMBER OF PROCEDURES REQUIRED PER YEAR IMPROVEMENTS IN VOICE QUALITY INTRALESIONAL IF LARYNGEAL LOCATION HIGHER DOSES THAN FAD APPROVED (45-50MG) SAFE Sidell et al, 2014 / Best et al, 2012 Rogers et al, 2013/ Zeitels et al, 2011 SYSTEMIC IF PULMONARY EXTENSION DOSES 5-10MG/DOSE/3W HEMOPTYSIS Mohr et al, 2014 / Zur et al, 2016 Best et al, 2017

56 CONCLUSION Conclusions

57 CONCLUSION Conclusions

58 CONCLUSION? WHY JUST A FEW OF EXPOSED DEVELOP THE DISEASE? THE CONTINUOUS DILEMMA WHY JUST A FEW OF PATIENTS SUFFER AGGRESSIVE FORMS? IS IMMUNE RESPONSE DEFECTIVE IN THIS PATIENTS OR THE VIRUS MODIFY IT? WHICH IS THE BEST ADJUVANT THERAPY? HOW DO WE USE ADJUVANT THERAPY?

59 CONCLUSION? WHY JUST A FEW OF EXPOSED DEVELOP THE DISEASE? THE CONTINUOUS DILEMMA WHY JUST A FEW OF PATIENTS SUFFER AGGRESSIVE FORMS? IS IMMUNE RESPONSE DEFECTIVE IN THIS PATIENTS OR THE VIRUS MODIFY IT? WHICH IS THE BEST ADJUVANT THERAPY? HOW DO WE USE ADJUVANT THERAPY? HOW LONG WOULD PEACE LAST THIS TIME?

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