Finding our way in RRP- remission can be induced by an heterologous effect of MMR vaccine.

Nigel R.T. Pashley, MB, BS; FRCSC; FAAP Rocky Mountain Hospital for Children, At Presbyterian St. Lukes Medical Centre, Denver, Colorado, USA.

Historical background of heterologous effects of vaccines.

• Bacille Calmette-Guérin (BCG) reduces non-accidental deaths from diseases other than TB by 53% (BMJ, 1959) - used to treat bladder carcinoma in humans.

- prevents malaria in mice. - protects against leprosy in humans.

• Measles immunisation in children in developing countries has a protective efficacy against death of 30-86%. (Aaby P et al BMJ, 1995) Girls respond best - effect disappears if DPT given after measles immunisation.

• Shann F: Heterologous immunity = activation of memory T cells. Prior infection is protective if Th1 response. Live BCG and measles induce this. Regulatory T cells probably mediate response. (J. Ped.Inf.Dis 2004)

Historical background of heterologous effects of vaccines.

 “No one is naïve…” T-cell memory pool laid down by prior infections and successive infection. Mumps more symptomatic in teenagers = activation of memory T cells? Welsh R. and Selin L. Nature Reviews / Immmunol. June 2002.

Some observed in nature:  GBV-C flavivirus virus co - infection reduces mortality in HIV infected patients. (Tillman H. et al NEJM. 345. 2001)

Historical background of heterologous effects of vaccines in RRP.

Pashley N.R.T. Can Mumps vaccine induce remission in RRP? Arch.Otolaryngol Head Neck Surg 128: July 2002: 783-6. (Intra-lesional mumps with laser excision) Pilot study:11 children, 82% remission, F/U 5-19 yrs Open series: 18 children, 78% remission, F/U 2-5 yrs 20 adults, 75% remission, F/U 2-5 yrs

Heterologous Mumps vaccine effect

Jan 2000 8 year old female 9 prior surgeries 10 amps monovalent Mumps x 4 Intervals 6-26 weeks April 2001

“Exploring” RRP 2002-6 2002: Mumps withdrawn fail to immunize”.

“20% 18 25% of Pashley’s RRP patients not in remission with mumps alone.

MMR converts most monovalent mumps failures.

2006: Shann, F. “MMR effect in RRP another example of an heterologous effect.” Hampson, I. “HPV blocks T cells in cervical ca.- MMR is unblocking memory T cells.” Tyson, W. “HPV found in placenta of HPV+ patients.”

Technique • Custom suspension laryngoscope (Sontec, Denver) • CO2 laser: 2-5 Watts: 0.1mm spot: 5 microsec pause ultrapulse mode (SSI laser, Nashville, Tenn.) • Laryngeal injection needle (Piling Co. Philadelphia, Pa.) • Absolute steroid avoidance.

• Single immunisation dose given with laryngeal injection.

Heterologous effect of MMR in RRP Results

Patients 38 Age yrs 1 - 58 10 children 28 adults M /F 3F / 7M 3F / 25M Severity score Pre Post 19-28 1-8 MMR # amps/dose 3-28 ml’s 1.8-17.5

Freq.Wks

3-28 Follow up 1-4 years

Heterologous effect of MMR in RRP Results

Remission 34/38 = 89.5% Follow up 1 - 4 years  9 “single injection” remissions  7 monovalent mumps failures converted   8 cidofovir failures converted No “non-responders”.

Remission = 2 disease free (suitably long) intervals.

Heterologous MMR vaccine effect

May 2002 38 years male 11 prior surgeries 15 amps MMR by single injection 20 weeks later October 2002 Remission 2 visits later.

Heterologous MMR vaccine effect

May 2002 29 years male 16 operations elsewhere Last 5 with cidofovir 10 amps MMR/dose 6-50 week intervals 9 operations (last 2 disease free) Remission- March 2006

Heterologous effect of MMR in RRP Conclusions: • Adjuvant to laser excision, both mumps and MMR have an heterologous effect on RRP.

• MMR is significantly better than monovalent mumps.

• The technique is simple but arduous, reproducible, cheap, effective, and has no identifiable risk. • MMR works elsewhere- (skin and peri-anal warts in HIV, laryngeal carcinoma -in- situ with RRP).

• The effect is likely mediated by memory T-cells.

The Heterologous effect of MMR in RRP

My thanks to the courageous patients who tried this “off label” use of a conventional vaccine with no assurance that it would be effective (or risk free).

The Heterologous effect of MMR in RRP

6 years male ∆ Armenia as “tumour.” Age 2 yrs Tracheostomy + L. cordectomy. Revised in Germany. Age 4yrs.

Sub-glottic stenosis + RRP.

January 2003: LTP with A/P costochondral grafts + MMR(20amps) May 2007 Remission “pending”- no trach, near normal husky voice. No O2 req. @ 5800’ Immigration pending! Wants to go to medical school.

Back to basics - the HIV example after Silverstein G. Lancet: 369: April 28 2007 • Non-self molecules elicit inflammatory cells (T-cells and antigen presenting cells). Both cell types are subject to HIV infection.

• If large #’s of inflammatory cells present in an area, more infections would be anticipated (seen in HIV patients using microbicide cellulose sulphate vs placebo).

Is this why GER, or local traumatic inflammatory response to laser char etc. makes laryngeal HPV worse?

Common sense - the HIV example after Silverstein G. Lancet : 369: April 28 2007 • HIV-1 isolated 1983-4. Proteins extracted from tissue culture (or produced thru genetic engineering), unsuccessful attempts made to develope a vaccine.

• High rate of mutation and how HIV strains evolve now need to be considered - a successful immune response to HIV has yet to be defined.

Could the same thing occur in RRP? The quadrivalent HPV vaccine, if used for RRP, is only being applied in females.

Back to basics - immunogenesis of RRP • Patients with HPV are already immunized (to their maximum) by presence of disease (= “non-self.”) Epigenetic hypermethylation of tumor suppressor genes in RRP suggests gene silencing as one mechanism allowing growth, (but maybe not origin.) • MMR and monovalent mumps vaccine may induce remission by unblocking T cells. A successful immune response to HPV has yet to be defined.

Are intra-uterine exposure to HPV, heavy marijuana use, and cell to cell apposition important?