1 DIAGNOSIS AND TREATMENT OF HUMAN INFECTION BY MYCOBACTERIUM AVIUM PARATUBERCULOSISJ. Todd Kuenstner, M.D.

2 DISCLOSURE Kuenstner is a shareholder of AVIcure Bioscience, LLC which has proprietary interests in UVBI.

3 CASE 1 In June 2004, 9 year old boy developed diarrhea, weight loss (from 80 to 72 lbs) and belly pain. At diagnosis he was 4’8.75” CD diagnosis made based on elevated ESR and CRP with abnormal findings in the stomach and colon accompanied by granulomas on biopsy. Blood culture positive for MAP organism in Naser Laboratory with elevated MAP Ab August 2004, treated with azathioprine and low dose clarithromycin and rifabutin.

4 CASE 1 CONTINUED For 8 months, his condition improved. Afterward, he gradually relapsed. Late fall 2005, he received a total of 11 once weekly UVBI treatments. (200 cc of blood removed from the patient which is then run through a device that irradiates the blood with UV light and returns the blood to the patient) Jan 2006 the clarithromycin and rifabutin doses were increased. Cipro was added in February and the other antibiotics were increased again. May 2006,in remission (no signs of CD since), clofazimine added. Blood culture for MAP negative in July Antibiotics discontinued May 2011. Normal colonoscopy in March 2017, 5’10.5” and 190 lb.

5 CASE 2 In Feb. 2012, the sister of case 1, a 23 yr. old female noted pain and tingling in her hands that progressively involved her elbows, shoulders, neck and then legs. Workup showed normal EMG, CT of the brain, and serologic studies were negative for RF, SLE, Systemic Sclerosis, Sjogrens Syndrome, Celiac disease and CD. High cryoglobulins 57 U/L (0-50), ACE 59 U/L (8-53). Her Diagnosis at Cleveland Clinic (CC)- thoracic outlet syndrome with likely evolving complex regional pain syndrome (CRPS-devastating disease of unknown etiology). “Profound Raynauds phenomenon” noted at CC. Standard therapy (gabapentin) initiated and then discontinued. Blood from 11/20/12 sent for MAP testing to Collins laboratory showed a MAP ELISA result of Six months later, MAP was cultured from this blood sample.

6 CASE 2 CONTINUED Rapid progression of disease during the month of November 2012. Combination UVBI and antibiotics initiated in December 2012 with several days of fever beginning 4 days after start of antibiotics. She received 12 UVBI treatments once weekly over 3 months and was on clarithromycin, rifampin, clofazamine and levofloxacin for 2 yrs. Gradual and progressive improvement of her symptoms with complete loss of Raynaud’s phenomenon. She can now swim one mile or walk 10 miles.

7 Case 3 Paternal uncle of case 1 and 2 with longstanding T1DM on insulin therapy. Blood culture for MAP sent to Aitken laboratory was positive. Also had elevated ASCA IgA. He declined anti-MAP therapy.

8 CASE 4 First cousin of cases 1 and 2 with a history of lymphangiomatosis (unknown etiology) and Raynaud’s phenomenon in his legs. VEGF 506 pg/ml (ref ). A blood sample sent to the Collins laboratory showed an elevated MAP ELISA antibody of 1.72 with a negative MAP culture. This patient declined anti-MAP therapy.

9 CASE 5 Apparently healthy 61 year old male and father of case 1 and case 2 noted to have elevated MAP antibodies by Naser method in June 2004 but negative blood culture for MAP. In January 2013, blood culture positive for MAP in the Collins Laboratory.

10 Table 1- Summary of Map antibody, PCR and culture results for cases 1 through 5.MAP Ab 5/11/04 Naser p p 11/6/12 Collins 1.24 1/14/13 0.49 3/14/13 1.72 1/10/13 0.15 MAP PCR negative MAP culture positive 8/18/04 p35-0.5 p36-0.3 anti-MAP therapy started 8/19/04 11/20/12 1.31 anti-MAP therapy started 12/15/12 1/18/13 Aitken 9/20/04 p p 4/17/13 1.20 7/9/07 5/7/14 1.69

11 TREATMENT OF INFECTION BY MAPCOMBINATION OF AT LEAST 3 ANTIBIOTICS FOR AT LEAST 2 YEARS: CLARITHROMYCIN, RIFAMPIN, CIPROFLOXACIN AND CLOFAZIMINE ONCE WEEKLY UVBI TREATMENTS FOR 3 MONTHS WHILE ON ANTIBIOTICS SUPPLEMENTAL VITAMIN D AND PROBIOTICS AVOIDANCE OF MILK, MILK PRODUCTS AND UNDERCOOKED BEEF

12 EVIDENCE OF MAP PATHOGENICITY IN THESE CASESVIABLE MAP ORGANISM IS PRESENT WITH ELEVATED ANTIBODIES WITH ACTIVE CD AND CRPS- Th1/Th2 switch IN THE ABOVE CASES, WHEN THE VIABLE ORGANISM AND ANTIBODIES ARE NO LONGER DEMONSTRABLE, THE ABOVE DISEASES ARE ABSENT. IN CASE 2, THERE IS NO “LEAKY BOWEL”

13 This family has an extensive history of mycobacterial infection with earlier generations suffering from tuberculosis and recent generations suffering from MAP associated diseases. With the knowledge that antibiotic therapy may not be sufficient to treat MAP, and that controlled trials from Russia showed more rapid resolution of TB with adjunctive use of UVBI and antibiotics, the same approach was used for MAP. One of the pioneers of UVBI appears in the next slide.

14 World J Gastroenterol. 2015 Apr 7;21(13):4048-62. doi: 10. 3748/wjgWorld J Gastroenterol Apr 7;21(13): doi: /wjg.v21.i Resolution of Crohn's disease and complex regional pain syndrome following treatment of paratuberculosis. Kuenstner JT1, Chamberlin W1, Naser SA1, Collins MT1, Dow CT1, Aitken JM1, Weg S1, Telega G1, John K1, Haas D1, Eckstein TM1, Kali M1, Welch C1, Petrie T1

15 Dr. Niels Finsen RECEIVED THE NOBEL PRIZE IN 1903 FOR HIS WORK ON THE TREATMENT OF LUPUS VULGARIS (TUBERCUL0SIS OF THE SKIN) WITH ULTRAVIOLET LIGHT EXPOSURE OF SKIN

16 Report to International Central Bureau for the Eradication of TB, 1902I. Cured 412 a) no recurrence in 2 to 6 years 124 b) observation < 2 years 288 II. Insignificant residual disease 192 III. Currently under treatment 117 IV. Interrupted treatment 83 a) unsatisfactory result 16 b) dead (31) or other disease (13) 44 c) absent unrelated to disease 23 Total number of patients treated 804

17 Dr. Emmett Knott, inventor of UVBI

18 KNOTT HEMO-IRRADIATORUS PATENT 1,683,877 TO LESTER EDBLOM AND EMMETT K. KNOTT ON SEPT. 11, 1928 FOR THIS DEVICE TO TREAT INFECTIONS.

19 MODIFIED HEMOIRRADIATOR

20 Int J Infect Dis. 2015 Aug;37:58-63. doi: 10. 1016/j. ijid. 2015. 06Int J Infect Dis Aug;37: doi: /j.ijid Epub 2015 Jun 17. The treatment of infectious disease with a medical device: results of a clinical trial of ultraviolet blood irradiation (UVBI) in patients with hepatitis C infection. Kuenstner JT1, Mukherjee S2, Weg S3, Landry T4, Petrie T5

21 MAINTENANCE INFLIXIMAB FOR CROHN’S DISEASE: THE ACCENT I RANDOMIZED TRIAL, HANAUER58% OF PATIENTS RESPONDED TO INFLIXIMAB (REMICADE) 30 WEEKS LATER, 45% OF THE 58% OR 26% WERE STILL IN REMISSION. THIS THERAPY FAILS 74% OF PATIENTS.

22 AUTOIMMUNE OR UNKNOWN? “AUTOIMMUNITY” AS AN EXPLANATION OF DISEASE IS LIKELY RARE. DISEASE OF UNKNOWN ETIOLOGY SHOULD BE REFERRED TO AS SUCH UNTIL THE CAUSE IS KNOWN.

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25 A NEW CONTROVERSY Should MAP infection in humans be called Dalziels disease or Johnes disease?