1. Patient 1 – acute abdomen 19 year old male – no prior medical history Just back from a trip to Israel Two days of “writhing in pain”, fever to 102.5 – Similar episode about a week ago in Israel resolved Pediatrician – acute abdomen, wbc 30,000 CT – pelvic abscess, inflamed small and large bowel, inflamed Ileum

3. Questions In an acute presentation, how does one differentiate between: – Perforated appendix – Newly presenting Crohn’s with perforation – Other causes of pelvic abscess How do you determine which patients warrant emergency surgery, vs. which should be “cooled off” medically? What is your protocol for medical management prior to surgery?

4. Management 1.Abscess drained by IR 2.One week in ICU 3.IV antibiotics (Piperacillin/ Tazobactam) 3.NG suction to decompress 4.IV hydration 5.Pain medication 6.Parenteral nutrition 7.Re-imaging after 10 days

5. Questions What additional evaluation would you perform at this time to establish a Crohn’s diagnosis? Would you consider treating this patient medically? – Short term vs. long term? – With what agent? If you choose surgery, what is the appropriate time to intervene? – Laparoscopic vs. open?

6. “ Abdominal phlegmons in Crohn's disease: outcomes following antitumor necrosis factor therapy ” Thirteen patients with abdominal phlegmon treated with antibiotics and anti-TNF - 2004-2010 – 12 patients also had abscess Anti-TNF with antibiotics – Two patients underwent surgery within a year “Penetrating CD complicated by phlegmon formation may be safely and effectively managed with a combination of antibiotics and anti-TNF therapy” Selection bias? Cullen et al, IBD Journal 2013

7. Management and outcome Hospitalized with PN, NPO, decompression and medical management for approximately 3 weeks. EGD/Colonoscopy – no gastric or colonic disease Laparoscopic ileocecectomy – Fibrotic ileum and cecum – Residual abdominal abscesses – 30 cm of ileum plus cecum resected Uneventful recovery

8. Postoperative management How would you monitor patient postoperatively? – Clinical follow-up and labs only? – Small bowel imaging? – Colonoscopy (timing) What (if any) postoperative medical therapy would you utilize ? – Aminosalicylate – Thiopurine – Infliximab

9. Postoperative management and outcome Discussion with family and patient Opted for mercaptopurine – Transaminitis developed – Changed to low dose 6MP and allopurinol Surveillance 1 year after initial presentation – Normal MRI, normal colonoscopy No clinical or laboratory recurrence 3 years after his initial surgery. – Follow up colonoscopy planned

10. Presenting history 7 year old female Presented with Serratia osteomyelitis at 3 months of age History of multiple GI issues in infancy – Poor weight gain requiring NG tube – Diarrhea – Rectal bleeding as infant while breast-fed, responsive to mother eliminating milk from diet. Diagnosis of CGD by dihydrorhodamine test

11. Chronic granulomatous disease Winkelstein et al 2000; Medicine 79:155 Primary immunodeficiency characterized by inability of cells to kill bacteria and fungi. – Staphylococcus, Aspergillus cause serious infection – Catalase positive organisms – Pneumonia most common infection (80%) 75% of patients present under age 5 years Autosomal recessive or X-linked GI manifestations – Colitis present in approximately 20% – Perianal abscess – Gastric outlet obstruction Diagnosis – defective NADPH oxidase – Dihydrorhodamine test

12. Dihydrorhodamine test Children’s Hospital of Wisconsin Neutrophils given DHR dye, activated Normal neutrophils produce superoxides that oxidize DHR, resulting in fluorescence.

13. Chronic granulomatous disease Mimics Crohn disease on endoscopy and histology Granulomas in only 34 % (Levine, Histopathology 2005) Paucity of neutrophils compared to UC (Shappi JPGN 2003) Decreased CD68+ macrophages (Liu et al, IBD Journal 2009) Therapy – gamma-IFN, steroids, thalidomide, SCT

14. Clinical course Continued with diarrhea, anemia for over a year despite therapy. – Labial abscess grew E. coli By age 4: – 3 BM daily, no bleeding – Height at 25% ile, but falling off – Colonoscopy with ileal and colonic granulomas – Therapies included Alpha - Interferon Bactrim and fungal prophylaxis

15. Medical options for this colitis Aminosalicylates Antibiotics Probiotics Corticosteroids Azathioprine GM-CSF Anti-TNF agents

16. Medical options for this colitis Aminosalicylates - intolerant, got diarrhea Antibiotics – vancomycin for C. difficile Probiotics – VSL 3 Corticosteroids – recurrent courses Azathioprine – tried for over 6 months – unable to wean off steroids without worsening GM-CSF Anti-TNF agents?

17. Caution with anti-TNF in CGD! NIH published experience with 5 patients – All with active colitis despite thiopurines – Two deaths from opportunistic lung disease Infliximab effective for GI disease (including fistulizing disease), but severe infectious complications developed – B. cepacia – CMV colitis – S. aureus liver abscess

18. Potential options GM-CSF – Wang et al, J. Allergy Clinical Immunology 2005 Anakinra – Rationale – upregulation of IL-1 beta pathway – van de Veerdonk et al, Netherland Journal of Medicine 2011 Stem cell transplant – Controversial in CGD – No matched siblings in this case.

19. Current outcome Anakinra 200 mg daily for 3 weeks – Azathioprine stopped Diarrhea improving with 2 stools daily Prednisone weaned to 6 mg daily CRP improved from – 2.2 mg/dL to 0.9 mg/dL Plan for 3-6 months of Anakinra, the re- evaluate with colonoscopy

20. Fever in CD Patient on 6-MP

21. Presenting history 18 year old male with CD Maintained on 6-MP for four years with stable remission and mucosal healing Headache, fever and malaise Leukopenia and elevated transaminases No lymphadenopathy or HSM EBV IgM+ EBV PCR 291 copies/mcg DNA

22. Options Additional diagnostic tests? What to do with 6-MP? Follow-up?

23. Clinical course Initially improved Within a few weeks fevers & chills returned Became jaundiced

24. Options Additional diagnostic tests? Differential diagnosis?

25. Diagnostic Tests Hyponatremia, pancytopenia, elevated bilirubin and transaminases Increased EBV PCR Elevated sIL2R, ferritin Abdominal ultrasound: massive HSM Diagnosis? Other tests?

26. Diagnostic Tests EGD/colon: multiple gastric polypoid lesions with path consistent with EBV+ lymphoma Liver biopsy: EBV+ lymphoma infiltrate Bone marrow: hemophagocytosis PET-CT: widespread

27. Discussion What to do with 6MP with febrile illness/mono? RISK of EBV associated HLH or lymphoma with 6-MP? Different for primary EBV infection versus reactivation? Monitoring for this?