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  1. 1. Gastrointestinal and Liver Graft Versus Host Disease (GVHD) Peds GI Case Conference Joanna Yeh 9/27/2012
  2. 2. Objectives • Discuss a case of pediatric GVHD. • Review background on GVHD. • Understand differential diagnosis of liver and GI GVHD. • Familiarize with characteristics and histologic findings of acute and chronic GVHD.
  3. 3. Case • 22 month old boy with familial HLH (hemophagocytic lymphohistiocytosis). • s/p matched, unrelated cord bone marrow transplant on 10/24/2011. • He had been conditioned with busulfan, etoposide, cyclophosphamide, and ATG. • Diagnosed with skin GVHD early on (worst on face) and placed on solumedrol (day +1 to day +19) and transitioned to tacrolimus and IVIg ppx. • He had hospitalizations for skin GVHD needing steroid pulse 4mg/kg/day in Jan 2012, Feb 2012.
  4. 4. Case • Skin GVHD up to grade 3 (>50% BSA but no bullae). • He had on/off diarrhea which always improved with increased immunosuppression so no biopsies were obtained. • In May 2012, he was admitted with diarrhea (no quantification, “watery” stool “all day”). At that time he was on prograf 0.8 mg bid and cellcept 250 mg bid. Wt ~10kg.
  5. 5. Case • Stool studies including c diff, campy bacterial, rota, adeno, noro, and cells all negative. • Medications included prograf, enalapril, cellcept, pepcid, magnesium, fluconazole, and valycte. • CMV and EBV PCR were negative. • Endoscopy in May 2012 c/w colonic GVHD. • Placed on solumedrol 4mg/kg/day and IV cellcept. He was also put on PO budesonide and continued on IVIg. • He was put on trophic NG feeds and TPN/IL. • LFTs have also been elevated, thought to be from HHV6 chronic infection (liver biopsy obtained).
  6. 6. EGD: Normal except for loss of vascularity in duodenum.
  7. 7. Flex sig: Strawberry like mucosa in rectum, cleared by sigmoid. Sigmoid colon with loss of vascularity.
  8. 8. EGD Pathology Report • Duodenum and antrum were normal • Mid body of stomach with mild active inflammation. H. pylori negative. • Overall: Not consistent with GVHD.
  9. 9. Flex Sig Pathology Report • Sigmoid: mild active inflammation with increased crypt apoptotic bodies, consistent with GVHD grade 1. No PTLD or viral inclusions. • Rectum: moderate active inflammation with increased crypt apoptotic bodies c/w GVHD grade 2-3. No PTLD or viral inclusions. • Comment: Also consider drug injury and less likely ischemia.
  10. 10. Flex Sig Pathology Report • There is crypt dilation, increased crypt apoptoses, mild lamina propria neutrophilic inflammation. • Crypt abscesses and crypt dropout is appreciated. • CMV stains negative.
  11. 11. Graft vs. Host Disease (GVHD)
  12. 12. Overview • GVHD is one of the most common complications of hematopoietic stem cell transplant (HSCT). • In 1955, Barnes and Loutit described diarrhea, skin changes, and “wasting syndrome” in mice. • Involvement can include skin, liver, GI tract, and more rarely, lung. • It is a leading cause of morbidity and mortality after HSCT. It can be fatal in up to 15% of transplant recipients.
  13. 13. Pathogenesis • Transplanted immune cells (graft or donor) recognize patient’s (host) cells as foreign. • Primarily T cell mediated disease • 3 phases – 1: conditioning regimen damages and activates host tissues to secrete cytokines that upregulate MHC antigens – 2: donor T cell activation – 3: Multiple inflammatory cascades • Th1 CD4 -> TNFa, IL1 -> apoptosis
  14. 14. Blazar, et al, 2012
  15. 15. When can you get GVHD? • Hematopoietic stem cell transplant – Non autologous (allogeneic) – autologous • Blood transfusion • Solid organ transplantation 10-40% of patient develop significant (grade 2-4) GVHD and ½ of these patients will die from GVHD or therapy related complications
  16. 16. Definitions • Acute: less than 100 days after transplant. • Chronic: more than 100 days after transplant. • But there is now a shift towards defining acute and chronic based on clinical and histologic manifestations. • Hyperacute: mismatched or underprophylaxed patients without engraftment.
  17. 17. Symptoms • Skin rash (classically first and most common) • Jaundice (liver is 2nd most common) – Rarely do patients have moderate to severe hepatic GVHD without evidence of cutaneous disease or GI disease – Rise in direct bili and alk phos (damage to bile canaliculi, leading to cholestasis) • Hepatitic variant (acute transaminitis >10x) • Diarrhea and abdominal cramping – Watery diarrhea +/- blood – Edema (PLE) • Anorexia, nausea, dyspepsia, vomiting
  18. 18. Grading Bombi, et al, 1995.
  19. 19. Differential Diagnosis Liver – VOD (relatively common toxicity associated with high dose therapy or specific conditioning regimens like busulfan or cytoxan) – Infection (most often viral hepatitis) • CMV, EBV • Hepatitis A, B, C • Herpes simplex virus, HHV6 • Bacterial/fungal – Medication • Chemo agents • Immunosuppressants – CSA (cyclosporine) – Methotrexate – Biliary sludge/gallstones/cholecystitis – Iron overload / hemosiderosis
  20. 20. Differential Diagnosis Gastrointestinal – Infection • Clostridium difficile • CMV* – Antibiotic associated diarrhea – Medication effect • MMF (cellcept) : colitis – Drug reaction (i.e. chemo) – Radiation effect – Chemotherapy effect *Send tissue for CMV PCR / stain (characteristics overlap) *One center routinely sent gastric and sigmoid bx for CMV and herpes simplex virus culture Toxicity usually resolved 1 month later
  21. 21. Tuncer, et al
  22. 22. Liver: Diagnosis • Most definitive method is biopsy. • If not feasible (low platelets), can do transjugular approach. • Stains can include CMV, EBV, adenovirus, herpes simplex virus. • Histology: – Bile duct atypia and degeneration (“vanishing bile duct syndrome”) – Epithelial cell dropout – Lymphocytic infiltration of small bile ducts – Severe cholestasis
  23. 23. Histology: Hepatic GVHD Shulman, 2006
  24. 24. GI tract: Diagnosis • Flex sig +/- EGD (20% of pts have GVHD in upper tract only) • ?Colonoscopy • Normal gross exam in up to 21% of histologically confirmed GVHD. • Histology: – Crypt cell necrosis with accumulation of degenerative material in the dead crypts – Denuded areas with total loss of epithelium if severe • Don’t forget to stain for CMV Iqbal, et al, 2000 Roy, et al, 1991
  25. 25. Cruz, et al, 2002
  26. 26. Cruz, et al, 2002
  27. 27. Histology: Grading of GI tract • Grade 1: isolated apoptotic epithelial cells without crypt loss • Grade 2: loss of isolated crypts without loss of contiguous crypts; apoptosis with crypt abscess • Grade 3: loss of 2 or more contiguous crypts; crypt necrosis • Grade 4: extensive crypt loss with mucosal denudation *grain of salt: inter-observer agreement among pathologists is only moderate
  28. 28. Histology: Gastric GVHD Washington, et al, 2009
  29. 29. Histology: Acute SB GVHD Washington, et al, 2009
  30. 30. Histology: Acute Colonic GVHD Washington, et al, 2009
  31. 31. Histology: Acute Colonic GVHD Ross, et al, 2008
  32. 32. Optimal GI tract biopsy sites • Not well established. • Discordance between upper and lower tract sensitivity. • Is GI GVHD a panintestinal process? Not always… • Stomach more likely to show change of GVHD than distal sites? Early on? • Can miss up to 38% of GI GVHD if only biopsy rectum. • Standard of care at different centers vary immensely: pan biopsies, flex sig first, gastric first, avoid duodenum, etc. • Increased risk of bleeding at duodenal biopsy sites? • Ross study (2008) in adults: rectosigmoid bx more sensitive (retrospective).
  33. 33. Location of GI biopsies Aslanian, 2012
  34. 34. Pediatric Data on GI GVHD • JPGN Feb 2012 • 48 patients, single center (Wisconsin) retrospective cohort • Common symptoms prompting endoscopy – Diarrhea (70%) – Nausea and vomiting (67%) • GVHD diagnosed in 83% of patients. • 55% patients had both upper and lower endoscopy • Most common endoscopic finding was normal mucosa. • Rectosigmoid and combined upper endoscopic biopsies were equally sensitive for diagnosis of acute GVHD in children. • “If GVHD is found on rectosigmoid biopsy, upper endoscopy would not be needed.” Sultan, 2012
  35. 35. Novel biomarkers GI • REG3alpha (antimicrobial protein expressed in Paneth cells) GI & liver • HGF (hepatocyte growth factor) • KRT18 (cytokeratin fragment 18) – apoptotic protein Harris, et al
  36. 36. Chronic GVHD • Occurs in more than 50% of long term survivors of HLA identical sibling transplants. • Acute GVHD has strong inflammatory component; chronic GVHD displays more autoimmune and fibrotic features. • More B cell involvement. Antibodies deposit in tissues? • Risk factors – High recipient age – Previous acute GVHD – Female donor to male recipient – CML Blazar, et al
  37. 37. Chronic liver GVHD • Lobular hepatitis, chronic hepatitis, reduced or absence of small bile ducts with cholestasis. • Pathophysiology is suggestive of primary biliary cirrhosis. • Portal fibrosis suggests long term persistence of GVHD. • Cirrhosis has been reported but is rare.
  38. 38. Chronic GI tract GVHD • Oral mucosa: dry, ulcerations, erythematous lesions • Esophagus: dysphagia, ulcers, weight loss, webs, strictures – Esophagus usually spared in acute GVHD • Chronic diarrhea, malabsorption, fibrosis, sclerosis
  39. 39. Schulman, 2006
  40. 40. Washington, et al, 2009
  41. 41. Washington, et al, 2009
  42. 42. Akpek, 2003
  43. 43. Capsule Endoscopy • Most literature in adult population. • 1 case report of a 8 year old with large volume bloody diarrhea. • Diagnostic purposes to then guide treatment.
  44. 44. Treatment • Steroids are first line (1-2 mg/kg/day) • CSA, FK, ATG, cellcept, the list goes on… • Infliximab is helpful in refractory GI tract GVHD • Oral budesonide (non absorbable) can be helpful • Abx? Ppx? Ciprofloxacin, rifaximin? • Rare cases of liver tx
  45. 45. Complications with liver biopsy and endoscopy • Bleeding (goal plt>50) • Hematoma (particularly duodenal?) • Bacteremia (ppx abx if ANC<1000) • Perforation 2006 pediatric study of 191 patients (endoscopy) – 13 complications out of 418 procedures (3%), 8 of which occurred in the first 100 days Khan, et al, 2006
  46. 46. Important questions to ask: • Date of transplant, post transplant course • Other organ involvement of GVHD • Conditioning regimen and immunosuppression • R/o other diagnoses before invasive procedures – Infection (what antivirals, antibiotics, antifungals they are and have been on) – Check CMV PCR • Response of sx to increasing/decreasing immunosuppression • How will biopsy change management?
  47. 47. How should a pediatric gastroenterologist called to evaluate nonspecific GI symptoms that could be from GVHD proceed?
  48. 48. Berquist and Dvoark, 2006
  49. 49. Summary & Conclusions • GI and hepatic complications represent a major cause of morbidity and mortality in pediatric BMT recipients. • Symptoms of liver and GI GVHD are nonspecific. • Currently, need tissue for diagnosis thus essential role of endoscopy and liver biopsy to guide therapy. • Chronic GVHD is not well defined, is often seen with some type of other acute GVHD. • Flex sig is safest and most productive method of diagnosing GI GVHD but EGD may be needed especially for upper GI sx (nausea, vomiting). • Liver and GI GVHD can be difficult to diagnosis. Often, have to exclude other causes.
  50. 50. References • Akpek, et al, Gastrointestinal Involvement in Chronic GVHD: A Clinicopathologic Study, Biology of Blood and Marrow Transplantation, 2003. • Aslanian, et al, Prospective Evaluation of Acute GVHD, 2012. • Berquist and Dvorak, Optimizing care for GI disorders in children after HSCT, Gastrointestinal Endoscopy, 2006. • Blazar, et al, Advances in GVHD biology and therapy, Nat Rev Immunol, 2012. • Cruz-Correa, et al, Endoscopic Findings Predict the Histologic Diagnosis in Gastrointestinal GVHD, Endoscopy, 2002. • Harris, et al, Plasma biomarkers of lower GI and liver acute GVHD, Transplantation, 2012. • Iqbal, et al, Diagnosis of Gastrointestinal Graft Versus Host Disease, American Journal of Gastroenterology, Nov 2000. • Khan, et al, Diagnostic endoscopy in children after hematopoietic stem cell transplantation, Gastrointestinal Endoscopy, 2006. • Ma, et al, Hepatitic GVHD after HSCT, Transplantation, 2004. • Melin-Aldana, et al, Hepatitic Pattern of GVHD in Children, Pediatr Blood Cancer, 2007. • Ross, et al, Endoscopic Biopsy Diagnosis of Acute Gastrointestinal GVHD: Rectosigmoid biopsies are more sensitive than upper gastrointestinal biopsies, American Journal Gastroenterology, 2008. • Shulman, et al, Histopathologic Diagnosis of GVHD: NIH Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD, Biology of Blood and Marrow Transplantation, 2006. • Sultan, et al, Endoscopic Diagnosis of Pediatric Acute Gastrointestinal GVHD, JPGN, 2012. • Tuncer, et al, GI and hepatic complications of hematopoietic stem cell transplantation, World J Gastroenterology 2012. • Washington and Jagasia, Pathology of GVHD in the gastrointestinal tract, Human Pathology, 2009.