Graft versus host disease

Graft versus host disease (GVHD) is an immune mediated disease due to complex interaction between donor (lymphoid tissue) and recipient’s immunity occurring after transplantation.
Two types
Acute (less than 100 days)
Chronic (more than 100 days)

1. GRAFT VERSUS HOST DISEASE Presenter – Dr. Deepak R. Chinagi Guide – Dr. L. S. Patil Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 1

2. Greetings At the end of this topic, we will understand: Define GVHD and its mechanism, How is it different from graft rejection, Identifying GVHD and differentials. How to treat and how to prevent. Future perspectives. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 2

3. Introduction Graft versus host disease (GVHD) is an immune mediated disease due to complex interaction between donor (lymphoid tissue) and recipient’s immunity occurring after transplantation. Two types Acute (less than 100 days) Chronic (more than 100 days) It occurs when immunologically competent T cells or their precursors are transplanted into recipients who are immunologically compromised. Incidence - 1-2 % Mortality - up to 75% Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 3

4. Procedures with risk of GVH disease Allogenic HSC Transplantation (hematopoietic stem cell transplantation) Bone marrow transplantation. Umbilical cord blood. PBSC (peripheral blood stem cell) transplantation. Solid organ transplantation (esp. organs containing rich lymphoid tissue) Kidney transplantation.(rare) Liver transplantation. () Heart transplantation Transfusion of unirradiated blood products. It can also be caused by whole blood transfusion in patients with severe combined immunodeficiency. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 4

5. Pathophysiology of GVHD Immune-competent T cells transplanted into immune-compromised host. Host cannot reject the graft due to decreased immunity. But graft T cells perceive the recipients tissue as foreign and react against it. This leads to activation of CD4 and CD8 T cells ultimately causing inflammation and killing of host cells. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 5

6. Pathophysiology of GVHD (Future Scope) GVHD can be minimized but cannot be eliminated HLA typing is useful Donor T cell suppression before transplant – mixed blessing Multi-functional T cells not only mediate GVHD but are also required for efficient engraftment of transplanted HSC s and elimination of leukemic cells The disease is less understood due to its complex mechanism. It is known to occur in autologus form also. Usually after PBSC transplantation. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 6

7. Effector cells(Donor T cells) Proinflammatory Cytokines(IL1, IL2, TNF, IFN) Target Host tissues (Skin, Liver, Intestines) Allogenic recognition & Autologous dysrecognition Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 7

8. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 8

9. Clinical Features Types of manifestations Hyperacute Acute Chronic Severity of GVHD depends on the degree of HLA disparity and other factors like… Cryopreservation of BMT and Cord blood are known for lower incidence of GVHD. Allogenic PBSC has high incidence of chronic GVHD Post- transplanational prophylaxis ( immuno-supression ) decrease the incidence of GVHD Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 9

10. Hyperacute Form - GVHD Usually develops after 7-14 days after transplantation Symptoms are …. Fever, generalized erythroderma, desquamation may occur. Later follows a similar course as acute form. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 10

11. Acute GVHD Triad of dermatitis, hepatitis and enteritis. Skin Manifestations- ( onset 5-50 d, M=19 d) Pruritic and Painful rash Red to Violet lesions, first appear on palms and soles, cheeks, neck, ear, trunk. In severe cases, bullae and vesicles may form. In cases of chronic GVHD, Lichenoid lesions or sclerodermatous thickening can be seen. Contractures can occur, Joints get restricted mobility. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 11

12. Hepatic Manifestations- Jaundice Pruritis Skin excoriations due to scratching Rare manifestations are cirrhosis, portal hypertension, hepatic coma and death. Raised serum bilirubin, ALT, AST, ALP Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 12

13. Gastrointestinal Manifestations- Upper GI Symptoms- Anorexia , Dyspepsia Lower GI Symptoms- Diarrohea , Intestinal Bleeding, Cramping Abdominal Pain and Ileus . Diarrohea is usually described as voluminous, secretory , green, mucoid , watery, associated with exfoliated cells Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 13

14. Pulmonary Manifestations- Pneumonia – infectious and noninfectious. Pleural Effusions – usually sterile. Other Manifestations- Hemorraghic cystitis Thrombocytopenia Anemia Hemolytic Uremic syn. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 14

15. Clinical Staging criteria of Acute GVHD Criteria Skin Findings Liver findings Gut findings + Maculo – Papular rash < 25 % Bilirubin = 2 – 3 mg/dl Diarrohea 500 – 1000 ml/d ++ Maculo – Papular rash 25 – 50 % Bilirubin = 3 – 6 mg/dl Diarrohea 1000 – 1500 ml/d +++ Generalised Erythroderma Bilirubin = 6 – 15 mg/dl Diarrohea more than 1500 ml/d ++++ Desquamation and Bullae Bilirubin > 15 mg/dl Abdominal Pain ± ileus Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 15

16. Clinical Staging of Acute GVHD Grade Skin Liver Gut Functional impairment 0 (None) 1 (Mild) +/++ 2 (Moderate) +/+++ + + + 3 (Severe) ++/+++ ++/+++ ++/+++ ++ 4 (Life-Threatening) ++/++++ ++/++++ ++/++++ +++ Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 16

17. Chronic GVHD May occur as extension of already existing disease or de novo. Usually it emerges after an interval after acute GVHD. Skin Manifestations- Lichenoid lesions, sclerodermatous thickening, contractures of skin and restricted joint mobility. Ocular Manifestations- Burning sensation of eyes, irritation, photophobia, pain, dryness of eyes. Hemorrhagic conjunctivitis, pseudo membrane formation, lagophthalmos, keratoconjunctivitis sicca, punctate keratopathy, corneal erosions. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 17

18. Oral Manifestations- Dryness of mouth, atrophy of mucosa, dysphagia, odynophagia, weight loss Pulmonary Manifestations- Wheeze, dyspnea, chronic cough. Bronchiolitis obliterans . Neuromuscular manifestations- Weakness , neuropathic pain and muscle cramps. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 18

19. Differentials Chronic GVHD has similar manifestations as that of systemic sclerosis, SLE, lichen planus , sjogrens syn., eosinophilic fasciitis, rheumatoid arthritis, primary biliary cirrhosis. Erythema Multiforme (SJS) Viral Hepatitis Malabsorption Mixed Connective Tissue Disease Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 19

20. Investigations CBC LFT Serum Electrolytes USG Abdomen- liver and gall bladder Barium swallow Schirmer test – ocular manifestations PFT , ABG Biomarkers IL2 receptor α TNF receptor 1 IL8 Hepatocyte growth factor Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 20

21. Investigations Skin Punch Biopsy UGI endoscopy Sigmoidoscopy /Colonoscopy Liver Biopsy Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 21

22. Treatment Primary prophylaxis CSP A / Tacrolimus for 6 mths and short course MTX and added with prednisolone . ATG decerases severity but doesn’t alter survival ECP – 8methoxy-psoralen . After UV light , cell undergoes apoptosis. Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 22

23. Treatment Primary therapy Topical steroids / continue immunosupressive prophylaxis. ATG , CSP alone , Mycophenolate Mofetil Secondary therapy steroid refractory cases ATG / multiple pulses of methylprednisolone Mycophenolate mofetil 2g/d Muromomab Anti IL2 receptor PUVA Tacrolimus , Visilizumab , Daclizumab , Infliximab , TNF α inhibitor ( etanercept ) Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 23

24. Treatment Chronic GVHD Prednisolone 1mg/kg ± Azathioprine . TNF modulator- Thalidomide Steroid refractory cases – Azathioprine , CSP / prednisolone , thalidomide Clofazimine PUVA / ECP Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura 24