Graft Versus Host Disease Criteria for Development of GVHD Graft contains immunologically competent cells Host appears foreign to the graft; it has alloantigens that are capable of antigenically stimulating the graft Host is unable to mount an effective immunological reaction against the graft Patients at High Risk for GVHD Allogeneic & autologous hematopoietic cell transplantation (age, HLA disparity, gender disparity, allosensitized donor) Solid organ transplantation (liver, small bowel) Transfusion of unirradiated blood products (fetuses, neonates, immunodeficiency syndromes, chemoradiotherapy) Pathophysiology of GVHD – 3 stages Damaged host tissue cytokines (TNFα, IL1) stimulate APCs recognition of host Ag by donor T cell Donor T cell activated cytokines (IFNγ, IL2) induce CTL, NKC, phagocytes Phagocytes release more cytokines cell lysis/apoptosis tissue destruction Pathophysiology of GVHD 2 Types of GVHD Acute (10-30 days posttransplant) - triad of derm, hepatic, and GI manifestations (barriers to infection thus APCs) - 40-80% incidence (depends on HLA match) Chronic ( >100 days posttransplant) - diverse range of affected organ systems - 70-90% evolve from acute GVHD - 20% occur de novo - 10% occur after acute GVHD resolves Acute GVHD – Dermatological Painful or pruritic erythematous macules of palms, soles, trunk, limbs Confluent erythema, erythroderma and/or papule formation Subepidermal bullae and vesicle formation Stages 1-4 based on % BSA involved and presence of bullae/vesicles Acute GVHD – Dermatological Boy who developed stage 3 skin involvement with acute graft versus host disease despite receiving prophylaxis with cyclosporin A. The donor was a sister matched for human leukocyte antigen. The gender disparity increased the risk for acute graft versus host disease. Acute GVHD – Hepatic Asymptomatic elevations in bilirubin, ALT, AST, alkaline phosphatase similar to cholestatic jaundice Acute GVHD – GI Anorexia Dyspepsia Cramping abdominal pain Diarrhea (secretory diarrhea may persist despite NPO) Intestinal bleeding Ileus Chronic GVHD - Dermatological Same as acute GVHD Atrophy and erythema of oral mucosa Lichenoid lesions of skin, buccal and labial mucosa Sclerodermatous skin thickening Joint contractures Chronic GVHD – Ocular Keratoconjunctivitis sicca may lead to corneal erosions Hemorrhagic conjunctivitis Pseudomembrane formation Lagophthalmos Chronic GVHD – Pulmonary Obstructive lung disease Dyspnea, wheezing, chronic cough Nonresponsive to bronchodilators Bronchiolitis obliterans Chronic GVHD – GI Same as acute GVHD Sensitivity to acidic or spicy foods Odyno/Dysphagia Esophageal strictures or dysmotility Weight loss Chronic GVHD – Hepatic Same as acute GVHD Hyperbilirubinemia – jaundice, pruritis and excoriations Portal HTN, cirrhosis, and hepatic failure are rare Chronic GVHD – Neuromuscular Weakness Neuropathic pain Muscle cramps Symptoms may resemble myasthenia gravis or polymyositis Chronic GVHD – Misc. Many similarities to autoimmune disorders SLE Sjogren syndrome Rheumatoid arthritis Primary biliary cirrhosis Lichen planus Prevention Depletion of T cells from donor has reduced the incidence of GVHD, however, this results in increased incidence of graft failure and malignancy occurrence Leukemic cells may have specific antigen profiles that make them susceptible to the GVL effect. Graft vs. Leukemia Effect Mortality of GVHD with no leukemic relapse vs. mortality of leukemic relapse and no GVHD is under investigation Prophylactic Treatment Cyclosporine (CSP) + Methotrexate (MTX) +/- Prednisone 180 days Tacrolimus (Prograf) + MTX 180 days IVIG for antibody prophylaxis Qweek x12 (good for acute , not chronic) Primary Treatment for Acute GVHD CSP or Prograf + methylprednisolone (MP) Antihymocyte globulin (ATG) Mycophenolate mofetil (CellCept) Anti-CD5 immunotoxin XomaZyme – pan T cell immunotoxin Secondary Treatment for Acute GVHD ATG Increased MP doses Muromonab-CD3 IL-1 receptor antagonist Conversion from CSP to Prograf Psoralen +UVA light (PUVA) for cutaneous GVHD Primary Treatment for Chronic GVHD Prednisone 1 mg/kg QOD +/- CSP Thalidomide Secondary Treatment for Chronic GVHD Azathioprine (Imuran) Alternating CSP & Prednisone Thalidomide Clofazimine (antileprosy agent) and PUVA for cutaneous GVHD Prognosis Acute GVHD: response to tx 25% mortality vs. 75% mortality with no response or progression. Chronic GVHD: 6 yr. mortality is 58% overall and 90% for progressive disease. Mortality for both acute and chronic GVHD is mostly due to sepsis. Higher mortality in patients with HLA mismatched donor, bilirubin > 2 mg/dL, thrombocytopenia, lichenoid skin histology, high dose prednisone. References Fleming DR, Graft-vs-host disease: what is the evidence? Evidence-based Oncology 2002; 3. Mandanas RA, et al. Graft versus host disease. Emedicine.com/med/topic926. Hoffman: Hematology: Basic Principles and Practice, 3rd ed., 2000. Kuechle MK, et al. Graft versus host disease. Emedicine.com/derm/topic478.
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