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Transfusion associated graft versus host disease
This document presents a detailed case history of a 63-year-old male who developed transfusion-associated graft-versus-host disease (TA-GVHD) following coronary artery bypass grafting (CABG) and multiple blood transfusions. Despite aggressive medical management, the patient suffered from severe complications and ultimately died due to rapid decline in hemoglobin levels, leading to a clinical diagnosis of viral-induced hemophagocytic syndrome and suspected TA-GVHD. The document outlines the pathophysiology, risk factors, clinical presentation, diagnosis, management, and prevention strategies for TA-GVHD.
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Transfusion associated graft versus host disease
- 1. Journal club presentation G.D.A.Samaranayaka
- 2. Case history • 63year old male – Heavy smoker (90 pack year) • Past history of minimally invasive squamous cell carcinoma of the larynx – curative radiotherapy completed 1 year back. • Known patient with COAD and peptic ulcer disease • Presented to emergency medical department with acute onset chest pain • Diagnosed to have NSTEMI with coronary artery disease – (TVD with LMCA >90%)
- 3. Case history • Onadmission – Hb – 8.5mg/dl – WBC – 8900/μL – Lymphocytes - 630/μL – Renal and liver profile - normal • Bone marrow biopsy – Normocellular marrow • Received 4 random units of RBC
- 4. Case history • UnderwentCABG 1 week following admission • During surgery – 3 units of random RCC • Post operative period – Uncomplicated • Discharged 4 days following the surgery • Readmitted 5 days after surgery – with fever nausea, vomiting and abdominal pain • O/E – Febrile, icteric – Erythematous petechial rash-trunk + extremities – Cardiac and respiratory –NL – No lymphadenopathy
- 5. Case history • BiochemicalInvestigations – S.Cr – 3.7mg/dL – ALP – 200U/L – Hb – 8g/dL – SGOT – 1231U/L – SGPT – 3241U/L – LDH – 4360U/L – Total bilirubin – 6.3g/dL direct – 5.8g/dL – Amylase – 477U/L Lipase - 2,145 mIU/mL
- 6. Case history • Serologicaltest - Hepatitis A,B,C & Parvovirus B19 – Negative • HIV- negative • All cultures – negative • ANA, RF & Anti-mitochondrial antibody - negative • Started on broad spectrum antibiotics • In the next few days • Deterioration of renal functions • Continuing fever • Diarrhoea • Worsening coagulopathy • Encephalopathy
- 7. Case history • Admittedto ICU and started on CRRT • Pancytopaenia • WBC - 200/μL • Plt - 3 x103/μL • Hb – needed multiple transfusions • DIC and HIT were excluded • A bone marrow biopsy - severe hypoplasia with less than 5% overall cellularity. • Skin biopsy of rash - vacuolar dermatitis with a sparse lymphocytic infiltrate and abundant necrotic keratinocytes.
- 8. Case history • Continueddeterioration despite aggressive medical mx with broad-spec antibiotics, antifungal treatment, ET-intubation with mechanical ventilation and IABP and CVP monitoring. • Died on 26th day following first transfusion due to rapid declining of Hb 9.5 -> 5g/dL • Working clinical diagnosis at the time of death • Viral-induced haemophagocytic syndrome • Severe drug reaction
- 9. However • A pathologisthad suspected TA GvHD • First 4 RBC donors – consented for HLA typing • DNA fingerprinting - Multiplex PCR • Patient’s myocardium, lymph nodes, and spleen -for DNA extraction. • Myocardium as control – Histologically no lymphocyte infiltration
- 10. Autopsy findings • Skinbiopsy – vacuolar dermatitis with a mild lymphocytic infiltrate and abundant necrotic keratinocytes. • Liver - portal triads - scattered lymphocytes invading bile duct epithelium with atypia • GI tract - complete mucosal denudation with prominent mucosal hemorrhage, reactive epithelial changes, and focal apoptosis
- 11. Autopsy findings • Bonemarrow - overall cellularity of less than 5%. The marrow spaces were replaced by numerous macrophages • Diffuse alveolar damage and early Aspergillus flavus pneumonia of the lungs. • Immunohistochemical stains for cytomegalovirus and herpesvirus in the skin, liver, gastrointestinal tract - negative
- 12. • DNA fingerprinting- absence of foreign DNA HLA Typing
- 13. Transfusion Associated Graft versusHost Disease
- 14. Introduction • Rare complicationdue to transfusion of lymphocyte containing blood products. • Clinically similar to BMT & HSCT associated GvHD • Usually arises 4 to 30 days after transfusion • Onset of symptoms occur early with signs and symptoms of bone marrow apalasia
- 15. Pathophysiology • Immunocompetent host- When donor is Homozygous and recipient is heterozygous for HLA haplotype (sp Class I) – Host does not recognize donor lymphocytes as foreign • Immunocompromised host – congenital/acquired- lack the ability to reject the donor T cells • Not removed from the recepient – T cell engraftment
- 16. • Host APCspresent host antigens to Donor CD4+ (HLA Class II) and cytotoxic CD8+ cells (HLA Class I ) – recognized as foreign • Activation of T lymphocytes, proliferation and migration (migration by chemokines like CCL2-5, CXCL2, CXCL9-11) • Massive release of TNF-alpha IL-1 and 2 (by Th1 TLC) • TNF alpha – key inflammatory cytokine • Activate dendritic cells • Recruitment and activation of T lymphocytes (effectors) – cause target cell apoptosis • Directly cause tissue necrosis • Causes a cytokine storm – wide spread tissue damage – manifest as skin rash, abnormal liver functions ect • Target organ damage by both soluble inflammatory mediators and cell mediated cytolysis
- 18. Factors for developingTA GvHD 1) HLA haplotype sharing • Donor who is HLA homologous to the recipient. • Ex - donor is a family member, HLA matched products • Degree of population’s genetic diversity – The estimated risk of developing TA-GvHD • In Japan - 1:874 • In France – 1:16,835
- 19. Factors for developingTA GvHD 2) Degree of recipient immunodeficiency – Inability to reject the donor T cells 3) No. of viable T cells in transfusion • Minimum no. of leukocytes required to cause the disease is unknown. • Some studies <1 to 5x10^5 T cells/kg recipient body weight are safe. • Can also occur after transfusion of even 4x10^3 T cells/kg recipient body weight.
- 20. Factors for developingTA GvHD 3) CABG – reduced mitogenic lymphocyte transformation and reduced interleukin 2 production – Usage of fresh blood 4) Usage of fresh products – Contains maximal numbers of viable lymphocytes. (Blood less than 4 days old) – Lymphocyte viability is retained in stored red cells for at least 3 weeks – During storage the number of viable lymphocytes declines as does the expression of cell-surface lymphocyte activation antigens.
- 21. Patients at riskof developing TA GvHD • Recipients of donations from first or second degree relatives. • Patients receiving HLA-matched components. • All T lymphocyte immunodeficiency syndromes - SCID • Intra-uterine transfusion of red cells or platelets. • Red cell or platelet transfusions – who had in-vitro transfusions - up to the age of 6 months after the EDD. • Hodgkins disease • Patients treated with purine analogues, e.g. fludarabine, cladribine or deoxycoformycin. • Following alemtuzumab (anti-CD52) therapy. • Aplastic anaemia patients receiving immunosuppressive therapy with ATG.
- 22. • Recipients ofallogeneic SCT from the time of initiation of conditioning chemoradiotherapy until GVHD prophylaxis is completed and/or lymphocyte count >1 x109/L. • Following SCT, if chronic GvHD or if continued immunosuppressive treatment is required, irradiated blood components should be given indefinitely. • Patients undergoing bone marrow or peripheral blood stem cell 'harvesting' for future autologous transplant, should receive irradiated cellular components during and for 7 days before the bone marrow/stem cell harvest - prevent the collection of viable allogeneic T lymphocytes - potentially withstand cryopreservation • All patients undergoing autologous bone marrow transplant or peripheral blood stem cell transplant, from initiation of conditioning chemo/radiotherapy until 3 months post- transplant (6 months if total body irradiation)
- 23. Patients not atrisk • Solid organ transplant • HIV • Solid tumours • Routine surgery • Non-Hodgkins lymphoma • Premature or term infants (unless previous IUT) • Acute leukemia
- 24. Clinical Presentation • Signsand symptoms usually begin 4-30 days after transfusion. • Initially fever with skin manifestations • GI manifestations • Hepatic dysfunction • BM failure with pancytopenia • Death often occurs with infection or bleeding manifestations
- 25. Skin manifestations • ErythematousMaculopapular rash • Pruritic • Involves palms and soles and spreads throughout the body • Blisters and ulcers - in severe cases.
- 26. GIT - manifestations •Diarrhoea – secretory, voluminous (>2L/day) • Bleeding - life threatening intestinal hemorrhage. • Nausea, vomiting. • Anorexia • Abdominal pain
- 27. Liver • Jaundice andhepatomegaly • Mainly cholestatic hepatitis – lymphocytic infiltration of portal tracts – damage to bile duct epithelium – consequent destruction of bile ducts. • Increased liver enzymes • Increased serum billirubin
- 28. Diagnosis • TA-GVHD isprobably underdiagnosed since it may be wrongly attributed to Intercurrent infection Severe drug reaction Auto immune diseases • Histopathological/hematological features and detection of donor lymphocytes or DNA (mixed chimerism)
- 29. Histopathology of skin •Epidermal mononuclear infiltrates • Basal membrane degeneration • Necrotic keratinocytes • Bullae formation in the absence of eosinophils • Eosinophils would be more supportive of a drug reaction.
- 30. Histopathology of GIT •Apoptosis of crypt epithelial cells • Lymphocytic infiltration • Patchy ulceration • Loss and flattening of surface epithelium
- 31. Histopathology Liver • Subendotheliallymphocyte infiltration • Portal and lobular inflammation • Bile duct damage • Canalicular cholestasis
- 32. Histopathology of Bonemarrow • Marked hypoplasia with numerous macrophages and erythroid precursors. • Haemophagocytosis • Lymphohistiocytic infiltrate
- 33. Detection of donorlymphocytes Techniques to establish donor lymphocyte engraftment are based on genetic differences between the donor and the host and include • HLA Typing • Chromosome differences – DNA fingerprinting - Variable number tandem repeat & short tandem repeat profiles – Pre and post transfusion blood samples, bone marrow, affected and non affected skin – Hair follicle or nail clipping samples – alternative source of pre-tarsnfusion DNA
- 34. Differential diagnoses • Acuteseroconversion illness due to HIV infection - fever, skin rash, diarrhea, abdominal discomfort, jaundice and lymphadenopathy, • Acute viral hepatitis can present with similar illness and is associated with progressively rising AST and ALT levels and positive serologic tests. • Severe drug reaction • Dengue fever and leptospirosis
- 35.
- 36. Management of Suspected/proven disease •Poor prognosis with >90% mortality rate • Must be treated in a specialized unit • High dose steroids –First line - antilymphocyte and anti- inflammatory activity • Methotrexate & Cyclosporine-A – to prevent the disease • Steroid refractory GvHD – Anti-thymocyte globulin (ATG) – Azathioprine – Intravenous immunoglobulins • Supportive therapy – Antibiotics
- 37. Management of at-riskpatients received non-irradiated blood components • Establish which blood components are involved. • HLA type patient and store mononuclear cell and DNA samples. • Careful clinical observation of the transfusion recipient – for features of TA-GVHD
- 38. Prevention • Prevention isbetter than cure • Irradiation and non irradiation methods
- 39. Prevention γ-Irradiation • 25Gy allparts of the pack. – Max 50Gy • Prevent TA GvHD by lymphocyte DNA cross linkage. • Does not damage platelets or granulocytes • But shortens the shelf life of red cell components - increased plasma membrane permeability, potassium leakage, hemolysis – IUT / ET RCC - 24 hours. – Other RCC - irradiate within 14days of collection and store for not more than 14 days post-irradiation. – Platelets. Irradiate at any stage in shelf life - no effect on total shelf life of 5 days except 24 hours for IUT platelets. – Granulocytes. Transfuse as soon as possible after preparation
- 40. Prevention γ-Irradiation • Controversy existsregarding the optimal prevention strategies due to rarity of the disease • Irradiating all units - not practicle • Targeted irradiation – does not prevent in immune competent patients • Japan – genetically homogenous population – Universal cellular product irradiation.
- 41. Prevention Non-irradiation Prevention Strategies •Leukocyte reduction has been shown to reduce the risk of TA- GVHD, especially in a genetically diverse population, but is not a substitute for irradiation in at-risk populations. • Psoralen (S59) + ultra-violet A – used for pathogen inactivation
- 42. Case Discussion • Mildlymphocytopaenia and the 2 doses of methylprednisolone 80mg for COAD • Shared class I HLA haplotypes - critical for the development of TA-GVHD. • Negative DNA fingerprinting result - Number of foreign lymphocytes in the tissue sections was very small • The negative DNA fingerprint supports the degree of difficulty in diagnosing
- 43. References • Transfusion-Associated Graft-vs-HostDisease. A Fatal Case Caused by Blood From an Unrelated HLA Homozygous Donor. Timothy E. Gorman, DO, Carmen J. Julius, Rolf F. Barth, A. Ng, Melanie S.Kennedy, Thomas W. Prior, James Allen, Larry C. Lasky;Am J Clin Pathol2000;113:732-737 • Transfusion-Associated Graft-VersusHost Disease in Severe Combined Immunodeficiency; S Sebnem Kilic, S Kavurt,S Balaban Adim: J Investig Allergol Clin Immunol2010; Vol. 20(2): 153-156 • Transfusion-associated graft-versus-host disease; D. M. Dwyre & P. V. Holland :Vox Sanguinis, 2008 95;85–93 • Review - Transfusion-associated graft-versus-host disease, BJH 2002;117:275–287 • Rossi's Principles of Transfusion Medicine • TA-GvHD management guidelines -NHS
Editor's Notes
- #4 On admission mild anaemia (? Secondary to peptic ulcer disease) with mild lymphocytopenia NL Lymphocyte count – 1000-3000/uL
- #6 Bilirubin – Total - 0.2-1.2 mg/dL direct bilirubin is 0.1-0.4 mg/dL ALP – 44-147IU/L Amylase 23-85U/L & Lipase 0-160U/L(acute pancreatitis, gallstones,peptic ulcer, CA)
- #7 Cultures – Bacterial and fungal AMA – primary billiary cirrhosis
- #9 Haemophagocytic syndrome - dysfunction of cytotoxic T cells and NK cells. This T cell/NK cell dysregulation causes an aberrant cytokine release, resulting in proliferation/activation of histiocytes with subsequent haemophagocytosis. Histiocytic infiltration of the reticuloendothelial system results in hepatomegaly, splenomegaly, lymphadenopathy and pancytopenia ultimately leading to multiple organ dysfunctions.
- #10 Microsatellites - short tandem repeats (STRs) - repetitive DNA in which certain DNA motifs (ranging in length from 2–5 base pairs) are repeated, typically 5–50 times.[
- #11 Skin – like in post admission day 4 report
- #15 Most of our understanding of the pathophysiology of GVHD comes from the hematopoietic stem cell transplant (HSCT) setting.
- #16 Typically, in immunocompetent hosts,viable T lymphocytes are destroyed by the recipient’s immune system. In susceptible patients, whether immunocompetent or with congenital or acquired cellular immune deficiency,transfused T cells are not destroyed. Ex – inherited -severe combined immuno deficiency, acquired-Hodgkins lymphoma
- #17 A cytokine storm, also known as cytokine cascade and hypercytokinemia, is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and white blood cells, The additional presence of “danger signals”—such as lipopolysaccharide (LPS) or infl ammatory cytokines—help APCs activate T cells and the presence/absence of “danger signals” may make the difference between an immune response and tolerance.
- #18 The additional presence of “danger signals”—such as lipopolysaccharide (LPS) or inflammatory cytokines—help APCs (dendritic cells) activate T cells and the presence/absence of “danger signals” may make the difference between an immune response and tolerance.10
- #21 Mitogens (chemicals commence cell devision) are very potent stimulators of T-cell activation and proliferation independent of their antigenic specificity.(3) It has been suggested that mitogens can induce T-cell proliferative responses even if they are incapable of responding adequately to antigenic (physiologic) stimuli.
- #25 Typical course of the disease
- #30 Vacuolar interface dermatitis - dermatitis where degenerative changes occur at the dermoepidermal junction, with lymphophatic inflammation at the epidermis and dermis.
- #34 STR/microsatellite - tract of repetitive DNA in which certain DNA motifs (ranging in length from 2–5 base pairs) are repeated, typically 5–50 times Tandem repeats - pattern of one or more nucleotides is repeated and the repetitions are directly adjacent to each other. VNTR/minisatellite
- #37 Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells
- #42 Using properly irradiated blood components would prevent this disease; however, without completely knowing which patients are at risk, all transfused cellular blood products would have to be irradiated for adequate prevention. The cost and logistics of such a task and the radiation effects of shortening the shelf life of the blood supply and increasing plasma potassium in RBC units make the value of widespread irradiation questionable given the uncertain benefits for such an apparently rare disease
- #44 The transfused lymphocytes recognized the patient as foreign; however, the patient recognized the transfused lymphocytes as self. Only a few other reported cases of TA-GVHD demonstrate only a class II HLA mismatch. If a patient develops a skin rash, diarrhea, liver failure, and bone marrow aplasia shortly after blood transfusion,TA-GVHD should be considered in the differential diagnosis.