transfusion associated graft vs host disease

In transfusion-associated graft-vs-host disease (TA-GVHD), transfused T lymphocytes travel to, and then establish a home base in, host lymphoid tissues, where they encounter host human leukocyte antigens (HLAs). The donor CD4+ and CD8+ lymphocytes react to the unshared class I and/or class II HLAs. Two days to 6 weeks later, the donor T lymphocytes travel to nonlymphoid organs, such as the skin, gut, and liver, and characteristic lesions such as the ones experienced in this patient begin developing. In acute GVHD, the skin, GI tract, and liver are the major target organs involved. This patient’s clinical picture demonstrates the characteristic findings of skin rash, diarrhea, and elevated bilirubin levels, all of which strongly suggest the diagnosis. The classic skin lesion is described as being an erythematous maculopapular morbilliform eruption that starts on the face, ears, palms, and soles. Papular rashes can occur. Skin lesions often spread to the trunk and may evolve to erythroderma, affecting an extensive body surface area and progressing in severe cases to resemble toxic epidermal necrolysis. The histopathological skin findings that support the diagnosis of TA-GVHD include epidermal lymphocytic infiltrates and vacuolization of the basal membrane. There is usually absence of circulating eosinophils, which would be more characteristic of a drug reaction. The histological changes on skin biopsy are not specific for TA-GVHD and must be considered in the context of the overall clinical picture. As an immunologic organ like the lung, the GI tract can be involved in a similar lymphocyte response, with resultant mucosal inflammation followed by diarrhea. Liver involvement completes the spectrum of involvement in acute GVHD. Important predispositions to developing TA-GVHD are lymphoproliferative malignancies (in particular, Hodgkin’s lymphoma) and prior receipt of certain chemotherapeutic medications. Use of irradiated blood products may prevent TA-GVHD in groups predisposed to developing the condition. Awareness of the disease entity and caution to prevent unnecessary transfusions in individuals predisposed to developing TA-GVHD are of paramount importance.

Proton pump inhibitors (PPIs) have been associated with severe delayed-type hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms (DRESS). This patient’s lesions on the palms and soles are characteristic of the location of erythema multiforme, which can progress to include mucous membrane involvement that presents as this patient’s diarrhea. In addition, the liver can be characteristically involved with certain adverse reactions to medications. Because drug eruptions are type IV hypersensitivity reactions, the development of all of this patient’s problems 4 days after starting a PPI is quicker than would be expected for such widespread adverse effects to a medication.

With his WBC count of 1,648/µL (1.65 × 109/L), of which 78% were polymorphonuclear leukocytes, this patient has an absolute neutrophil count of 1,285/µL (1.28 × 109/L). By definition, this does not meet the criteria for neutropenia, which is an absolute neutrophil count of <500/µL (0.50 × 109/L). Bacteremia with P aeruginosa is a significant problem in neutropenic patients and without appropriate therapy is associated with a high rate of mortality. Because of this factor, empiric therapy for febrile neutropenic patients targets P aeruginosa as the main bacterial pathogen requiring coverage. Even though this patient could still have P aeruginosa infection with an adequate number of granulocytic cells, the skin lesions he demonstrates are not the bullous hemorrhagic lesions of ecthyma gangrenosum that are so characteristic of P aeruginosa bloodstream infection.

In contrast to contaminated platelet concentrates that predominantly transmit gram-positive bacteria from the skin flora, contamination of RBC products involves primarily gram-negative organisms, usually Enterobacteriaceae that are part of normal flora. Y enterocolitica is the most characteristic organism involved in such RBC-related transfusion reactions. Often transmitted from infected donors with minimal or no GI symptoms, the organism can grow at refrigerated temperatures. The reactions are due to transfusion either of the organism itself or of toxin produced by the organism. The clinical result is similar, with severe sepsis or septic shock being the consequences of either the organism or its endotoxin. The skin and liver involvement experienced by this patient are not consistent with Y enterocolitica transfusion infection.12345

A 60-year-old man with a history of refractory Hodgkin’s lymphoma that has been treated in an academic medical center 3 h from his home with second-line chemotherapy now has persistent anemia and thrombocytopenia. He presents to an ED in the rural hospital in his hometown with fatigue, weakness, and a 1-day history of melena that began 2 weeks after starting ibuprofen 800 mg tid for back pain. His WBC count is 1,648/µL (1.65 × 109/L) with 78% polymorphonuclear leukocytes, hemoglobin is 0.67 g/dL (6.7 g/L), and platelet count is 78 × 103/µL (78 × 109/L). The patient is admitted, a proton pump inhibitor is started, and he receives 2 U of packed RBCs. The next day, esophagogastroduodenoscopy shows a 2-cm gastric outlet ulcer. The patient is discharged from the hospital the following day feeling back to normal. One week later, he returns to the ED acutely ill-appearing, with a history of profuse diarrhea over the past 3 days. Temperature is 39.1°C, BP is 148/82 mm Hg, pulse is 104/min, and respirations are 16/min. There is marked pallor of his conjunctiva. He has an erythematous maculopapular morbilliform eruption that he says was initially pruritic and began over his face, ears, palms, and soles; it is now also present on his upper trunk and abdomen. WBC count is 1,224/µL (1.22 × 109/L) with 83% polymorphonuclear leukocytes and 5% bands; hemoglobin is 0.58 g/dL (5.8 g/L), platelets are 64 × 103/µL (64 × 109/L), and reticulocyte count is 1%. Bilirubin is 3.1 mg/dL (53.02 µmol/L), with indirect of 0.6 mg/dL (10.26 µmol/L). What is the most likely cause of this clinical presentation?

Footnotes

  1. SEEK Questionnaires ↩

  2. Bahar B, Tormey CA. Prevention of transfusion-associated graft-versus-host disease with blood product irradiation: the past, present, and future. Arch Pathol Lab Med. 2018;142(5):662-667. PubMed ↩

  3. Dwyre DM, Holland PV. Transfusion-associated graft-versus-host disease. Vox Sang. 2008;95(2):85-93. PubMed ↩

  4. Guinet F, Carniel E, Leclercq A. Transfusion-transmitted Yersinia enterocolitica sepsis. Clin Infect Dis. 2011;53(6):583-591. PubMed ↩

  5. Lin CY, Wang CW, Hui CR, et al. Delayed-type hypersensitivity reactions induced by proton pump inhibitors: a clinical and in vitro T-cell reactivity study. Allergy. 2018;73(1):221-229. PubMed ↩