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Editor,—Ahya et alreported a case of transfusion associated graft versus host disease (TA-GVHD) in a non-immunocompromised patient resulting from blood transfusion after coronary artery bypass grafting (CABG).1 They concluded that this devastating complication of transfusion is probably underreported. There is no doubt that diagnosing this condition needs a high index of suspicion because its manifestations can be seen in other more common conditions such as septicaemia. Moreover, histological diagnosis needs specialist expertise in tissue typing.
We report another patient with TA-GVHD acquired following elective four-vessel CABG and perioperative transfusion of a total of six units of blood. A 68 year old man was admitted three weeks after surgery with a seven day history of skin rash, breathlessness, cough, and expectoration of brown sputum. He had an extensive erythrodermic maculopapular eruption, oral thrush, tachycardia, hypotension, bilateral chest crepitations, and mild hepatomegaly. His condition worsened progressively with development of profound pancytopenia, disseminated intravascular coagulation, metabolic acidosis, hepatitis, and acute renal failure. His bone marrow was aplastic and skin biopsy showed monocytic infiltration with cellular apoptosis supporting the clinical diagnosis of TA-GVHD. Treatment with high dose steroids, ciclosporin, and OKT3 was initiated, but despite maximum support he died within seven days of readmission.
Although TA-GVHD does occur in immunocompetent individuals who had blood transfusion for other reasons, it is more frequent following cardiopulmonary bypass surgery. This type of major surgery appears to induce a transient immunodeficiency state, the mechanism of which is poorly understood and is likely to be multifactorial. Stress of surgery, use of fresh blood with more viable lymphocytes, immunosuppressive effect of multiple transfusions, and transient reduction of interleukin 2 production and mitogenic lymphocyte transformation following cardiopulmonary bypass may all cause a degree of immune dysfunction.2-5 If the donor’s blood happens to be homozygous for one of the recipient’s major HLA types, this transient immune dysfunction may facilitate donor’s lymphocyte engraftment and development of TA-GVHD.
We emphasise the relation of this highly dangerous condition with cardiopulmonary bypass surgery. One can only speculate as to the nature of this association.
This letter was shown to the authors, who reply as follows:
Ghrew et al report a patient with TA-GVHD following elective four-vessel CABG and perioperative transfusion of six units of blood. It would be interesting to know in this case about the freshness of the transfused blood and whether shared haplotypes between the donor(s) and recipient was a feature in addition to the transient immunomodulatory effect of cardiopulmonary bypass.
The Oxford report re-emphasises that TA-GVHD as a complication of cardiopulmonary bypass surgery is seen in Europe. The association was first made in Japan, where the reported frequency of one way matching or sharing HLA haplotype in a non-first degree relative ranges from 1:312 to 1:874 and, probably as a result, more than 200 cases of TA-GVHD have been reported in immunocompetent individuals.1-1 Greater HLA diversity probably accounts for the reduced incidence in immunocompetent white patients, but it is clear that shared haplotype is not the sole requirement for the development of TA-GVHD after cardiopulmonary bypass. This is supported by data from the USA where in the caucasian population the most common haplotype is HLA A1, B8, DRB1*03 with a reported frequency of 6.6%.1-2 Given this haplotype frequency, 0.05% of the transfusions in this population would be expected to result in a one way HLA match. If shared haplotype was the sole requirement for the development of TA-GVHD then around 1500 cases might be expected each year. The reported frequency is well below this (less than 10 reports in total of which we are aware). Several explanations for this can be offered.
First the transfused units may contain an insufficient number of immunocompetent lymphocytes; second, some recipients may be able to destroy the donor lymphocytes on the basis of subtype differences in the class 1 or other minor histocompatiblity antigens between the donor and recipient.1-3 Finally, it is possible, and quite likely, that some cases have remained unrecognised and unreported.
We hope that our publication in Heart of two cases of TA-GVHD after cardiac surgery will heighten awareness of this complication of transfusion, and result in full investigation and reporting of all suspected cases to SHOT (serious hazards of transfusion). It is necessary to establish the true incidence of TA-GVHD in cardiac surgery so that cost–benefit analysis and informed review of guidelines on the irradiation of cellular blood products for this indication can be completed.