Case Report

Transfusion-associated graft-versus-host disease in a presumably immunocompetent patient after transfusion of

stored packed red cells

K. SUZUKI, H. AKIYAMA, S. TAKAMOTO, Y. MARUYAMA, H. SAKAMAKI, K. AKAGI, Y. MAEDA, M. TAKENAKA, AND Y. ONOZAWA

A 54-year-old woman developed transfusion-associated graft-versus-host disease FA-GVHD) after the transfusion of stored packed red cells obtained from unrelated donors. The patient was presumed to be immunocompetent. A diagnosis of TA- GVHD was made by clinical features and postmortem pathologic findings. Sex chro- matin analysis of the patient’s lymphocytes demonstrated chimerism. HLA typing of the blood donors revealed one to be HIA-homozygous for one of the patient‘s HLA haplotypes (A33-B44-Cblank). This case illustrates the risk in the general patient population of TA-GVHD after routine blood transfusion therap Workers should be aware of this possibility and should continue searching for an ekcient way to prevent it. TRANSFUSION 1992;32:358360.

Abbreviations: TA-GVHD = transfusion-associated graft-versus-host dlsease.

TRANSFUSION-ASSOCIATED graft-versus-host disease (TA-GVHD) is a well-known complication of blood transfusion in an immunocompromised patient and in an immunocompetent host, especially when fresh blood components donated by close relatives are There have been two reported case^^*^ of TA-GVHD in an im- munocompetent patient after the administration of stored packed red cells taken from unrelated donors. These re- ports, however, lack definite diagnostic evidence, leav- ing in doubt the existence of this complication in such patients. We present here a report of TA-GVHD in an immunocompetent patient after transfusion of 2-day-old packed red cells, which shows that this type of compli- cation can occur after routine blood transfusion therapy.

Case Report A 54-year-old Japanese woman developed upper gastroin-

testinal bleeding with generalized weakness. Eight units of packed red cells, collected from four unrelated blood donors 2 days before, were transfused. Ten days after transfusion, the patient developed fever with chills, and within 24 hours, an erythematous skin rash appeared on her face and trunk. She was admitted to the Komagome Hospital for further evaluation.

From the Departments of Hematology, Dermatology, Pathology, and Blood Bank, Tokyo Metropolitan Komagome Hospital, and the Tokyo Metropolitan Blood Center, Japanese Red Cross, Tokyo, Japan.

Supported in part by a grant from the Tokyo Metropolitan Government. Received for publication June 26, 1991; revision received October

7, 1991, and accepted October 12, 1991.

She had a history of total hysterectomy and fractional ex- ternal irradiation to the pelvic area 7 months previously, after a diagnosis of uterine cervical cancer, stage 1B. No chemo- therapy or blood transfusion was given. Her course was stable and uneventful with normal blood counts during follow-up pe- riod. Her physical examination revealed a temperature of 39°C and diffuse erythematous skin rash on her face, neck, and upper trunk.

Her white cell count was 500 per pL (0.500 x 109/L) with 19 percent atypical lymphocytes; the hemoglobin level was 8.5 g per dL (0.85 gL), and the platelet count was 113,000 per p L (113 x 109/L), but it dropped quickly after admission. The bone marrow examination showed severely hypoplastic marrow with reactive histiocytes and atypical lymphocytes that were positive for CD8.

Administration of broad-spectrum antibiotics was begun im- mediately, but without benefit. On the second hospital day, she began to have nausea, vomiting, and bloody diarrhea. The patient became mentally disturbed and had several seizures. She became progressively hypotensive and oliguric in spite of aggressive medical treatment. Blood counts showed progress- ing pancytopenia, and her liver function also deteriorated. Prednisolone (90 mglday) was given, and hemodialysis was initiated, but without any remarkable response. She died on hospital Day 6, of sepsis due to Cundidu ulbicum.

At autopsy, erythroderma was noted to cover almost the entire body. Pathologic studies of the skin revealed sparse in- filtration of lymphocytes into the upper dermis and basal cell necrosis surrounded by lymphocytes (Fig. 1). Immunohisto- chemical studies demonstrated diffuse expression of HLA-DR by keratinocytes and an absence of CDla-positive Langerhans’ cells. The majority of lymphocytes infiltrating into the dermis were CDCnegative and CD8-positive, which is consistent with cytotoxic T cells.

Cryptic abscesses were noted in the ascending colon. Sparse lymphocytic infiltration into the portal areas of the liver and

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TRANSFUSION 1992-Vol. 32. No. 4 TRANSFUSION-ASSOCIATED GVHD 359

FIG. 1. Autopsy specimen of skin showing infiltration of lympho- cytes into the upper dermis and basal cell necrosis surrounded by lymphocytes, which are compatible with the findings in graft-versus- host disease. Magnification x 720.

FIG. 2. Quinacrine dihydrochloride staining of lymphocytes ob- tained from the spleen. The arrow shows brightly fluorescent spots of Y chromatin. Magnification x 4200.

HLA analysis

H LA A B C

c / d c / d e / d haplotype a 24 46 11 Pt

b 1 1 48 8 + 0 0

b / c b / c

donor

I 0

a l c

1 : A(11,26) B(62,60) C ( 4, - > 2 : A(24,26) B(52,62) C ( - , - > 3 : A(24,31) B ( 7 ,51> C ( 7 , - ) 4 : A(33, - > B(44, - > C ( - , - )

c 33 44 -

d 24 52 -

e 33 61 -

FIG. 3. Results of HLA typing of patient (Pt), her family, and the involved blood donors.

necrosis of the hepatocytes were found. The lymph nodes showed atrophy of lymphatic tissue and some erythrophagocytic his- tiocytes in the sinus. The white pulp of the spleen was also atrophic. vical cancer.

Diffuse mucosal candidiasis in the patient’s oral cavity, tra- chea, and gastrointestinal tract was observed. There was no evidence of local recurrence or metastasis of the uterine cer-

360 SUZUKI ET AL. TRANS FU S I0 N Vol. 32. No. 4-1992

Materials and Methods Lymphocytes were obtained from the patient’s spleen at the

time of autopsy, and we performed quinacrine dihydrcchloride staining of lymphocytes according to the methods of Matsush- ita et a1.lo We carried out HLA typing of the patient, her family, and the four unrelated blood donors using an HLA typing tray (Terasaki HL4 Tray, One Lambda, Inc., CA) and the standard lymphocyte microcytotoxicity technique.

Results Lymphocytes obtained from the patient’s spleen revealed

brightly fluorescent spots of Y chromatin, which suggested a male origin (Fig. 2). HLA typing of the patient, her family, and the blood donors is shown in Fig. 3. One of the four blood donors was male and was found to be homozygous for the patient’s haplotype, A33-B44-Cblank.

Discussion TA-GVHD is a well-known phenomenon in immu-

nocompromised hosts and in patients who received fresh blood components, especially those donated by rela- tives. ’-’ The possibility of TA-GVHD after routine trans- fusion therapy using stored blood obtained from unrelated donors also has been pointed out by two previous case report^,^.^ even though they lack definitive evidence of TA-GVHD. The diagnosis of TA-GVHD in this case seems to be firm, and the patient shares an HLA hap- lotype with an HLA-homozygous blood donor. This re- port thus illustrates the possibility in the general patient population of developing TA-GVHD from routine blood transfusion with stored blood components.

In Japan, fresh blood donated by patients’ relatives had been transfused rather frequently during major sur- gical operations, such as open heart surgery. The inci- dence of postoperative erythroderma, considered to be the same as that of TA-GVHD, has been reported as 1 in every 659 operation^.^ Fortunately, it is becoming rare in Japan to use nonirradiated fresh blood donated by relatives (Nankou H. Oral communication, May 1991).

The chance of developing TA-GVHD remains, how- ever, because blood components donated by random do- nors can still cause TA-GVHD in immunocompetent patients, as in the case presented. In Japan, the chance of transfusion from an HLA-homozygous donor to a pa- tient with the HLA haplotype A33-B44-Cblank, for ex- ample, was calculated as 1 in every 3000 transfusions.6 Although the actual incidence of TA-GVHD seems to be much lower, we cannot ignore this risk.

Because TA-GVHD is a rapidly fatal disease for which there is no known effective treatment, prophylaxis is the only recourse. Currently, the sole effective way to re- move the functional lymphocytes is irradiation of blood components. Because of the cost of that procedure, an alternative method of preventing TA-GVHD should be investigated. Even though it is not clinically proven,

longer storage of the blood components before their use might result in the inactivation of the functional lym- phocytes and, thus, the prevention of TA-GVHD.6

We should be aware of the risk of developing TA- GVHD after routine blood transfusion, especially in areas where the population’s HLA types are rather homoge- neous. We should also investigate and establish a more efficient way to prevent this serious complication of blood transfusion.

Acknowledgment The authors are indebted to Ryoko Otani for assistance in the prep-

aration of the manuscript.

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Ken Suzuki, MD, Department of Hematology, Tokyo Metropolitan Komagome Hospital.

Hideki Akiyama, MD, PhD, Department of Hematology, Tokyo Metropolitan Komagome Hospital, 3-18-22, Honkomagome, Bunkyo- ku. Tokyo 113, Japan. [Reprint requests]

Shigeru Takamoto, MD, PhD, Head, Department of Blood Bank, Tokyo Metropolitan Komagome Hospital.

Yasuo Maruyama, MD, PhD, Department of Hematology. Hisashi Sakamaki, MD, PhD, Department of Hematology. Kumiko Magi , MD, Department of Dermatology, Tokyo Metro-

Yoshiharu Maeda, MD, Department of Pathology, Tokyo Metro-

Michiko Takenaka, MD, Tokyo Metropolitan Blood Center, Japa-

Yasusuke Onozawa, MD, PhD, Head, Department of Hematology.

politan Komagome Hospital.

politan Komagome Hospital.

nese Red Cross, Tokyo, Japan.