FATAL GRAFT-VERSUS-HOST DISEASE FOLLOWING TRANSFUSION OF GRANULOCYTES FROM NORMAL DONORS

1167 are often short-lived.6 Attempts orthostatic hypotension with sympathomimetic drugs have also met with limited success.3 One recent example has been the combination of cheese containing the indirect sympathomimetic compound tyramine and a M.A.O.I. 7-9 A major difficulty in the few cases reported has been the erratic pressor response, probably due to variable amounts of tyramine in cheese.’8 We have overcome this difficulty by using a chemical preparation of tyramine. An exact dose of tyramine can then be given and the amount adjusted to suit each patient. Six patients were treated and three patients are able to walk and lead active daily lives without symptoms of orthostatic hypotension. In another patient the treatment was successful in alleviating these symptoms, but his mobility is restricted by pronounced cerebellar ataxia. Treatment was stopped in one patient after a fortnight as he became confused. This may have been a reaction to the tranylcypromine since confusional states are a wellrecognised complication of M.A.o.i. The remaining patient in our study (case 3) did not respond to treatment with tyramine and tranylcypromine. His orthostatic hypotension was apparently due to failure of noradrenaline release despite adrenergic innervation of peripheral

itially,

but the benefits

to treat

blood-vessels. 12I

Tyramine is a sympathomimetic agent which released noradrenaline from peripheral sympathetic nerves in laboratory animals.13 In our patients measurements of plasma-catecholamines after a dose of tyramine and tranylcypromine suggest that release of noradrenaline explains the pressor response with this therapy. As patients with both afferent and efferent autonomic block benefited from the treatment, it seems probable that even in patients with an efferent block some adrenergic activity supplies peripheral blood-vessels. 14 The only patient with neurogenic orthostatic hypotension we studied who did not respond to the therapy was unable to release noradrenaline from his sympathetic nerve endings and therefore showed no pressor response with tyramine.’2 In one patient treatment with fludrocortisone was also continued. Plasma-volume contraction has been reported with noradrenaline administration, and increased noradrenaline release by tyramine may explain why this patient needed to take fludrocortisone.15 We observed that patients who had a good response to this therapy nevertheless had considerable variation of their blood-pressure, although gross orthostatic hypotension was prevented for 2-4 h after tyramine ingestion. The absence of symptoms is compatible with maintenance of autoregulation of cerebral blood-flow which we have demonstrated in patients with this disorder. ’6 We found that a combination of tyramine and tranylcypromine was successful in treating neurogenic orthostatic hypotension, particularly when there were no abnormal symptoms and signs apart from those resulting from autonomic failure. Patients in whom there is failure of catecholamine release may not respond to the therapy. In addition, patients who have multiple nervous-system involvement are less likely to fare well, for, although the orthostatic hypotension may be relieved, their mobility is restricted because of involvement of other cerebrospinal pathways. A chemical preparation of tyramine meant that a known quantity of the drug could be given and the dosage adjusted. Our results indicate that patients with neurogenic orthostatic hypotension should receive a trial of this treatment. It should be

remembered that tyramine may cause hypertensive crises in patients receiving M.A.o.i. The treatment therefore requires monitoring, but with care, patients with neurogenic orthostatic hypotension may benefit. We thank the patients for their cooperation, Mrs A. Coleman for tyramine capsules, and Roche Products and the Scottish Hospital Endowments Research Trust for financial support.

preparing the

Requests for reorints should be addressed

to

R. N. N.

REFERENCES 1.

Johnson, R. H., Spalding, J. M. K. in Disorders of the Autonomic Nervous System. Oxford, 1974. 2. Johnson, R. H., Spalding, J. M. K. Br. J. Hosp. Med. 1976, 15, 266. 3. Barnett, A. J., Wagner, G. R. Am. Heart J. 1958, 56, 412. 4 Schatz, I. J., Miller, M. J., Frame, B. Cardiology, 1976, 61, suppl. 1. p. 280. 5. Rosenhamer, G., Thorstrand, C Acta med scand. 1973, 193, 277. 6. Bannister, R., Ardill, L., Fentem, P. Q. Jl Med 1969, 38, 377. 7 Diamond, M. A., Murray, R. H., Schmid, P. G. J. clin. Invest. 1970, 49, 1341.

Lewis, R K., Hazelrig, C. G., Fricke, F. J., Russell, R. O. Archs intern Med. 1972, 129, 943. 9. Frewin, D. B., Robinson, S. M., Willing, R. L. Aust. N.Z. J. Med. 1973, 3, 8.

180. 10. Johnson, R. H., Keogh, H. J., Nanda, R. N. Br. med. J. 1975, IV, 405. 11. Rennie, M. J. PH.D. thesis; University of Glasgow, 1974. 12. Nanda, R. N., Boyle, F. C., Gillespie, J. S., Johnson, R. H., Keogh, H. J. J. Neurol. Neurosurg. Psychiat. (in the press). 13. Kopin, I. J. Pharmac. Rev. 1966, 18, 513. 14. Nanda, R. N., Boyle, F. C., Gillespie, J. S., Johnson, R. H., Keogh, H. J. J. Neuropath. appl. Neurobiol. (in the press). 15. Finnerty, F. A., Jr., Buccholz, J. H., Guillauden, R. L. J. clin. Invest. 1958,

37, 425. 16. Nanda, R N., Wyper, D. J., Harper, A. M., Johnson, R. H. in Blood Flow and Metabolism in the Brain (edited by A. M. Harper, W. B. Jennett, J. D. Miller, and J. O. Rowan); p. 22. Edinburgh, 1975.

FATAL GRAFT-VERSUS-HOST DISEASE FOLLOWING TRANSFUSION OF GRANULOCYTES FROM NORMAL DONORS

J. M. FORD M. H. CULLEN

J. J. LUCEY J. S. TOBIAS T. A. LISTER

Departments of Medical Oncology, Pathology, and Hœmatology, St. Bartholomew’s Hospital, London EC1

of fatal

disease adult with acute leukæmia, after transfusion of leucocytes from normal donors. This is the first reported case of graft-versus-host disease following transfusion of normal blood-products to a patient with a disease not usually associated with severe immunoincompetence. The number of lymphocytes transfused was no higher than that given when platelet concentrates are prepared from a single donor.

Summary

A

case

was seen

in

graft-versus-host

an

Introduction GRAFT-VERSUS-HOST

(G.V.H.)

disease

occurs

in

60-70‘c of recipients of bone-marrow transplants, desclose tissue-matching of donor and recipient. It is the cause of death in 10-20% of transplanted patients.1 Several cases of G.V.H. disease have been reported in children with Swiss-type agammaglobulinaemia after small transfusions of whole blood from normal donors.2-4 G.v.H. disease has also been reported in cancer patients receiving leucocytes from donors with chronic myelogenous leukaemia (c.s.L.).5-’ There are no previous reports of G.v.H. disease following transfusion of blood-products from normal donors for the suppor-

pite

1168 tive

of cancer patients receiving intensive chemotherapy. One of our patients has died of acute G.v.H. disease after receiving leucocyte transfusions from his care

relatives.

Case-report A 50-year-old man presented with a 6-week history of malaise. Past history, family history, and drug exposure were unremarkable. He had had no previous blood-component therapy and denied any history of allergy. Clinical examination was normal. His initial blood-count showed: hxmoglobin 8.11 g/dl, white-cell count

8600/mmB platelets 49 000/mm. The bone-marrov. interpreted as showing acute promyelocytic teuksmia. {’here was no clinical or laboratory evidence of disseminated intravascular coagulation. His HLA type vas Al, B8/All, B12. was

Induction therapy was given as shown in fig. 1. Alternateday granulocyte transfusions were given as part of a current trial. A combined granulocyte and platelet harvest was

obtained from relatives with

a

semicontinuous-flow cell separa-

(Hxmonetics Corporation, Natick, Mass., U.S.A.), using a previously described technique.’ The cell collections invanably

tor

contained large numbers of lymphocytes but were not irradiated. Relatives were premedicated with 10 mg dexamethaas sone orally 9 h before donating. A total of ten transfusions uas A HLA 4 transdonor All, B12/AW30, (son, B13) type given: fusions ; donor B (brother, HLA type A2, BW35/All, B123 transfusions; donor C (son, HLA type Al, B8/A2, BlflS 3 transfusions (fig. 1).The mean number of granulocvtes, platelets, and lymphocytes per transfusion were respectivelv: 2.49x1010, 6-14x10",and 0.21x1010. On day 8 he became pyrexial and remained febrile until death. Intravenous antibiotics were given. Blood-cultures,

urine-cultures, and chest X-rays were repeatedly negative. Viral-antibody litres in serum samples fell consistently from da’v 0 to day 20. On day 14 splenomegaly was detected, and a red maculopapular skin rash appeared on the trunk, neck, and upper arms. 24 h later this had progressed to a generalised

erythroderma. A sensitivity reaction to one of his antibiotics suspected. They were discontinued, and he was given cephalothm and oral steroids. On day 18 he became jaundiced, Liver function progressively deteriorated until death (day 18: bilirubin 2.55 mg/dl, serum-glutamic-oxaloacetic transaminase (s.G.o.T.) 315 B.u., alkaline phosphatase (A.P.) 70 i.u.; day 20: bilirubin 8.3 mg/dl, S.G.O.T. 356 B.U., A.P. 230 t.u,). A diagnosis of G.v.H. was suggested, and a skin-biopsy sample was taken on day 19. His final granulocyte transfusion was irradiated to a dose of 1500 rads. He became increasingly confused and tachypnoeic and died in coma on day 21. At no stage was there diarrhoea or vomiting. Marrow examination on day 19 showed little change from the picture at presentation. At necropsy hepatomegaly (2100 g) and splenomegaly (350 g) were noted. There were no discernible lesions in the intestines. Histological examination revealed an aggressor lymphocyte reaction and parenchymal damage in many organs, particularly the liver, skin, and intestines. The epidermis showed several areas of basal vacuolation and spongiosis with mam eosmophilic bodies (fig. 2). The liver contained a diffuse cellular infiltrate, predominantly involving the portal tracts and to a lesser extent the parenchymal cells. Approximately 50r; of the small bileducts showed atypical features with f9ci of cell was

Fig. 2 Aggressor lymphocyte reaction in skin at necropsy, with irregularity of the epidermal-dermal junction following 1-Treatment and clinical sion and death (day 21).

Fig.

state

of

patient

between admis

basal-cell destruction.

(Hsematoxyhn

and

eosin, reduced by half from z275.

1169

unit," but since it is not usual to transfuse several such units from a single donor to a single recipient, the dose of lymphocytes necessary to cause G.v.H. disease is probably seldom reached. However, it seems that all transfusions of platelet concentrates prepared with the Haemonetics machine carry a risk of causing G.v.H. disease. We have given over 300 Hxmonetics-derived platelet concentrates, and worldwide experience runs into

Fig. 3-Section of liver, showing destruction of a bileduct portal tract. (Hxmatoxylin and eosin, reduced by half from x275.)

many tens of thousands. G.V.H. disease has not been seen in any platelet recipient, but mild and transient cases may easily have been overlooked, in view of the critical clinical state of many of the patients. All blood-products given to marrow-graft recipients should be irradiated. However, the need to irradiate leucocyte concentrates from c.M.L. donors given to nonmarrow-graft recipients remains controversial. Such transfusions can result in transient myeloid engraftment followed, rarely, by G.V.H. disease.5-7 Lowenthal et al,7 recommended irradiation of such cells after observing three cases of G.V.H. disease (one fatal) in recipients of c.M.L. leucocytes.7 Others have suggested that a myeloid graft can tide the recipient over a period of neutropenia and that G.V.H. disease, providing it can be controlled, may have an anti-tumour effect. Despite the severity of our patient’s G.v.H. disease, there was no apparent effect on the leukaemia as judged by the marrow appearance on day 19. Our findings demonstrate clearly that platelet (as well as leucocyte) concentrates prepared by certain techniques may be contaminated with a dose of lymphocytes sufficient to cause G.v.H. disease. We cannot recommend routine irradiation of all leucocyte and platelet concentrates on the basis of this single case, bearing in mind the considerable administrative problems which such a policy would entail. However, it may be wise to irradiate those concentrates given in close temporal relationship

in the

shrinkage, cell swelling, and complete loss of some cells (fig. 3). The mucosa of the small and large intestine showed many dilated crypts with atypical epithelial linings and containing degenerating cellular debris, neutrophils, and eosinophils. There was no evidence of opportunist infection. Discussion The diagnosis of G.V.H. disease is based on a triad of clinical symptoms (dermatitis, diarrhoea, and jaundice), abnormal tests of liver function (elevated levels of bilirubin, transaminase, and alkaline phosphatase), and highly characteristic histological findings in skin, liver, and gastrointestinal mucosa. 1Although we lack cytogenetic confirmation of engraftment of donor lymphoid tissue, it seems reasonable to conclude that this patient died of G.V.H. disease, as he fulfils all the above criteria except diarrhoea. Since the gut showed striking histological changes, he may have died before gastrointestinaltract dysfunction became clinically apparent-a clinicopathological dissociation noted by others.9 Dogs given histoincompatible marrow grafts without prior immunosuppression die with G.V.H. disease within 9-14 days.’° Our patient received leucocytes from histoincompatible relatives and died 19 days after his first transfusion. Myelogenous leukaemia is not known to be associated with profound immunoparesis, though this may have been induced by the administration of antiteukaemic chemotherapy, allowing engraftment of immunocompetent donor cells. In irradiated adult mice fatal G.v.H. disease can be produced by intravenous infusion of only 10’ homologous lymph-node cells/kg body-weight.Our patient received a mean of 3 x 107/keg peripheral lymphocytes per transfusion. Donor premedication with dexamethasone causes lymphopenia, but considerable numbers of lymphocytes are still present in each transfusion of granulocytes obtained with the Hxmonetics machine. The mean lymphocyte dose (139 transfusions) is 3x109 cells per transfusion. 12 The Hxmonetics machine was designed primarily for harvesting large numbers of platelets from a single donor, and in platelet concentrates obtained in this way we have demonstrated a mean lymphocyte contamination of 3-53x10" (34 transfusions). Standard units of blood-bank platelets contain up to 109 lymphocytes per

to ’

immunosuppressive chemotherapy.

We are indebted to Linda Brown, department of haEmatology, for expert technical assistance, and to the nursing staff of the cell-separator unit for supervising the donations. We are extremely grateful to Dr Kenneth G. Lerner, Fred Hutchinson Cancer Research Centre, Seattle, U.S.A., and Dr Richard Slavin, Johns Hopkins University, Baltimore, U.S.A., for reviewing histological material.

Requests for reprints should be sent to J. M. F., Hospital, West Smithfield, London EC1A 7BE.

St. Bartholomew’s

REFERENCES

Thomas, E D., Storb, R., Clift, R. A., Fefer, A., Johnson, F. L., Neiman, P. E., Lerner, K G., Glucksberg, H., Buckner, C D. New Engl. J. Med 1975, 292, 832. 2. Hathaway, W. E., Githens, J. H., Blackburn, W. R., Fulginiti, V., Kempe, C. H. ibid. 1965, 273, 953. 3. Hathaway, W. E., Brangle, R. W., Nelson, T. L., Roeckle, I. E. J. Pediat. 1966, 68, 713. 4. Hathaway, W. E., Fulginiti, V. A., Pierce, C W , Githens, J. H., Pearlman, D S., Munschenheim, F., Kempe, C. H J. Am med Ass. 1967, 201, 1.

1015. 5.

Schwarzenberg, L., Mathé, G., Amiel, J. L., Cotton, A., Schneider, M., Schlumberger, J. R. Am. J Med. 1967, 43, 206. 6. Graw, R. G., Jr., Buckner, C D., Whang-Peng, J., Leventhal, B G., Kruger, G , Berard, C , Henderson, E. S Lancet, 1970, ii, 338 7. Lowenthal, R. M., Goldman, J. M., Buskard, N. A., Murphy, B. C., Grossman, L., Storring, R A., Park, D S., Spiers, A S. D., Galton, D. A. G. ibid 1975, i, 353. 8. Huestis, D. W., White, R. F., Price, M. J., 9. 10. 11. 12. 13.

Inman, M. Transfusion, 1975, 15, 559. Slavin, R E., Santos, G. W. Clin. Immun. Immunopath. 1973, 1, 472. Storb, R., Epstein, R. B., Graham, T. C., Thomas, E D. Transplantation, 1970, 9, 240 Van Vekkum, D. W. Israel J. med. Sci 1965, 1, 879. Ford, J. M., Cullen, M. H., Brown, L. M. Unpublished. Yankee, R. A., Grumet, F. C., Rogentine, G N. New Engl. J Med. 1969, 281, 1208