Fatal Pulmonary Hypersensitivity Reaction to HL-A Incompatible Blood Transfusion: Report of a Case and Review of the Literature C. F. W. WOLFAND V. C. CANALE From the Departments ojPathology and Pediatrics. The New York Hospital-Cornell Medical Center, and The New York Blood Cenrer, N e w York City, N e w York
A girl with Thalassemia major reacted to a transfusion of packed red blood cells with increasing respiratory ds-
tress until death 12% hours later. Chills and fever were followed by dry cough, dyspnea, and pulmonary edema. The recipient had lymphocytotoxic antibodies specific for donor leukocyte antigens H L A l l and possibly W14. At autopsy, the lungs showed pulmonary edema with extensive nonspecific acute alveolar injury. Similar cases in the literature are reviewed.
MORE THAN 20 cases of noncardiac pulmonary edema occurring as a reaction to the transfusion of blood or components have been reported since 1951. An additional case with fatal outcome will be reported here in which cytotoxic antibodies in the recipient's serum were shown to be specific for one and possibly two donor leukocyte HL-A antigens. Pulmonary edema apparently occurs insidiously after a variable latent period following the onset of transfusion. The delay in response is similar to that observed with febrile reactions to donor leukocytes and platelet^.^ The response occurs less abruptly than do severe reactions attributed to immunoglobulin antigen^.^^*^^.^^ Prominent clinical findings are pulmonary edema without cardiac enlargement, fever, cough, tachycardia, chills, and dyspnea. Sometimes significant respiratory impairment occurs. The most commonly noted effect of leukocyte incompatibility is acknowledged
to be a febrile response related to the leukocyte antigen d o ~ e , often ~ ~ ,involving ~ ~ the HLA system.I7 Dyspnea is sometimes reported in such instance^.'^ Pulmonary edema is often overlooked clinically and only discovered when a chest x-ray is taken for other reasons. A diffuse, patchy, bilateral pattern of pulmonary densities on chest xray associated with transfusion reaction is readily distinguished from the edema of cardiac failure.I5 Platelet c~ncentrates,'~ fresh frozen plasma,23 whole blood 9.12.22.28,31.33.37.38.40.41 and packed red blood cells'g have been implicated. Pulmonary edema reported to occur soon after onset of cryoprecipitate infusions was probably not related to leukocyte or plasma protein antigen incompatibility. Case Report
Patient A. M. was a 13-year-old Greek girl with Thalassemia major admitted to the New York Hospital pediatric intensive care unit because of pulmonary edema of sudden onset associated with a reaction to blood transfusion experienced earlier in the outpatient.clinic. Her anemia was diagnosed at age seven months, and she received only four transfusions until age 27 months, when she was first admitted to the hospital because of pallor and weakness with congestive heart failure and a hemoglobin of 3 g/dl. Subsequently, she was treated with transfusion of one unit of packed red blood cells every two weeks as an outpatient with acetaminophen (650 mg) premedication every two weeks as an outpatient, and experienced no reactions. On examination one month before her reaction, she was small of stature with a bone age of ten years, weight 34 kg. She had enlarged liver and spleen, bronzed skin, and Thalassemic facies.
Received for publication March 10, 1975, accepted June 15, 1975. This study was supported in part by the Health Research Council of New York City (U-2372) and The Children's Blood Foundation, Division of Pediatric Hematology-Oncology, Department of Pediatrics, The New York Hospital-Cornell Medical Center.
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A transfusion of 250 ml of packed red blood cells was begun at 1:45 p.m. A standard blood infusion set with filter (170 micron) was used. At 3:30 p.m., after nearly half the unit had been infused, she developed mild chills and a temperature elevation (38 C). Diphenhydramine (25 mg) was given orally and hydrocortisone (50 mg) was given intravenously. Blood pressure (BP) was 102/60, respiratory rate (RR) 24 per minute, and heart rate (HR) 112 per minute. Based on experience with occasional similar reactions while transfusing approximately I 1,000 units of blood of Thalassemic children over the preceding nine years, it was decided to resume the transfusion under close observation at a slower rate following the medication. At 5:15 p.m. with 50 ml remaining to be transfused, she suddenly developed a dry cough and respiratory distress. The transfusion was stopped. On examination, there were diffuse rales and wheezes, an enlarged liver and spleen both 13 cm below the costal margins (unchanged from pretransfusion examination), and R R had increased to 56, HR to 180 and BP was 130/80. Cough produced white foamy sputum which soon became gold-colored and tinged with blood. The diagnosis was anaphylactic bronchospasm with pulmonary edema caused by a transfusion reaction. Intravenous digoxin (0.25 mg), hydrocortisone (50 mg), and furosemide (40 mg) were given. Because of moderate tachycardia epinephrine was not given. An hour later moist rales persisted, R R was 60, and HR was 140. The diuretic and corticosteroid were repeated. The patient had become cyanotic and was admitted to the intensive care unit at 7:OO p.m. She was alert and in marked respiratory distress with peripheral and perioral cyanosis, intercostal and substernal retractions, and diffuse wet rales on auscultation. Peripheral pulses were strong, with H R 120, R R 40, BP 104/50, and temperature 38.5 C. She was placed in bed in the sitting position and given 60 per cent oxygen by mask. At 8:35 p.m., a chest x-ray showed bilateral infiltrates suggestive of pulmonary edema. At 8:45 p.m., intravenous furosemide (100 mg) was given. Urine output since the initial diuretic dose at 5:15 p.m. was 100 ml. Intravenous digoxin (0.25 mg) and morphine sulfate (8 mg) were given. Her condition did not improve, and at 1O:OO p.m. blood (venous) pH was 7.10, pC0, 54 m m of mercury, p02 22 m m , oxygen saturation less than 30 per cent, HR had risen to 150, and R R to 68. Hydrocortisone (50 mg) and aminophylline (250 mg) were given intravenously, and a mechanical ventilator was brought to the bedside. When catheterized, the bladder drained less than 100 ml. A central venous pressure line was placed and pressure was not elevated. At 10:30 p.m., a
Mar.-Apr. 1976
cardiac arrest occurred. She was intubated and resuscitated with external cardiac massage, assisted ventilation, intravenous epinephrine (1 ml of 1:lOOO dilution) and 50 mEq sodium bicarbonate. A repeat chest x-ray showed increased density of both lungs. Blood pH had decreased to 6.94, pC0, was 65 and PO, 16, and oxygen saturation was less than 30 per cent. A second arrest occurred at 11:30 p.m. and she was resuscitated again. On auscultation, the lungs sounded slightly improved. Blood pH was then 6.8, pC0,43, PO, 39, and oxygen saturation 38 per cent. A third arrest occurred at 12:30 a.m. and she began to have grand ma1 seizures controlled with intravenous diazepam. Intermittent cardiac arrhythmias occurred and blood pressure began to decline. A fourth arrest occurred a t 1:OO a.m., and a fifth a t 2:OO a.m. Despite resuscitation and attempts to correct acid-base imbalance and hyperkalemia, heart rate decreased and pulses became undetectable. She was pronounced dead at 2:20 a.m.
Laboratory Studies Pre- and posttransfusion blood specimens showed no evidence of hemolysis. Repeat typing of the blood from the donor unit, pilot tube, and patient confirmed the type as B Rh positive. No evidence of serologic incompatibility was demonstrated by anti-human globulin tests incubated for 30 minutes with pre- and posttransfusion samples from the patient and samples from the unit and pilot tube. The sera contained no isoimmune antibodies that could be detected when tested with normal and enzyme (ficin) treated red cells. When tested with broad-spectrum anti-human globulin serum, both pre- and posttransfusion samples of patient’s cells were nonreactive. No organisms were grown from the residual contents of the donor unit. As determined by radial immunodiffusion, IgA, IgG and IgM in the pre- and posttransfusion sera and the donor plasma were within normal range. The IgE content of posttransfusion serum was also normal by radioimmunoassay. Cellulose acetate electrophoresis of donor plasma followed by immunodiffusion against the patient’s pretransfusion serum gave no detectable precipitin bands suggestive of IgA/ anti-IgA interaction. Similarly, an Ouchterlony double-diffusion assay using myeloma protein of IgA, and IgA, heavy chain subclasses showed no precipitation. Haptoglobin levels both before and after transfusion were depressed to less than 10 mg/dl because of the underlying congenital hemolytic anemia. Complement C 3 levels, determined by a I.6-hour radial immunodiffusion technique on pre- and posttransfusion sera, were unchanged at 105 and 103 mg/ dl. Donor serum and plasma, and recipient sera
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pre- and posttransfusion were studied for presence and specificity of cytotoxic antibodies to HL-A antigens. The patient’s serum contained anti-HL-A 10 and I I immediately before and within several hours after transfusion. Because of insufficient sera, titers were not performed. An anti-HL-A W14 found in the posttransfusion serum is unexplained, since the donor serum and plasma contained no detectable antibody. To clarify the source of the anti-HL-A W14, recipient sera collected periodically on six occasions from 1967 to 1973 for other studies and stored frozen were examined for the presence of cytotoxic antibodies. The antibody was not present in samples from seven to five years before the reaction. Five years before the reaction, antiHL-A W14 with titer 1:2 was first detected. Nineteen months later, no cytotoxic antibodies were detectable. A serum sample obtained two months before the reaction, contained anti-HL-A W14 and anti-HL-A 11, both with titers greater than 1:3. These results suggest that the assay for antiHL-A W14 may have been functioning at its limit of sensitivity in this case, explaining variable results on successive specimens. In addition, initiation of a secondary immune response by the transfusion may have aided antibody detection in the posttransfusion serum. Donor cells and cells from both of the recipient’s parents were HL-A typed. Donor antigens were HL-A 7, 9, 11, and W 14. A major incompatibility between recipient antibody and donor leukocyte antigen HL-A 1 1 and possibly W14 was thus demonstrated. Paternal antigens were HL-A 2, W5, and W17. Maternal antigens were HL-A 2 and W5.Additional parental antigens were not disclosed by the typing sera used. The recipient’s cells were not HL-A typed. The leukocyte typing and antibody data are summarized in Table 1.
Postmortem Examination The usual stigmata of Thalassemia major treated with frequent blood transfusions found were: disseminated hemosiderosis, extramedullary hematopoiesis with splenomegaly and micronodular cirrhosis of the liver. Body weight was 32 kg and length was 136 cm. The morphologic findings were those of a nonspecific acute pulmonary alveolar i n j ~ r y . ~The * l ~changes were superimposed on the effects of multiple cardiac arrests, several hours of mechanical ventilation with oxygen concentrations up to 100 per cent, aspiration of gastric contents, and Thalassemia major treated with blood transfusions. The lungs together weighed 800 grams, were markedly congested and the subpleural lymphatics were dilated. Abundant edema fluid was
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Table 1. Summary of Leukocyte HL-A Typing and Anti- HL-A An tibodv Data Recipient Pretransfusion serum: anti -1 0, -1 1 Posttransfusion serum: anti -1 0, -1 1, -W14 Cell type (parents): 2, W5, W17 Donor Serum: no lymphocytotoxic antibodies detected Cell type: 7.9,1 1 , W 1 4
expressed from the cut surfaces. There were numerous foci of intraalveolar edema and there were foci of marked accumulations of acute inflammatory cells within alveoli. ‘Hyaline membranes were prominent. There was evidence of agonal aspiration of gastric contents. Luna stains of sections for e o ~ i n o p h i l disclosed s~~ some increase in eosinophils within the alveolar septa1 walls, occasionally as many as three per high power field, but they were not prominent in the inflammatory cell alveolar exudates. Throughout the lungs, there was marked edema of the walls of the dilated and congested alveolar capillaries. Frozen sections of lung and kidney were examined with immunofluorescent reagents for immunoglobulins G, M, A, and E, C 3 and fibrinogen. None of those antigens was found deposited in the tissues, except that fibrinogen was present in hyaline membranes in the lung. Thrombotic agglutinates of leukocytes were not seen, but in occasional small arteries platelet thrombi of usual morphology with trapped leucocytes were seen. In multiple sections, however, this was not a prominent finding. No significant changes in the kidney were noted.
Discussion A review of autopsy findings in this and three similar fatal cases shows that a marked pulmonary edema ’ is uniformly found which is unlike the hyperinflated appearance of the lungs in rapidly fatal anaphylaxis.2.20Kernoff,et ul.23 described the lungs at autopsy following a reaction to frozen plasma as edematous, indurated, dark blue in color, with extensive hemorrhagic edema, and with areas of agonal acute inflammation characterized by an alveolar exudate of polymorphonuclear cells among strands of fibrin. Flury and ReutterI4observed massive hemorrhagic pulmonary edema after a reaction to platelet concentrate. Within alveoli, there were focal aggregates of hemosiderin-laden phagocytes. The capillaries
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and veins were dilated and engorged with aggregates of erythrocytes. Leukocyte agglutinates, platelet aggregates, and th ro mbi were not seen. Felbo and Jensen12 reported that the lungs were heavy and showed increased consistency after a reaction to whole blood. Nearly all alveoli were filled by edema fluid, and there were “fairly large numbers of leukocytes in pulmonary vessels and collections of granulocytes in the alveolar spaces.” In all of these autopsies, including the present case, the lungs were heavy, markedly edematous and with fluid and cells occupying alveolar spaces. By contrast, the lungs in six cases of rapidly fatal anaphylaxis (16 to 20 minutes) after onset of exposure to soluble antigens were hyperinflated in five and showed minimal pulmonary edema in one.2.20The principle change in those cases was upper laryngeal, tracheobronchial respiratory tract edema and probable bronchospasm. A single report of an atypical case of pulmonary edema in rapidly fatal anaphylaxis caused by anti-IgA occurred in the presence of an evolving small acute myocardial infarction and could therefore have been due to cardiac failure.35 Lymphocytotoxic antibodies were subsequently sought in the recipient’s and donor’s serum, but none was found.34 Perhaps in the pulmonary hypersensitivity reaction, transfused leukocytes are preferentially sequestered temporarily in the microvasculature of the lower respiratory tract as has been observed with compatible labeled leukocytes in rabbits.42Immunologic incompatibility and its sequelae could thereby be localized in the alveolar vessels. There is contrasting evidence, however, that incompatible leukocytes may be preferentially removed by the spleen.ii The eosinophils in the alveolar septa1 capillary walls in our patient suggests that an immunologic reaction may have taken place at that site.25 A postreaction eosinophilia of from 4 to 15 per cent has been r e p ~ r t e d . ~ ’ . ~ ~ Autopsy studies have thus far not disclosed the presence of prominent multiple microthrombi of aggregated leukocytes in
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the lungs as was postulated based on animal experiment^.^^+^^ The morphologic changes of acute alveolar injury are nonspecific and are consistent with early thromboembolic injury with subsequent disappearance of thrombi5 or with a variety of other mechanisms of injury.I3 Often patients with severe systemic anaphylactic reactions are found to be atopic when challenged with soluble antig e m 2 Atopy has been correlated with an HL-A haplotype within a particular family.24 This has been interpreted to imply the presence of immune response (Ir) genes inherited (i.e.. closely linked) with the haplotype as Mendelian dominant characters resulting in atopy for the antigen in question. One can speculate that by HL-A typing of victims of pulmonary hypersensitivity reactions to transfusion it may be possible to identify patients and kindred with the peculiar immune response pattern which predisposes to the reactions. If this c,ould be done, precautions could be taken to minimize reactions. In a subsequent mild case of pulmonary hypersensitivity to transfusion of packed red cells in this hospital, frozen thawed red blood cells were used to avoid a reaction. In that recipient, lymphocytotoxic antibodies with specificity for the HL-A 11, 10, and W19 crossreacting group were found. When possible, chronically transfused patients should be given such red blood cells which are as free of extraneous antigens as possible. This practice is now followed in our Thalassemia clinic. Micropore filtration may further reduce the amount of antigenic material infused.’O Anti-leukocyte antibodies in patients after febrile reactions u ~ u a l l y ’but ~ not always3? have been shown to have specificities within the HL-A system. The precise antigen responsible for the pulmonary hypersensitivity reactions remains to be proven. In the present case even though incompatibilities were found in the HL-A system, incompatibilities in the Gm system, for example, were not ruled out, and more sensitive assays for
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anti-IgA of limited specificity are available than were used here. It is well known that multiply transfused Thalassemic children often have antibodies to Gm factors.'*26An incompatibility between donor anti-Gm' and recipient antigen was demonstrated in one of the fatal pulmonary reactions However, the absence of anti-leukocyte antibodies in that recipient was not documented. The finding of anti-leukocyte antibodies in many donors and recipients involved in these reactions is impressive,s. 12*18~28*37*40*41but remains merely circumstantial evidence for their causative role. The failure of traditional therapy3 in severe cases thus far and the self-limited course of milder cases suggests that adequate respiratory support for one to three days might suffice to overcome the effects of pulmonary damage. The prolonged use of a membrane oxygenator with partial extracorporeal circulation to overcome. acute respiratory failure has been reportedL8and might be lifesaving in this type of reaction. The role of pharmacologic agents which might moderate the anaphylactic response, such as prophylactic cromolyn sodium which inhibits mast cell degranulation, remains to be explored. Acknowledgment The assistance of Dr. Ian Wanless in contributing to a review of the literature, Dr. Jaime Prat, autopsy prosector and Dr. Carl G. Becker for immunofluorescence study of the autopsy tissues is gratefully acknowledged. The initial HL-A studies were done in the laboratory of Dr. Paul Terasaki, other HL-A studies were done in the laboratory of Dr. Marilena Fotino.
References I.
2.
3.
4.
5.
Allen, J. C., and H. G. Kunkel: Antibodies to genetic types of gamma globulin after multiple transfusions. Science 139:418, 1963. Austen, K. F.: Systemic anaphylaxis in the human being. N. Engl. J. Med. 291:661, 1974. -, and A. L. Sheffer: Vascular responses: the anaphylactic syndrome. I n Dermatology in General Medicine, Fitzpatrick, et al.. a s . New York, McGraw-Hill Book Co., 1971, p. 1244. Barnard, R. D.: Indiscriminate transfusion: a critique of case reports illustrating hypersensitivity reactions. N.Y. State J. Med. 51:2399, 1951. Blaisdell, F. W.: Pathophysiology of the respira-
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tory distress syndrome Arch. Surg. 108:44, 1974.
Brittingham, T. E.: Immunologic studies on leukocytes. Vox Sang. 2:242, 1957. 7. -, and H. Chaplin, Jr.: Febrile transfusion reactions caused by sensitivity t o donor leukocytes and platelets. J A M A 165:819, 1957. 8. Burman, D., A. K. Hodson, C. B. S. Wood. and N. G. W. Brueton: Acute anaphylaxis, pulmonary edema, and intravascular hemolysis due to cryoprecipitate. Arch. Dis. Child 48:483.
6.
1973.
Byrne, J. P., Jr., and J. A. Dixon: Pulmonary edema following blood transfusion reaction. Arch. Surg. 102:91, 1971. 10. Crowley, J. P., M. ODonnell, K. W. Sell, and C. R. Valeri: The purification of red cells for transfusion by freeze-preservation and washing. IV. The use of micropore filtration to reduce the residual HL-A antigenicity of previously frozen, washed red cells. Transfusion 15:34, 1975. I . Eyre, H. J., I. M. Goldstein, S. Perry, and R. G. Graw, Jr.: Leukocyte transfusions: function of transfused granulocytes from donors with chronic myelocytic leukemia. Blood 36:432, 9.
1970.
2.
3.
Felbo, M., and K. G. Jensen: Death in childbirth following transfusion of leukocyte-incompatible blood. Acta Haematol. 27:113, 1962. FitzGerald, M. X.,C. B. Carrington, and E. A. Gaensler: Environmental lung disease. Med. Clin. North Am. 57593, 1973.
Flury, R., and F. Reutter: Letaler anaphylaktischer schock wtlhrend transfusion eines thrombocytenkonzentrats. Schweiz. Med. Wochenschr. 96918, 1966. IS. Could, D. M., and D. J. Torrance: Pulmonary edema. Am. J. Roentgenol. Rad. Ther. Nuc. Med. 73:366, 1955. 16. Grumet, F. C., and R. A. Yankee: Nonred cell reactions. In New Approaches to Transfusion Reactions. American Association of Blood Banks. Technical Workshop, 1974. p. 39. 14.
Heinrich, D., C. Mueller-Eckhardt, and W. Stier: The specificity of leukocyte and platelet alloan-. tibodies in sera of patients with nonhemolytic transfusion reactions. Vox Sang. 2 5 4 2 , 1973. 18. Hill, J. D., T. G. O'Brien, J. J. Murray, L. Dontigny, M. L. Bramsoh, J. J. Osborn, and F. Gerbode: Prolonged extracorporeal oxygenation for acute posttraumatic respiratory failure (shocklung syndrome). N. Engl. J. Med. 286:629, 17.
1972.
Hirsch, E. O., and A. R. Caracta: Pulmonary edema following packed cell transfusion. J. Med. SOC.N. J.63:45, 1966. 20. James, L. P., Jr., and K.F. Austen: Fatal systemic anaphylaxis in man. N. Engl. J. Med. 270597, 19.
1964. 21.
Jensen, K. G.:The significance of leuko-agglu-
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tinins for development of transfusion reactions. Dan. Med. Bull. 9:198, 1962. and F. Kissmeyer-Nielsen: Immunology 22. -, of leukocytes. Progress Clin. Pathol. 2:131, 1969. 23. Kernoff, P. B. A., I. J. Durrant, C. R. Rizza, and F. W. Wright: Severe allergic pulmonary edema after plasma transfusion. Br. J. Hematol. 23:777, 1,972. 24. Levine, B. B., R. H. Stember, and M. Fotino: Ragweed hay fever: genetic control and linkage to HL-A haplotypes. Science 178:1201, 1972. 25. Litt, 'M.: Eosinophils in lungs. N. Engl. J. Med. 280:835, 1969. 26. London, W. Thomas: The genetic relationships of Australia antigen. Vox Sang. Suppl24:1, 1973. 27. Luna, L. G., Ed.: Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, 3rd ed. New York, McGraw-Hill, 1968;~. I 1 I. 28. Medynski, M., J. Szydlowski,, and E. Babicka: Ciezki wstrzas poprzetoczeniowy o nieustalonej przyczynie. Pol.Tyg. Lek. 26:1001, 1971. 29. Mendes de Leon, D. E., and M. van der Hart: A ' severe plasma reaction after transfusions of blood and serum. Vox Sang.5:30,1955. 30. Miesther, P.: Leucopenie chronique par autoanticorps: Acta Haematol. 11:152, 1954. 31. Pearlstein, A. T.: Pulmonary hypersensitivity 1 'reaction. N.Y. State J. Med. 71:2683, 1971. 32. Perkins, 'H. A,, R.' Payne, J. Ferguson, and M. Wood: Nonhemolytic febrile transfusion reactions. Vox Sang.41578, 1966. 33. Phillips, E., and F. G. Fleischner: Pulmonary ' . edema in the course of a blood transfusion without overloading the circulation. Dis. Chest 50:619, 1966. 34. Pineda, A. A,: Personal communication. and H. F. Taswell: Transfusion reactions 35. -, . associated with anti-lgA antibodies: report of four cases and review of the literature. Transfusion 15:10, 1975. '
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36. Schmidt, A. P., H. F. Taswell, and G. J. Gleich: Anaphylactic transfusion reactions associated with anti-IgA antibody. N. Engl. J. Med. 280:188, 1969. 37. Thompson, J. S., C. D. Severson, M. J. Parmely, B. L. Marmorstein, and A. Simmons: Pulmonary 'hypersensitivity' reactions induced by transfusion of non-HL-A leukoagglutinins. N. Engl. J. Med284:1120, 1971. 38. Waldvogel, F. A,, M. Jeannet, H. Rudolf, and E. Arnold: lnfiltrats pulmonaires par leuco-agglutinines. Rev. Tuberc. Pneumol. (Paris) 36:952, 1972. 39. Walford, R. L.: Leukocyte Antigens and Antibodies. New York, Grune and Stratton, 1960, p. 78. 40. Ward, H. N.: Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann. Intern. Med. 73:689, 1970. 41. -,
42.
T. S. Lipscomb, and L. P. Cawley: Pulmonary hypersensitivity reaction after blood transfusion. Arch. Intern. Med. 122:362, 1968.
Weisberger, A. S., R. W. Heinle, J. P. Storaasli, and R. Hannah: Transfusion of leukocytes labeled with radioactive phosphorous. J. Clin. Invest. 29:336, 1950.
I!
43. Vyas, G. N., and H. H. Fudenberg: lsoimmune anti-lgA causing anaphylactoid transfusion reactions. N. Engl. J . Med 280:1073, 1969.
Carl F. W. Wolf, M.D., Assistant Director, Blood Bank, The New York Hospital; Assistant Professor of Pathology, Cornell University Medical College; Associate Investigator, The New York Blood Center, New York City, New York, 10021. Virginia C. Canale, M.D., Associate Professor of Pediatrics, Director of the Thalassemia Clinic and Research Center, The New York Hospital-Cornell Medical Center, New York City, New York 10021.
A girl with Thalassemia major reacted to a transfusion of packed red blood cells with increasing respiratory ds-
tress until death 12% hours later. Chills and fever were followed by dry cough, dyspnea, and pulmonary edema. The recipient had lymphocytotoxic antibodies specific for donor leukocyte antigens H L A l l and possibly W14. At autopsy, the lungs showed pulmonary edema with extensive nonspecific acute alveolar injury. Similar cases in the literature are reviewed.
MORE THAN 20 cases of noncardiac pulmonary edema occurring as a reaction to the transfusion of blood or components have been reported since 1951. An additional case with fatal outcome will be reported here in which cytotoxic antibodies in the recipient's serum were shown to be specific for one and possibly two donor leukocyte HL-A antigens. Pulmonary edema apparently occurs insidiously after a variable latent period following the onset of transfusion. The delay in response is similar to that observed with febrile reactions to donor leukocytes and platelet^.^ The response occurs less abruptly than do severe reactions attributed to immunoglobulin antigen^.^^*^^.^^ Prominent clinical findings are pulmonary edema without cardiac enlargement, fever, cough, tachycardia, chills, and dyspnea. Sometimes significant respiratory impairment occurs. The most commonly noted effect of leukocyte incompatibility is acknowledged
to be a febrile response related to the leukocyte antigen d o ~ e , often ~ ~ ,involving ~ ~ the HLA system.I7 Dyspnea is sometimes reported in such instance^.'^ Pulmonary edema is often overlooked clinically and only discovered when a chest x-ray is taken for other reasons. A diffuse, patchy, bilateral pattern of pulmonary densities on chest xray associated with transfusion reaction is readily distinguished from the edema of cardiac failure.I5 Platelet c~ncentrates,'~ fresh frozen plasma,23 whole blood 9.12.22.28,31.33.37.38.40.41 and packed red blood cells'g have been implicated. Pulmonary edema reported to occur soon after onset of cryoprecipitate infusions was probably not related to leukocyte or plasma protein antigen incompatibility. Case Report
Patient A. M. was a 13-year-old Greek girl with Thalassemia major admitted to the New York Hospital pediatric intensive care unit because of pulmonary edema of sudden onset associated with a reaction to blood transfusion experienced earlier in the outpatient.clinic. Her anemia was diagnosed at age seven months, and she received only four transfusions until age 27 months, when she was first admitted to the hospital because of pallor and weakness with congestive heart failure and a hemoglobin of 3 g/dl. Subsequently, she was treated with transfusion of one unit of packed red blood cells every two weeks as an outpatient with acetaminophen (650 mg) premedication every two weeks as an outpatient, and experienced no reactions. On examination one month before her reaction, she was small of stature with a bone age of ten years, weight 34 kg. She had enlarged liver and spleen, bronzed skin, and Thalassemic facies.
Received for publication March 10, 1975, accepted June 15, 1975. This study was supported in part by the Health Research Council of New York City (U-2372) and The Children's Blood Foundation, Division of Pediatric Hematology-Oncology, Department of Pediatrics, The New York Hospital-Cornell Medical Center.
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A transfusion of 250 ml of packed red blood cells was begun at 1:45 p.m. A standard blood infusion set with filter (170 micron) was used. At 3:30 p.m., after nearly half the unit had been infused, she developed mild chills and a temperature elevation (38 C). Diphenhydramine (25 mg) was given orally and hydrocortisone (50 mg) was given intravenously. Blood pressure (BP) was 102/60, respiratory rate (RR) 24 per minute, and heart rate (HR) 112 per minute. Based on experience with occasional similar reactions while transfusing approximately I 1,000 units of blood of Thalassemic children over the preceding nine years, it was decided to resume the transfusion under close observation at a slower rate following the medication. At 5:15 p.m. with 50 ml remaining to be transfused, she suddenly developed a dry cough and respiratory distress. The transfusion was stopped. On examination, there were diffuse rales and wheezes, an enlarged liver and spleen both 13 cm below the costal margins (unchanged from pretransfusion examination), and R R had increased to 56, HR to 180 and BP was 130/80. Cough produced white foamy sputum which soon became gold-colored and tinged with blood. The diagnosis was anaphylactic bronchospasm with pulmonary edema caused by a transfusion reaction. Intravenous digoxin (0.25 mg), hydrocortisone (50 mg), and furosemide (40 mg) were given. Because of moderate tachycardia epinephrine was not given. An hour later moist rales persisted, R R was 60, and HR was 140. The diuretic and corticosteroid were repeated. The patient had become cyanotic and was admitted to the intensive care unit at 7:OO p.m. She was alert and in marked respiratory distress with peripheral and perioral cyanosis, intercostal and substernal retractions, and diffuse wet rales on auscultation. Peripheral pulses were strong, with H R 120, R R 40, BP 104/50, and temperature 38.5 C. She was placed in bed in the sitting position and given 60 per cent oxygen by mask. At 8:35 p.m., a chest x-ray showed bilateral infiltrates suggestive of pulmonary edema. At 8:45 p.m., intravenous furosemide (100 mg) was given. Urine output since the initial diuretic dose at 5:15 p.m. was 100 ml. Intravenous digoxin (0.25 mg) and morphine sulfate (8 mg) were given. Her condition did not improve, and at 1O:OO p.m. blood (venous) pH was 7.10, pC0, 54 m m of mercury, p02 22 m m , oxygen saturation less than 30 per cent, HR had risen to 150, and R R to 68. Hydrocortisone (50 mg) and aminophylline (250 mg) were given intravenously, and a mechanical ventilator was brought to the bedside. When catheterized, the bladder drained less than 100 ml. A central venous pressure line was placed and pressure was not elevated. At 10:30 p.m., a
Mar.-Apr. 1976
cardiac arrest occurred. She was intubated and resuscitated with external cardiac massage, assisted ventilation, intravenous epinephrine (1 ml of 1:lOOO dilution) and 50 mEq sodium bicarbonate. A repeat chest x-ray showed increased density of both lungs. Blood pH had decreased to 6.94, pC0, was 65 and PO, 16, and oxygen saturation was less than 30 per cent. A second arrest occurred at 11:30 p.m. and she was resuscitated again. On auscultation, the lungs sounded slightly improved. Blood pH was then 6.8, pC0,43, PO, 39, and oxygen saturation 38 per cent. A third arrest occurred at 12:30 a.m. and she began to have grand ma1 seizures controlled with intravenous diazepam. Intermittent cardiac arrhythmias occurred and blood pressure began to decline. A fourth arrest occurred a t 1:OO a.m., and a fifth a t 2:OO a.m. Despite resuscitation and attempts to correct acid-base imbalance and hyperkalemia, heart rate decreased and pulses became undetectable. She was pronounced dead at 2:20 a.m.
Laboratory Studies Pre- and posttransfusion blood specimens showed no evidence of hemolysis. Repeat typing of the blood from the donor unit, pilot tube, and patient confirmed the type as B Rh positive. No evidence of serologic incompatibility was demonstrated by anti-human globulin tests incubated for 30 minutes with pre- and posttransfusion samples from the patient and samples from the unit and pilot tube. The sera contained no isoimmune antibodies that could be detected when tested with normal and enzyme (ficin) treated red cells. When tested with broad-spectrum anti-human globulin serum, both pre- and posttransfusion samples of patient’s cells were nonreactive. No organisms were grown from the residual contents of the donor unit. As determined by radial immunodiffusion, IgA, IgG and IgM in the pre- and posttransfusion sera and the donor plasma were within normal range. The IgE content of posttransfusion serum was also normal by radioimmunoassay. Cellulose acetate electrophoresis of donor plasma followed by immunodiffusion against the patient’s pretransfusion serum gave no detectable precipitin bands suggestive of IgA/ anti-IgA interaction. Similarly, an Ouchterlony double-diffusion assay using myeloma protein of IgA, and IgA, heavy chain subclasses showed no precipitation. Haptoglobin levels both before and after transfusion were depressed to less than 10 mg/dl because of the underlying congenital hemolytic anemia. Complement C 3 levels, determined by a I.6-hour radial immunodiffusion technique on pre- and posttransfusion sera, were unchanged at 105 and 103 mg/ dl. Donor serum and plasma, and recipient sera
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pre- and posttransfusion were studied for presence and specificity of cytotoxic antibodies to HL-A antigens. The patient’s serum contained anti-HL-A 10 and I I immediately before and within several hours after transfusion. Because of insufficient sera, titers were not performed. An anti-HL-A W14 found in the posttransfusion serum is unexplained, since the donor serum and plasma contained no detectable antibody. To clarify the source of the anti-HL-A W14, recipient sera collected periodically on six occasions from 1967 to 1973 for other studies and stored frozen were examined for the presence of cytotoxic antibodies. The antibody was not present in samples from seven to five years before the reaction. Five years before the reaction, antiHL-A W14 with titer 1:2 was first detected. Nineteen months later, no cytotoxic antibodies were detectable. A serum sample obtained two months before the reaction, contained anti-HL-A W14 and anti-HL-A 11, both with titers greater than 1:3. These results suggest that the assay for antiHL-A W14 may have been functioning at its limit of sensitivity in this case, explaining variable results on successive specimens. In addition, initiation of a secondary immune response by the transfusion may have aided antibody detection in the posttransfusion serum. Donor cells and cells from both of the recipient’s parents were HL-A typed. Donor antigens were HL-A 7, 9, 11, and W 14. A major incompatibility between recipient antibody and donor leukocyte antigen HL-A 1 1 and possibly W14 was thus demonstrated. Paternal antigens were HL-A 2, W5, and W17. Maternal antigens were HL-A 2 and W5.Additional parental antigens were not disclosed by the typing sera used. The recipient’s cells were not HL-A typed. The leukocyte typing and antibody data are summarized in Table 1.
Postmortem Examination The usual stigmata of Thalassemia major treated with frequent blood transfusions found were: disseminated hemosiderosis, extramedullary hematopoiesis with splenomegaly and micronodular cirrhosis of the liver. Body weight was 32 kg and length was 136 cm. The morphologic findings were those of a nonspecific acute pulmonary alveolar i n j ~ r y . ~The * l ~changes were superimposed on the effects of multiple cardiac arrests, several hours of mechanical ventilation with oxygen concentrations up to 100 per cent, aspiration of gastric contents, and Thalassemia major treated with blood transfusions. The lungs together weighed 800 grams, were markedly congested and the subpleural lymphatics were dilated. Abundant edema fluid was
137
Table 1. Summary of Leukocyte HL-A Typing and Anti- HL-A An tibodv Data Recipient Pretransfusion serum: anti -1 0, -1 1 Posttransfusion serum: anti -1 0, -1 1, -W14 Cell type (parents): 2, W5, W17 Donor Serum: no lymphocytotoxic antibodies detected Cell type: 7.9,1 1 , W 1 4
expressed from the cut surfaces. There were numerous foci of intraalveolar edema and there were foci of marked accumulations of acute inflammatory cells within alveoli. ‘Hyaline membranes were prominent. There was evidence of agonal aspiration of gastric contents. Luna stains of sections for e o ~ i n o p h i l disclosed s~~ some increase in eosinophils within the alveolar septa1 walls, occasionally as many as three per high power field, but they were not prominent in the inflammatory cell alveolar exudates. Throughout the lungs, there was marked edema of the walls of the dilated and congested alveolar capillaries. Frozen sections of lung and kidney were examined with immunofluorescent reagents for immunoglobulins G, M, A, and E, C 3 and fibrinogen. None of those antigens was found deposited in the tissues, except that fibrinogen was present in hyaline membranes in the lung. Thrombotic agglutinates of leukocytes were not seen, but in occasional small arteries platelet thrombi of usual morphology with trapped leucocytes were seen. In multiple sections, however, this was not a prominent finding. No significant changes in the kidney were noted.
Discussion A review of autopsy findings in this and three similar fatal cases shows that a marked pulmonary edema ’ is uniformly found which is unlike the hyperinflated appearance of the lungs in rapidly fatal anaphylaxis.2.20Kernoff,et ul.23 described the lungs at autopsy following a reaction to frozen plasma as edematous, indurated, dark blue in color, with extensive hemorrhagic edema, and with areas of agonal acute inflammation characterized by an alveolar exudate of polymorphonuclear cells among strands of fibrin. Flury and ReutterI4observed massive hemorrhagic pulmonary edema after a reaction to platelet concentrate. Within alveoli, there were focal aggregates of hemosiderin-laden phagocytes. The capillaries
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and veins were dilated and engorged with aggregates of erythrocytes. Leukocyte agglutinates, platelet aggregates, and th ro mbi were not seen. Felbo and Jensen12 reported that the lungs were heavy and showed increased consistency after a reaction to whole blood. Nearly all alveoli were filled by edema fluid, and there were “fairly large numbers of leukocytes in pulmonary vessels and collections of granulocytes in the alveolar spaces.” In all of these autopsies, including the present case, the lungs were heavy, markedly edematous and with fluid and cells occupying alveolar spaces. By contrast, the lungs in six cases of rapidly fatal anaphylaxis (16 to 20 minutes) after onset of exposure to soluble antigens were hyperinflated in five and showed minimal pulmonary edema in one.2.20The principle change in those cases was upper laryngeal, tracheobronchial respiratory tract edema and probable bronchospasm. A single report of an atypical case of pulmonary edema in rapidly fatal anaphylaxis caused by anti-IgA occurred in the presence of an evolving small acute myocardial infarction and could therefore have been due to cardiac failure.35 Lymphocytotoxic antibodies were subsequently sought in the recipient’s and donor’s serum, but none was found.34 Perhaps in the pulmonary hypersensitivity reaction, transfused leukocytes are preferentially sequestered temporarily in the microvasculature of the lower respiratory tract as has been observed with compatible labeled leukocytes in rabbits.42Immunologic incompatibility and its sequelae could thereby be localized in the alveolar vessels. There is contrasting evidence, however, that incompatible leukocytes may be preferentially removed by the spleen.ii The eosinophils in the alveolar septa1 capillary walls in our patient suggests that an immunologic reaction may have taken place at that site.25 A postreaction eosinophilia of from 4 to 15 per cent has been r e p ~ r t e d . ~ ’ . ~ ~ Autopsy studies have thus far not disclosed the presence of prominent multiple microthrombi of aggregated leukocytes in
Transfusion Mar.-Apr. 1976
the lungs as was postulated based on animal experiment^.^^+^^ The morphologic changes of acute alveolar injury are nonspecific and are consistent with early thromboembolic injury with subsequent disappearance of thrombi5 or with a variety of other mechanisms of injury.I3 Often patients with severe systemic anaphylactic reactions are found to be atopic when challenged with soluble antig e m 2 Atopy has been correlated with an HL-A haplotype within a particular family.24 This has been interpreted to imply the presence of immune response (Ir) genes inherited (i.e.. closely linked) with the haplotype as Mendelian dominant characters resulting in atopy for the antigen in question. One can speculate that by HL-A typing of victims of pulmonary hypersensitivity reactions to transfusion it may be possible to identify patients and kindred with the peculiar immune response pattern which predisposes to the reactions. If this c,ould be done, precautions could be taken to minimize reactions. In a subsequent mild case of pulmonary hypersensitivity to transfusion of packed red cells in this hospital, frozen thawed red blood cells were used to avoid a reaction. In that recipient, lymphocytotoxic antibodies with specificity for the HL-A 11, 10, and W19 crossreacting group were found. When possible, chronically transfused patients should be given such red blood cells which are as free of extraneous antigens as possible. This practice is now followed in our Thalassemia clinic. Micropore filtration may further reduce the amount of antigenic material infused.’O Anti-leukocyte antibodies in patients after febrile reactions u ~ u a l l y ’but ~ not always3? have been shown to have specificities within the HL-A system. The precise antigen responsible for the pulmonary hypersensitivity reactions remains to be proven. In the present case even though incompatibilities were found in the HL-A system, incompatibilities in the Gm system, for example, were not ruled out, and more sensitive assays for
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PULMONARY HYPERSENSITIVITY REACTION
anti-IgA of limited specificity are available than were used here. It is well known that multiply transfused Thalassemic children often have antibodies to Gm factors.'*26An incompatibility between donor anti-Gm' and recipient antigen was demonstrated in one of the fatal pulmonary reactions However, the absence of anti-leukocyte antibodies in that recipient was not documented. The finding of anti-leukocyte antibodies in many donors and recipients involved in these reactions is impressive,s. 12*18~28*37*40*41but remains merely circumstantial evidence for their causative role. The failure of traditional therapy3 in severe cases thus far and the self-limited course of milder cases suggests that adequate respiratory support for one to three days might suffice to overcome the effects of pulmonary damage. The prolonged use of a membrane oxygenator with partial extracorporeal circulation to overcome. acute respiratory failure has been reportedL8and might be lifesaving in this type of reaction. The role of pharmacologic agents which might moderate the anaphylactic response, such as prophylactic cromolyn sodium which inhibits mast cell degranulation, remains to be explored. Acknowledgment The assistance of Dr. Ian Wanless in contributing to a review of the literature, Dr. Jaime Prat, autopsy prosector and Dr. Carl G. Becker for immunofluorescence study of the autopsy tissues is gratefully acknowledged. The initial HL-A studies were done in the laboratory of Dr. Paul Terasaki, other HL-A studies were done in the laboratory of Dr. Marilena Fotino.
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Brittingham, T. E.: Immunologic studies on leukocytes. Vox Sang. 2:242, 1957. 7. -, and H. Chaplin, Jr.: Febrile transfusion reactions caused by sensitivity t o donor leukocytes and platelets. J A M A 165:819, 1957. 8. Burman, D., A. K. Hodson, C. B. S. Wood. and N. G. W. Brueton: Acute anaphylaxis, pulmonary edema, and intravascular hemolysis due to cryoprecipitate. Arch. Dis. Child 48:483.
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Flury, R., and F. Reutter: Letaler anaphylaktischer schock wtlhrend transfusion eines thrombocytenkonzentrats. Schweiz. Med. Wochenschr. 96918, 1966. IS. Could, D. M., and D. J. Torrance: Pulmonary edema. Am. J. Roentgenol. Rad. Ther. Nuc. Med. 73:366, 1955. 16. Grumet, F. C., and R. A. Yankee: Nonred cell reactions. In New Approaches to Transfusion Reactions. American Association of Blood Banks. Technical Workshop, 1974. p. 39. 14.
Heinrich, D., C. Mueller-Eckhardt, and W. Stier: The specificity of leukocyte and platelet alloan-. tibodies in sera of patients with nonhemolytic transfusion reactions. Vox Sang. 2 5 4 2 , 1973. 18. Hill, J. D., T. G. O'Brien, J. J. Murray, L. Dontigny, M. L. Bramsoh, J. J. Osborn, and F. Gerbode: Prolonged extracorporeal oxygenation for acute posttraumatic respiratory failure (shocklung syndrome). N. Engl. J. Med. 286:629, 17.
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Hirsch, E. O., and A. R. Caracta: Pulmonary edema following packed cell transfusion. J. Med. SOC.N. J.63:45, 1966. 20. James, L. P., Jr., and K.F. Austen: Fatal systemic anaphylaxis in man. N. Engl. J. Med. 270597, 19.
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tinins for development of transfusion reactions. Dan. Med. Bull. 9:198, 1962. and F. Kissmeyer-Nielsen: Immunology 22. -, of leukocytes. Progress Clin. Pathol. 2:131, 1969. 23. Kernoff, P. B. A., I. J. Durrant, C. R. Rizza, and F. W. Wright: Severe allergic pulmonary edema after plasma transfusion. Br. J. Hematol. 23:777, 1,972. 24. Levine, B. B., R. H. Stember, and M. Fotino: Ragweed hay fever: genetic control and linkage to HL-A haplotypes. Science 178:1201, 1972. 25. Litt, 'M.: Eosinophils in lungs. N. Engl. J. Med. 280:835, 1969. 26. London, W. Thomas: The genetic relationships of Australia antigen. Vox Sang. Suppl24:1, 1973. 27. Luna, L. G., Ed.: Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, 3rd ed. New York, McGraw-Hill, 1968;~. I 1 I. 28. Medynski, M., J. Szydlowski,, and E. Babicka: Ciezki wstrzas poprzetoczeniowy o nieustalonej przyczynie. Pol.Tyg. Lek. 26:1001, 1971. 29. Mendes de Leon, D. E., and M. van der Hart: A ' severe plasma reaction after transfusions of blood and serum. Vox Sang.5:30,1955. 30. Miesther, P.: Leucopenie chronique par autoanticorps: Acta Haematol. 11:152, 1954. 31. Pearlstein, A. T.: Pulmonary hypersensitivity 1 'reaction. N.Y. State J. Med. 71:2683, 1971. 32. Perkins, 'H. A,, R.' Payne, J. Ferguson, and M. Wood: Nonhemolytic febrile transfusion reactions. Vox Sang.41578, 1966. 33. Phillips, E., and F. G. Fleischner: Pulmonary ' . edema in the course of a blood transfusion without overloading the circulation. Dis. Chest 50:619, 1966. 34. Pineda, A. A,: Personal communication. and H. F. Taswell: Transfusion reactions 35. -, . associated with anti-lgA antibodies: report of four cases and review of the literature. Transfusion 15:10, 1975. '
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36. Schmidt, A. P., H. F. Taswell, and G. J. Gleich: Anaphylactic transfusion reactions associated with anti-IgA antibody. N. Engl. J. Med. 280:188, 1969. 37. Thompson, J. S., C. D. Severson, M. J. Parmely, B. L. Marmorstein, and A. Simmons: Pulmonary 'hypersensitivity' reactions induced by transfusion of non-HL-A leukoagglutinins. N. Engl. J. Med284:1120, 1971. 38. Waldvogel, F. A,, M. Jeannet, H. Rudolf, and E. Arnold: lnfiltrats pulmonaires par leuco-agglutinines. Rev. Tuberc. Pneumol. (Paris) 36:952, 1972. 39. Walford, R. L.: Leukocyte Antigens and Antibodies. New York, Grune and Stratton, 1960, p. 78. 40. Ward, H. N.: Pulmonary infiltrates associated with leukoagglutinin transfusion reactions. Ann. Intern. Med. 73:689, 1970. 41. -,
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Carl F. W. Wolf, M.D., Assistant Director, Blood Bank, The New York Hospital; Assistant Professor of Pathology, Cornell University Medical College; Associate Investigator, The New York Blood Center, New York City, New York, 10021. Virginia C. Canale, M.D., Associate Professor of Pediatrics, Director of the Thalassemia Clinic and Research Center, The New York Hospital-Cornell Medical Center, New York City, New York 10021.
