anaphylactic transfusion reactions Hemagglutination ...

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1994 84: 2031-2035

Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions SG Sandler, R Eckrich, D Malamut and D Mallory

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Hemagglutination Assays for the Diagnosis and Prevention of IgA Anaphylactic Transfusion Reactions By S. Gerald Sandler, Robert Eckrich, Dorothy Malamut, and Delores Mallory Passive hemagglutination assays (PHA) may be used t o detect IgA antibodies t o confirm clinical diagnoses of suspected IgA anaphylactic transfusion reactions. Passive hemagglutinationinhibition assays(PHIA) may be used t o identify IgA-deficient blood donorswhose plasma-containing components are transfused t o prevent anaphylactic transfusion reactions in prospective recipients at risk because of the presence of IgA antibodies. Using a standard PHA, we detected class-specific anti-lgA in 76.3% of 80 IgAdeficient patients with a history of an anaphylactic transfusion reaction, and in 21.7% of 97 asymptomatic IgA-deficient blood donors or their IgA-deficient family members. Using PHIA, we confirmed IgA deficiency ( 10240

Titer

DISCUSSION

Our findingsconfirm other reports that PHIA for IgA is sensitive and effective for identifying safe IgA-deficient plasma-containingblood componentsand preventing IgA anaphylactic transfusion reactions i n recipients with IgA antibodies and/ora history of an anaphylactoidtransfusion reaction. This conclusion is based on the absence of acute clinical reactions when S25 plasma-containing blood components from donors determined to be IgA-deficient by PHIA were transfused in 48 patients at risk for IgA anaphylactic reactions. Nevertheless, wecannot attributeunequivocallythe absence of acutereactions in these 4X recipients to thefact that all subsequent transfusions were limited to IgA-deficient blood components.The relatively high frequency (one in 1,200) of class-spccilic anti-lgA detected by standard PHA in IgA-deficient donors, compared with the rarity of anaphy-

Table 2. Anti-lgA in IgA-Deficient Blood Donors or Their IgA-Deficient Family Members Anti-lgA Speclflcity

No

No Anti-lgA Class-specific only Anti-lgA2, Class-specific ianti-lgA2 Class-specific t 2anti-lgAZm(1) Class-specific + anti-lgA2m(2) Class-specific + anti-lgA2 + IgAZm(1) Total

156

IgA concentration less than 0.05 rng/dL.

82 3 8 1 4

lactic reactions in transfusion patients. strongly suggests t h a t using the standard PHA for. anti-IzA lcatls to an overestilnation of persons who are presumed t o be at risk for clinically significant 1gA anaphylacticreactions. This overestimation potentially includes persons among these 4X recipients who may have had a n x q h y l a c t i c reaction unrelated t o transfuthe sion and a coincidental IgA anlibodydctcctedduring subsequent investigation. I t is estimated that the incidence ofIgA anaphylactic transfusionreactions is between I in 20.000 to 47.000transfusions." I n the IO-year period 1982 t o 1992. 297. I 9 0 blood cotnponcntswcte transfusrd a t GeorgctownUniversityMedicalCenter.Washington.DC. During these I O years. approximately 0.9% of all component transfusions were investigated for adverse reactions. but no cases of IgA anaphylactic rcactions were idcntifictl (S. N o vak, personal communication. J U I L I L W 1994). ~ In Canada. the incidence of anaphylactic transfusion reactions has becn estimated to be I .3 per I.OOO.000 LJ blood or blood products transfused." As a consequence o f this nonspecificity o f PHA for IgA antibodies. a n excessivenumber of IgA-tleticient patients and healthy donors screened f o r lgA dcticicncy will be informed that they have anti-IgA i n their serum rrrrtl require IgA-deficient blood products for any future trnnsfusions. Such;I lifetime requirement Inay have serious implications if, for exumple. urgently needed blood transfusions are clelayed while efforts are made to locate lgA-delicient blood products. With regard to IgA antibodies of limited speciticity. the issue of the nonspeciticity of PHA is morc complex.The only case report o f a fatal anaphylactic transfusion reaction associated with358 anti-IgA that we have bccn able to identify i n the medical literatureinvolvcd a 57-yenr-old man who


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had a normal serum 1gA concentration and : m IgA antibody of limited specificity." Thc patient's antibody titer by PHA was h4 i n the pretransfusion sample and 16 i n the immediate postreaction sample. Other reports of severe transrusion reactionsattributed to IgA antibodies of limitedspecificity have described persons who also had normal serum concentrations of total IgA.'.'.'J.'4 To a certain degree, the idcntification of an IgA antibody of limited specificity is a function of the number, variety, and serologic integrity of IgA myeloma proteins used to coatindicator RBCs Cor the PHA. In our study. W C observed the frequency o f IgA deficiency associated with class-specific anti-IgA to be one in 1.200 i n volunteer blood donor-s using a PHA with h different myelomacoated indicator cells: two examples each of IgAI. I g A h ( l ) , and IgA2m(2).Sixteen o f 358 IgA-dcticient blood donors or theirfamilymernbers had IgAantibodies of limited specificity (Table 2). Rivat et alZ3screened 1.010 healthyblood donors by PHA using 12 diffcrent scrologically defined IgA myeloma proteins. They detectcd IgA antibodies of limited speciticity in S W . ;I fr-equcncy that did not differsignificantlyfrom that among patients with suspected IgA ;ulaphylactic reactions. Our finding of a disproportionally high frequency of anti-IgA i n health blood donors. compared with the rarity ofconfirlned IgA anaphylactic reactions in transfused paticnts, substantiates the impression of Mollison et al." who suggested that thc finding of IgA antibodics of limited specificity i n somc reports of anaphylactoid reactions "may have been. at least to some extent. coincidental."They cite a series of six patient\whose plasma contained IgA antibodies of limited specificity (titer seldom >72) and who had been transfused with standard blood component\ without reaction."." Efforts to identify a morc specificmarker for thc risk

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Fig 2. PHA titers of class-specific anti-lgA for 95 IgA-deficient blood donors or theirIgA-deficient family members. The titer represents the reciprocal of the highest dilution of a test serum that agglutinated all 6 IgAmyeloma-coated RBCs.

of an IgA anaphylactic transfusion rcaction have included attempts to detect IgE anti-lgA, hut with equivocal rewlts. Direct skin testing f o r reagin (ie. IgE anti-lgA) gave negativc results in one patient with a well-documented anaphylactic reaction associated with anti-IgA." Testing for IgE anti-lgA by the PrausnitL-Kustner passive transfer technique was negative i n another case.2 111 a previously reportedstudy.sera from seven of I6 of our patients with anaphylactic or anaphylactoidreactions and anti-lgA by PHA had detectable IgE anti-lgA by radioimmunoassay(RIA).'" RIA detected IgE anti-IgA in two patients with symptomatic hypog~umm~~globulinemia who had experiencedwell-documented recurrent anaphylactic reactions associated with anti-lgA by PHA after injcctions of immune serumglobulin (gamma globulin)."' Such approaches t o a more specific laboratory diagnosis o f IgA anaphylactic reactions arc promising. Further research is needed to identify a marker more specific than hemugglutinating anti-IgA i n patient\ a t risk for IgA anaphylactic tran\to fusionrcactions.While the currentalgorithm ofPHA detectanti-IgA a d PHlA to mearure IgA concentration is clinic:tlly snfc. i t is not optimal. ACKNOWLEDGMENT rhxnk ourcolleagucs in Kcd Cr-o\s Bloorl Sen ice\ for rclerring serum \amples and clinical dnia for t h i \ study. S u w 1 M. box MI(ASCP)SUB previou\ly te\ied se\eral \ample\ L I S C ~i n t h l \ study and est;lblished the lro7en SCI tlm lihr;ry f r o m u h i c h many \:lrnplc\ W C

1te1-c retrieved.

REFERENCES I. Vyas GN. Perhlns HA. Futlerther;! ttH: Anaphylacto~dIl'ansfus i o n reaction\ a\\ociared w i t h anti-lgA. Lancet 2:3 12. I%X 2. Schmidt AP. Ta\ucll [IF. Gleich GI: An:rphylnctic tran\I'tt\i(~n

From bloodjournal.hematologylibrary.org by guest on July 13, 2011. For personal use only. IGA ANAPHYLACTIC TRANSFUSION REACTIONS

reactions associated with anti-IgA antibody. N Engl J Med 280:188, 1969 3. Vyas GN, Holmdahl L, Perkins HA, Fudenberg HH: Serologic specificity ofhuman anti-IgA and its significance in transfusion. Blood 34573, 1969 4. Miller WV, Holland PV, Sugarbaker E, Strober W, Waldmann TA: Anaphylactic reactions to IgA: A difficult transfusion problem. Am J Clin Pathol 54:618, 1970 5. Bjemm OJ, Jersild C: Class-specific anti-IgA associated with severe anaphylactic transfusion reactions in a patient with pernicious anemia. Vox Sang 21:411, 1971 6. Nadorp JHS, Voss M, Buys WC, van Munster PJJ, van Tongeren JHM, Aalberse RC, van Loghem E: The significance ofthe present of anti-IgA antibodies in individuals with an IgA deficiency. Eur J Clin Invest 3:317, 1973 7. Leikola J, Koistinen J, Lehtinen M, Virolainen M: IgA-induced anaphylactic transfusion reactions: A report of four cases. Blood 42:111, 1973 8. Invernizzi F, Balestrieri G, Consogno G, Riboldi PS, Tincani A: Anti-IgA antibodies in two brothers with selective serum IgA deficiency. Acta Haematol 5 4 3 12, 1975 9. Pineda AA, Taswell HF: Transfusion reactions associated with anti-IgA antibodies: Report of four cases and review of theliterature. Transfusion 15:10, 1975 10. Wells JV, Buckley RH, Schanfield MS, Fudenberg HH: Anaphylactic reactions to plasma infusions in patients with hypogammaglobulinemia and anti-IgA antibodies. Clin Immunol Immunopatho1 8:265, 1977 11. Laschinger C, Shepherd FA, Naylor DH: Anti-IgA-mediated transfusion reactions in Canada. Can Med Assoc J 130:141, 1984 12. Koistinen J, Heikkila M, Leikola J: Gammaglobulin treatment and anti-IgA antibodies in IgA-deficient patients. Br Med J 2:923, 1978 13. Davenport RD, Burnie K L , RM Barr: Transfusion management of patients with IgA deficiency and anti-IgA during liver transplantation. Vox Sang 63:247, 1992 14. Strauss RA, Gloster ES, Schanfield MS, Kiltinger SP, Morgan BB: Anaphylactic transfusion reaction associated with a possible anti-A2m(l). Clin Lab Haematol 5:371, 1983

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15. Eckrich M,Mallory DM, Sandler SG: Laboratory tests to exclude IgA deficiency in the investigation of suspected anti-IgA transfusion reactions. Transfusion 33: 1, 1993 16. Koistinen J: Selective IgA deficiency in blood donors. Vox Sang 29: 192, 1975 17. Holt P, Tandy N, Anstee D: Screening of blood donors for IgA deficiency: A study of the donor population of South West England. J Clin Pathol 30:1007, 1977 18. Hunt AF, Allen DL, Aries DL, Strange JJ: A protocol for sensitive large-scale screening of blood donors for IgA deficiency. Vox Sang 48:84, 1985 19. Fudenberg HH, Koistinen J: Human allotype detection by passive hemagglutination with special reference to immunoglobulin A allotypes, in Rose NR, Friedman H (eds): Manualof Clinical Immunology (ed 2). Washington, DC, American Society for Microbiology, 1980, p 767 20. Fahey JL, McKelvey EM: Quantitative determination of serum immunoglobulins in antibody-agar plates. J Immunol 94:84, 1965 2 I . Ochterlony 0: Diffusion in gel methods for immunological analysis. Prog Allergy 5:1, 1958 22. Yap, PL, Pryde EAD, McClelland DBL: IgA content of frozen-thawed-washed red blood cells and blood products measured by radioimmunoassay. Transfusion 22:36, 1982 23. Rivat L, Rivat C, Daveau M, Popartz C: Comparative frequencies of anti-IgA antibodies among patients with anaphylactic transfusion reactions and among normal blood donors. Clin Immunol Immunopathol 7340, 1977 24. Mollison PL, Engelfriet CP, Contreras M: Blood Transfusion in Clinical Medicine (ed 9). Oxford, UK, Blackwell, 1993, p 693 25. Ropars C, Caldera LH, Griscelli C, Hombert JC, Salmon C: Anti-immunoglobulin antibodies in immunodeficiencies: Their influence on intolerance reactions to y-globulin administration. Vox Sang 27:294, 1974 26. Burks AW, Sampson HA,BuckleyRH: Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia: Detection of IgE antibodies to IgA. N Engl J Med 3 14560, 1986