A Patient With a Low IgA Level Requiring Transfusion During CABG Surgery

Gifford Lum, MD; Paula Szuflad, MS, MT(ASCP)SBB; Michael D'Amarino, MT(ASCP)BB


Lab Med. 2005;36(6):353-356. 

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1. An undetectable IgA level ( Table 1 ).

2. Because of the patient's undetectable IgA level, there was a concern that the patient might have anti-IgA antibodies that would react with IgA in any transfused products and cause an anaphylactic transfusion reaction. The first description of anaphylactic transfusion reactions associated with anti-IgA antibodies was reported in 1968 in Lancet and included 6 case studies with serious reactions following the administration of blood, plasma, or gamma globulin.[1] These 6 patients were divided into 2 groups: Group I, 3 patients who were IgA deficient with anti-IgA of broad reactivity, who experienced severe anaphylactic transfusion reactions; Group II, 3 multiply transfused patients with an anti-IgA of more limited specificity, who experienced less severe anaphylactoid reactions consisting of urticaria, wheezing, diffuse rashes, and tachycardia.[1]

3. The 3 most commonly used methods for the quantitative determination of serum IgA concentration are nephelometry (or turbidimetry), passive hemagglutination inhibition assay (PHAI), and enzyme-linked immunosorbent assay (ELISA) ( Table 2 ). The basic principle of nephelometric and turbidimetric assays for quantifying IgA concentration is light scatter at various angles by immune complexes formed between IgA (antigen) in the patient's serum and anti-IgA (antibody) antiserum added to the patient's serum. Passive hemagglutination techniques use hemagglutination as the end point of the antigen-antibody reaction, while ELISA methods use a capture antibody bound to the well of a microtiter plate to "capture" antigen (eg, IgA) and a signal antibody, containing an enzyme "signal", that recognizes a different epitope on the antigen than the capture antibody. The addition of substrate specific for the enzyme attached to the signal antibody results in the production of a color whose intensity is directly proportional to the amount of antigen present. Among these methods for the quantitation of IgA concentration, ELISA methods provide the best analytical sensitivity [ie, lower limit of detection (LLD) <0.005 mg/dL] ( Table 2 ). Nephelometric or turbidimetric methods are used routinely in most clinical laboratories for the quantitation of serum IgA concentration because these methods are rapid, easy to use, and are amenable to automation. According to the data in the College of American Pathologists (CAP) 2004 Diagnostic Immunology Survey Set-B Summary, 93.6% (712 of 760) of participating laboratories used nephelometric or turbidimetric methods for the quantitation of IgA, with the majority (55.2%) of these laboratories reporting the use of nephelometry over turbidimetry.[2]

4. IgA deficiency is defined clinically as a serum IgA level <7 mg/dL in males or females older than 4 years of age, but with normal serum IgG and IgM and in whom other causes of hypogammaglobulinemia (eg, drug-induced, infectious diseases, chromosomal abnormalities, and malignancy) have been ruled out.[3] Severe IgA deficiency has been defined generally as a selectively undetectable IgA concentration of <0.05 mg/dL.[4] The ARC American Rare Donor Program (ARDP) uses this definition to classify blood donors as IgA deficient. IgA deficiency with concomitant lack of secretory IgA is the most common form of primary immunodeficiency in the western world.[5]

5. The most common illnesses associated with IgA deficiency are recurrent sinopulmonary infections, including sinusitis, otitis media, pharyngitis, bronchitis, and bronchopneumonia. Gastrointestinal tract disorders may also be associated with selective IgA deficiency, including a 10-fold increased risk of celiac disease, pernicious anemia, milk intolerance, malabsorption syndrome, and mucosal infections due to acute diarrhea caused by bacteria, viruses, or Giardia lamblia.[6]

6. IgA deficiency is more prevalent in patients with autoimmune disease than in healthy individuals, possibly due to impaired immunoglobulin switching or a maturational failure of IgA-producing lymphocytes.[7] Moreover, the incidence of IgA deficiency varies not only with the population examined, but also with the analytical sensitivity of the IgA method used to screen individuals for IgA deficiency and the IgA cutoff value used to classify individuals as IgA deficient ( Table 3 ). At an IgA cutoff value of 1 mg/dL, the incidence of IgA deficiency varies from a high of 1:382 in the Austrian population to a low of 1:31,800 in Japanese blood donors.[8,9] These findings suggest a strong genetic component for inheritance of IgA deficiency.[10]

7. The demonstration of anti-IgA antibodies has been the sine qua non for the diagnosis of anaphylactic transfusion reactions in IgA-deficient patients. These preformed antibodies to transfused IgA may be class-specific (anti-IgA), subclass-specific (Anti-IgA1 or –IgA2), or allotype-specific [Anti-IgA2m(1) or anti-IgA2m(2)].[11] The most severe anaphylactic transfusion reactions are usually associated with class-specific antibodies in severely IgA deficient patients. The subclass and allotype-specific antibodies (generally referred to as antibodies of "limited specificity") are associated with less severe transfusion reactions, frequently seen in patients with low or, in some instances, normal levels of IgA.[12] Moreover, anti-IgA antibodies are usually of the IgG class, but may also be IgM or IgE class.[10] Anti-IgA antibodies have also been found in sera from healthy individuals with frequencies ranging from 2% to 59%.[10] The broad range of the frequency of anti-IgA antibodies in serum from healthy individuals has been attributed to methodological differences in the detection of anti-IgA antibodies, which hinders the assessment of the clinical significance of detecting anti IgA antibodies.[10] The frequency of anti-IgA antibodies in sera from IgA-deficient individuals can range from 11.5% to 46.8% ( Table 4 ). Based on data from a recent, large study in the United Kingdom, a frequently quoted estimate for the detection of anti-IgA antibodies in IgA-deficient patients is 33%.[11]

8. It is currently unclear what stimuli lead to the production of anti-IgA antibodies; however, it is known that some cases are associated with a history of exposure to IgA antigen from a variety of sources.[13] In a long term follow-up study of the development of anti-IgA antibodies in healthy IgA-deficient adults (n=159), there was no correlation between exposure to IgA antigen and the development of anti-IgA antibodies in 42% of these subjects with severe IgA deficiency ([IgA] <0.05 mg/dL) and a history of IgA exposure from pregnancy, blood transfusion, or immunoglobulin injection. Only 24% of these individuals had anti-IgA antibodies in serum from follow-up samples.[13] In this same study, serum from 45 blood donors with decreased serum IgA did not contain anti-IgA antibodies, compared to 30 of 159 (19%) patients with severe IgA deficiency whose serum was positive for anti-IgA antibodies. Moreover, the anti-IgA concentration in the serum from these 30 individuals remained fairly constant over a median follow-up period of 19 years (ie, only 6 of these 30 patients showed increases in IgA antibody concentration, with 4 of them showing significant increases).[13]

In a study of the prevalence of anti-IgA antibodies in 83 individuals with selective IgA deficiency, elevated concentrations of anti-IgA antibodies were detected in 25% to 30% of healthy individuals or those who had non-rheumatoid diseases.[14] However, the prevalence was 50% in those with rheumatoid arthritis, 77% in those with juvenile rheumatoid arthritis, and 100% in those with systemic lupus erythematosus. The authors of this study suggested an association between autoimmune (or immune) dysregulation, selective IgA deficiency, and the production of anti-IgA antibodies.[14] Based on a study of 32,376 random blood donors, the frequency of class-specific IgA antibodies in IgA-deficient patients was 1:1,200 (ie, 27 of 87 IgA-deficient donors had class-specific anti-IgA antibodies in their serum).[4] This same study found that there was a high incidence (76.3%) of class-specific anti-IgA antibodies in severely IgA-deficient patients with a history of anaphylactic transfusion reaction. In addition, these authors reported that 21.7% of 97 asymptomatic IgA blood donors or their IgA-deficient family members had class-specific IgA antibodies in their serum.[4] This finding suggests that the presence of anti-IgA antibodies may overestimate the number of patients at risk for an anaphylactic transfusion reaction.[4]

9. IgA anaphylactic transfusion reactions are rare events, with an estimated occurrence rate of 1:20,000 to 1:100,000 transfusions[12,15] As discussed previously, the frequency of detecting anti-IgA antibodies (1:1,200) exceeds the observed frequency of anaphylactic transfusion reactions suggesting that the presence of anti-IgA antibodies in a patient's serum is not a good predictor of the risk for an anaphylactic transfusion reaction.[11] In the United States population, 1:1,200 individuals will have severe IgA deficiency and anti-IgA antibodies in their serum. The prevalence of major analphylactic transfusion reactions in the United States population is approximately 2.4%.[11] Since the publication in 1968 of the first report of 3 cases of anaphylactic transfusion reactions associated with anti-IgA antibodies,[1] Sandler and colleagues described 30 additional cases in 1995.[12] In 2002, Vyas reported that at least 42 cases of anaphylactic transfusion reactions caused by anti-IgA were reported to his group at the University of California at San Francisco.[15] To date, there have been no documented cases of mortality due to anti-IgA-associated anaphylactic transfusion reactions.

10. If there is sufficient time to workup a patient with IgA deficiency, the first step should be to determine whether the patient has detectable levels of IgA and/or anti-IgA antibodies in their serum. If the patient has a low, but detectable, level of IgA (ie, >0.05 mg/dL, but <7 mg/dL), there is no need to transfuse the patient with any special blood product. If the patient has an undetectable concentration of IgA in their serum and is negative for the presence of anti-IgA antibodies, the patient should be transfused with caution. If the patient is severely IgA deficient, has anti-IgA antibodies in their serum, but no history of anaphylactic transfusion reaction, the patient may receive autologous products, washed RBCs/platelets, and should be supported medically. In a patient with severe IgA deficiency, who is positive for the presence of anti-IgA antibodies in their serum and with a history of anaphylactic transfusion reaction, washed RBCs, autologous products, or plasma products from an IgA-deficient donor should be transfused when needed. The aforementioned products are available through the ARC American Rare Donor Program. The release of IgA-deficient plasma is made on a case-by-case basis in consultation with the ARDP medical staff.[11] Washed plateletpheresis products may be used; however, such products are technically difficult to prepare and have only a 4-hour expiration after preparation. The ARDP maintains a registry of IgA-deficient donors in their apheresis program for situations in which washed plateletpheresis products are unavailable, not feasible, or contraindicated in patients who have previously experienced a reaction to washed platelet products.[11] If there is an emergent need for transfusion in a patient who has been screened for IgA concentration by conventional nephelometric methods and is considered IgA-deficient, and there is no prior history of an anaphylactic transfusion reaction, the likelihood of an adverse reaction is low since the estimated occurrence of anaphylactic reactions is approximately 1:20,000 to 1:100,000 transfusions. If, however, there is a history of an anaphylactic transfusion event, then the patient should receive autologous units, washed RBCs, or IgA-deficient blood products. Figure 1 provides a decision-making guide for managing the transfusion needs of patients with IgA deficiency and/or anti-IgA antibodies in their serum. LM

Possible algorithm for managing the transfusion needs of patients with IgA deficiency and/or anti-IgA antibodies in their serum. Quantifying Serum IgA Concentration


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