Association of anti-IgA antibodies with adverse reactions to γ-globulin infusion

Serum IgG anti-IgA antibody has been associated with the development of adverse reactions, (including non-IgE mediated anaphylaxis) to intravenous immunoglobulin (IVIG) in patients with undetectable IgA (here defined as 7mg/dL.2 Subclass-specific (or limited specificity) anti-IgA reacts with only one subclass [IgA1, IgA2m(1) or IgA2m(2)].2 It is estimated that up to 40% of patients with selective IgA deficiency and 9–25% of patients with common variable immunodeficiency (CVID) may have IgG anti-IgA.3 IgE anti-IgA has been found much less frequently. Three of four patients with IgE anti-IgA had anaphylaxis to gammaglobulin or other blood products.4,5 We conducted a retrospective and prospective observational study to evaluate the possible association with adverse reactions of IgG and/or IgE anti-IgA in IgA-deficient patients receiving IVIG or subcutaneous immunoglobulin (SCIG) at Children's Hospital Boston, Boston, MA, and Brigham and Women's Hospital, Boston, MA. All investigations were conducted according to the policies and procedures of the Institutional Review Boards of both institutions. Among 425 immunodeficient patients receiving IgG therapy, we identified 35 (8.2%) with undetectable IgA; 22 were enrolled. Twenty of these were studied retrospectively (medical record review for one year prior to enrollment) and prospectively (6 months) for symptoms related to IgG infusion. Thirteen patients (11 CVID, 2 IGAD) were excluded due to increase in IgA level (3), lack of consent (7), or non-adherence with study procedure (3). Blood was collected at enrollment and after the 6 month observation period. Subjects #22 and #23 were only studied prospectively since they did not receive IgG in the year prior to obtaining the serum specimens. Data were collected with respect to the IgG product, lot number, dose, rate of infusion, use of premedications, and symptoms recorded within 1 hour after the end of the infusion (acute) or up to 72 hours later (delayed). Symptoms were graded as mild (treated by the patients or medical staff without discontinuing the infusion), moderate (requiring telephone contact with, or a visit to an outpatient setting for assistance from a health-care provider, or requiring cessation of the infusion), or severe (requiring an emergency room visit or hospitalization, or resuscitation). We measured serum levels of IgA1, IgA2 and IgG anti-IgA1 and anti-IgA2 by ELISA using myeloma controls to establish approximate concentration standard curves. Serum specimens were also studied at the Mayo Clinic Laboratory (Rochester MN) using a Luminex®-based assay system and in the Red Cross Laboratory (Philadelphia, PA) by passive hemagglutination. IgE anti-IgA1 and anti-IgA2 were measured by ImmunoCAP assays at ViraCor-IBT Laboratories (Lenexa, KS). In all patients throughout the study, only mild symptoms were reported, including headache, fatigue and malaise. These were of a nature and frequency commonly seen in many clinical trials of IgG therapy that routinely exclude IgA-deficient patients. Therefore no attempt was made to correlate these symptom data with results of immunoassays. Results of the immunochemical analyses are shown in Table E1 (available online). Background levels for IgG anti-IgA1 or IgA2 ELISA ranged from 51–240 ng/mL (lower limit of assay detection, sera diluted 1:100). Three subjects had levels well above this range (504–4,528 ng/mL) (Table 1). Two individuals (#23 and #32) had class-specific IgG anti-IgA by ELISA. One subject (#33) had subclass-specific IgG anti-IgA2. Subjects #32 and #33 have only ever received SCIG and have never had adverse reactions. Their ability to tolerate IVIG is unknown. Seven years prior to enrollment, patient #23 had anaphylaxis requiring epinephrine during infusion of an IVIG product containing 1,000 arbitrary units and in the Red Cross Laboratory IgG anti-IgA was detected. Her IgG anti-IgA level repeated 2 ½ years later at the Mayo Laboratory was still >1000 AU. Table 1 Characteristics of patients with positive anti-IgA antibodies. Table E1 Results of immunochemical analysis. The two patients that had class-specific IgG anti-IgA in our assay also tested positive in the Mayo laboratory. The one individual with subclass-specific IgG anti-IgA2 did not test positive in the Mayo laboratory (result in the “equivocal” range). Subject #23 also tested positive in the Red Cross laboratory; subject #32 did not. The test was repeated with the same result. The reason for the discrepancy is unknown. The Red Cross laboratory did detect the subclass-specific IgG anti-IgA2 that was also found by our ELISA in pt. #33. Overall, there is good agreement between our results and these two clinical reference laboratories. IgE anti-IgA was not detected in any patient. Anaphylaxis is very rare among patients receiving IVIG.6 Therefore, a possible increased risk associated with IgG anti-IgA remains very difficult to quantify. None of the patients evaluated developed a significant reaction during the study period. We could not address the potential clinical significance of the subclass-specific anti-IgA2 with respect to IVIG, since the only such patient we identified had only ever received SCIG. Is IgG anti-IgA a “biomarker” of increased risk of non-IgE mediated anaphylaxis to gammaglobulin infusion containing IgA? Several anecdotal reports (including this one) suggest this may be the case. The mechanism whereby anti-IgA antibodies might cause an adverse reaction to IgG that contains some IgA is open to speculation. It has been reported that some individuals react to products with “high” IgA and tolerate products with “low” IgA.7, 8 This could be interpreted as an indication that the reaction mechanism involves interaction of IgG anti-IgA with infused IgA. However, patient #23 appears not to tolerate IVIG products containing even trace amounts of IgA and some patients with IgG anti-IgA tolerate IVIG without symptoms.9 Given the rarity of anaphylaxis to IVIG, much larger prospective studies are required to establish more clearly any possibility of increased risk associated with IgA deficiency. It is not clear that class or sub-class specific IgG anti-IgA antibodies have clinical relevance. Our data and others' suggest that further study of a possible association is warranted. In an individual patient, the presence of IgG anti-IgA may indicate a need for closer monitoring, or consideration of alternative therapy such as SCIG, which appears to be tolerated in many of these patients. Capsule summary In a cohort of 22 IgA-deficient patients receiving gammaglobulin, we found three with IgG anti-IgA antibodies, but only one had ever received intravenous infusion, and had non-IgE mediated anaphylaxis. All three tolerate subcutaneous IgG.