Is it possible to administer IVIG (or IMIG) to an IgA-deficient patient with anti-IgA who has had a previous anaphylactic reaction to IVIG?

A Transfusion Safety Officer in Canada reports that her hospital is caring for a patient with hypogammaglobulemia. The patient has a history of being treated with IVIG ten years ago, and having "reacted" to the initial dose, but there are no details on the type of reaction that the patient had. The patient in question did not have any other blood product or IVIG exposures until he came to the Canadian's hospital in September 2002. The patient received less than 25mL of a commercial IVIG product when he had a fairly severe anaphylactic reaction. It was then determined that the patient was IgA deficient with anti-IgA present. The Canadian's laboratory determined that the commercial IVIG product contained detectable IgA. It was decided to use a second commercial IVIG that was determined to also contain a IgA, but at a hundredth the amount compared with the first commercial IVIG. As a further precaution, the patient received the second IVIG product at a rate of 25mL/ 30 minutes. Unfortunately, the patient reacted after only approximately 1-2mL was infused, even though he had been premedicated with both Prednisone and Benadryl. The inquiring Canadian was hoping someone from the e-network forum has had experience with infusing IVIG to a patient with an anti-IgA present, including products used, rate of administration, and premedication strategy. Is it even possible to transfuse an IgA-deficient patient that has anti-IgA with any IVIG product? Would any of the intramuscular immune globulins be an option in this case? Please provide a scientific basis with your replies, to the extent that it is documented in the literature.

The following responses were received.

1. Another Canadian reported that for further information on strategies for transfusing an individual with anti-IgA antibodies, colleagues may want to consult the following reference: Cunningham-Rundles C, Zhou Z, Mankarious S, Courter S. Long-term use of IgA-depleted intravenous Immunoglobulin in immunodeficient subjects with Anti-IgA antibodies. J.Clin Immunol. 1993;13(4):272-278.
   
   
2. A transfusion medicine physician in Riyadh, Saudi Arabia suggests the following reference: Limaye S, Walls RS, Riminton S, Intern Med J 2001, 31:256-7. Safe and effective use of chromatographically purified intravenous immunoglobulin despite profound anti-IgA sensitization.

ADDENDA Jan. 21, 2003

3. A professor of clinical immunology in Sweden wrote that in his opinion one can use gamma globulin replacement therapy in patients even with high titers of anti-IgA, including patients with a history of anaphylaxis. In his experience, they treat these patients by the subcutaneous route using IMIG preparations (even using products that still contain some IgA). For further information on this method see the following references:
   • Gardulf A, Hammarström L, Smith CIE. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet 338:162-166, 1991.
   • Gardulf A, Andersen V, Björkander J, Ericson D, Frøland S, Gustafson R, Hammarström L, Jacobsen MB, Jonsson E, Möller G, Nyström T, Søeberg B, Smith CIE. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and cost. Lancet 345: 365-369, 1995.
   • Gardulf A, Hammarström L. Subcutaneous administration of immunoglobulins: What are the advantages. Clin Immunother 6: 108-116, 1996.
   • Gustafson R, Gardulf A, Granert C, Hansen S, Hammarström L. New strategy for prophylactic therapy to patients with "selective" IgA deficiency. Lancet 350: 865, 1997.
   • Sundin U, Nava S, Hammarström L. Disappearance of IgG-anti-IgA in IgA deficient patients on subcutaneous infusion therapy with gammaglobulin. Clin Exp Immunol 112: 341-346, 1998.
   Editor's cautionary note: The IM preparation is known to provoke anaphylactic reactions (C Ropars, et al Revue Francaise de Transfusion 1971; XIV:401), but the purity of the product and the route of administration may be important considerations.
   
   
4. Dr. Girish Vyas at UC San Francisco comments that since the first reports of anaphylactic transfusion reactions caused by anti-IgA in three patients with absence of IgA (G. Vyas et al Lancet 1968; 2312), at least 42 such cases have been reported to his group. Consequently, several regional registries of IgA deficient donors have been formed in the U.S.A., Canada, Europe, and South America. In his opinion, the plasma of donors with selective lack of IgA is the product of choice for the Canadian patient who suffered anaphylactic reactions to small amounts of infusion of IVIG, , unless the hospital can produce or obtain IVIG depleted of IgA (Cunningham-Rundles reference in response #1 above). Plasma (FFP) lacking IgA is readily available via the American Rare Donor Program (ARDP), a combined effort of AABB and the American Red Cross (see contact information in response #6 below). The IM preparation of gamma globulin is known to provoke anaphylactic reactions (C Ropars, et al, Revue Francaise de Transfusion 1971; XIV401). Dr. Vyas has graciously made himself available to be contacted if further assistance is needed (vyas@itsa.ucsf.edu).
   
   
5. Dr. Colleen W. Gilstad, (attribution used with permission), Medical Director, Transfusion Service and Armed Services Blood Donor Center National Naval Medical Center reports (caveat: her opinion does not represent the opinion of the U. S. Navy or Department of Defense) that many of the issues one needs to consider in patients with anti-IgA who need an IgA-containing blood product or IVIG were covered in a recent letter to the editor in the November 2002 issue of Vox Sanguinis (no abstract) in which she and her co-authors reported on a patient with an anti-IgA subclass antibody who needed IVIG. A very important issue to consider (in her opinion) is the test you are using to determine that a patient has "anti-IgA". Some tests that detect IgG anti-IgA do not seem to be very helpful in predicting adverse reactions. Her group did not have access to a test that they felt was reliable in predicting the risk for a significant anaphylactic reaction, so they undertook a trial with an infusion of solvent-detergent treated plasma before infusing IVIG. Probably the most useful reference to this particular situation would be the fourth reference mentioned in their letter (J Clin Immunol 2000;20:77-82). The authors of this article report on their experience with 5 patients with common variable immunodeficiency, and IgG anti-IgA who were treated with non-IgA depleted IVIG. One patient had a high titer of IgG anti-IgA and had an initial severe reaction to IVIG requiring interruption of the infusion but subsequently was able to tolerate infusions 6 months later with the same product with "mild reactions". Dr Gilstad adds: "I do not have a specific recommendation for the Canadian patient in question. This patient may indeed have a clinically significant (? IgE type) anti-IgA in which the above discussion would not apply, and this patient may indeed require an IgA-depleted product. My goal in replying is to point out that we need to define what test was used to label a patient as having "anti-IgA" before we can discuss patient management recommendations that can be applied to groups of patients.

ADDENDA Jan. 22, 2003

6. In connection with the the recommendation in response #4 above, Sandra Nance, MS, MT(ASCP)SBB of the National Reference Laboratory for Blood Group Serology and the American Rare Donor Program offers the following advice for institutions that wish to obtain FFP from an IgA-deficient donor for one of their patients.
   
   "The ARDP provides access to IgA-deficient products for patients with anti-IgA. The ARDP (American Rare Donor Program) is accessed through ARDP member facilities. These facilities are Immunohematology Reference Laboratories qualified by the American Association of Blood Banks or American Red Cross. Non-members should consult with one of those facilities for rare blood products, including IgA-deficient products. The ARDP member facility determines whether a sample is needed for evaluation in the case of rare red cell request . ARDP needs to evaluate a sample from the patient to determine IgA and anti-IgA status. If the need is urgent, the products will be made available prior to test result availability. (If the requesting person needs help in locating the nearest ARDP member facility, they should call the ARDP laboratory staff in Philadelphia at 215-451-4900)."

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