IgA deficiency

Author: Mindy Goldman, MD, FRCPC
Online publication date: March 2012

IgA deficiency

IgA deficiency is the most common human immunodeficiency. Although the majority of IgA deficient individuals are asymptomatic, some IgA deficient individuals have a higher prevalence of respiratory and gastrointestinal tract infections. From a transfusion medicine perspective, the presence of anti-IgA in an IgA deficient recipient is a possible cause of anaphylactic transfusion reactions. Approximately 20% of anaphylactic transfusion reactions in a Caucasian population may be associated with anti-IgA in IgA deficient recipients.1

Normal, low, and deficient IgA levels

IgA levels between approximately 100 and 600 mg/dL 2 are considered to be normal. However, many individuals have IgA levels below 100mg/dL but are not truly deficient. The double immunodiffusion assay may be used as a screening test to identify individuals with an IgA level below 2 to 4 mg/dL. A more sensitive ELISA method with a sensitivity of 0.02 mg/dL is then necessary to determine which individuals are truly IgA deficient. Truly deficient individuals, with levels below 0.05 mg/dL, may develop anti-IgA antibodies. At Canadian Blood Services, screening of approximately 100,000 donor samples identified 139 confirmed donors with IgA levels <0.05 mg/dL mg/dL.3,4 Based upon the number of individual donors the rate of severe IgA deficiency in our donors is approximately 1 in 300. At Héma-Québec, 73 IgA deficient blood donors were identified from close to 39,000 screened donor samples, for a frequency of 1 in 531.5

Frequency and clinical significance of anti-IgA antibodies

In the Canadian Blood Services donor screening program, anti-IgA antibodies were identified in 41% of severely deficient donors.4 In the Héma-Québec donor screening program, anti-IgA antibodies were found in 53% of severely deficient donors.5 Many anti-IgA antibodies are naturally occurring. Amongst Héma-Québec donors, only 9 of the 39 donors with antibodies had a history of transfusion or pregnancy. At Canadian Blood Services, there are 2 to 4 anaphylactic transfusion reactions possibly related to anti-IgA antibodies reported each year. At Héma-Québec, from 0 to 1 anaphylactic reactions related to anti-IgA are reported yearly.6 In the UK Serious Hazards of Transfusion (SHOT) Hemovigilance Program, only 1 anaphylactic reaction in 2010 was possibly related to anti-IgA antibodies.7 If the frequency of IgA deficiency and anti-IgA is similar in recipients and in donors, one would expect that approximately 1 to 1.6 patients in 1,000 in Canada would be IgA deficient with anti-IgA. However, the frequency of anaphylactic transfusion reactions related to anti-IgA is less than 1 in 500,000 components transfused annually. Therefore, the vast majority of anti-IgA antibodies do not appear to cause anaphylactic transfusion reactions.

Testing of patients with low IgA levels for IgA deficiency and anti-IgA

Individuals who have an anaphylactic transfusion reaction should be tested for IgA deficiency and the presence of anti-IgA. However, practice is less clear on the utility of performing testing on patients who appear to have low IgA levels but have not been transfused, or have not had a transfusion reaction.8,9,10 Given the high frequency of anti-IgA antibodies, and the low frequency of anaphylactic transfusion reactions attributable to anti-IgA, it is estimated that approximately 1 in 100 patients with IgA deficiency and anti-IgA antibodies develop transfusion reactions. There is no way at present to distinguish which anti-IgA antibodies may be of clinical significance. Therefore, the majority of practitioners do not recommend testing of patients who are low in IgA for IgA deficiency and the presence of anti-IgA, in the absence of a history of an anaphylactic transfusion reaction.8

Anaphylactic transfusion reactions

Definition

Anaphylactic transfusion reactions are severe allergic reactions characterized by pruritis, urticaria, upper or lower airway obstruction, hypotension and shock.1

Incidence

The incidence of anaphylactic transfusion reactions varies somewhat in different hemovigilance schemes, depending on the precise definition used. In general, the incidence is higher in components containing a high volume of plasma. In the Québec hemovigilance system, from 6.2 to 15.9 severe allergic reactions per 100,000 units transfused were reported annually from 2000 to 2008.6 In the Public Health Agency of Canada Transfusion Transmitted Injuries Surveillance System (TTISS), from 5.4 to 8.4 severe allergic reactions per 100,000 components were reported annually from 2002 to 2005.11 In the UK SHOT program, 34 anaphylactic reactions were reported in 2010, out of over 2.8 million blood components (RBCs, platelets, FFP, SD-FFP, and cryoprecipitate) distributed to hospitals.7 At Canadian Blood Services, from 2 to 4 allergic reactions were investigated in years 2010 and 2011, and found to be related to IgA deficiency with anti-IgA antibodies.

Clinical presentation

A severe allergic reaction may begin after infusion of only a few mL with symptoms that may be mild at first but can rapidly progress to loss of consciousness, shock, and, in rare cases, death. Reactions usually occur within 1 to 45 minutes of the start of transfusion, although the less severe anaphylactoid reactions may begin up to 2-3 hours after the transfusion was initiated.1 Differentiating features from severe reactions due to bacterial contamination or acute hemolytic transfusion reactions include the presence of cutaneous symptoms, the absence of fever and chills, and the presence of severe respiratory symptoms. Symptoms are listed in Table 1.

Table 1: Symptoms and signs of anaphylactic transfusion reactions
Cutaneous - pruritis
- urticaria
- erythema
- flushing
- angioedema
Pulmonary - hoarseness
- wheezing
- dyspnea
- cyanosis
- tightness in chest
- substernal pain
Gastrointestinal

- nausea

- cramps
- vomiting
- diarrhea

Cardiovascular - headache
- tachycardia
- cardiac arrhythmias
- cardiac arrest
- hypotension
- shock
Miscellaneous - apprehension
- sense of impending doom

Mechanism

These reactions are thought to be caused by the interaction between an allergen and a pre-formed IgE antibody, although the pathogenesis is incompletely understood. In most cases, the exact cause is unknown. In Caucasians, from 5 to 20% of cases involve anti-IgA in IgA deficient individuals. There are rare case reports of passive transfer of donor IgE antibodies against peanuts causing an anaphylactic reaction in recipients subsequently ingesting peanuts. There has also been a case of transfer of the peanut antigen by transfusion to a recipient with a severe peanut allergy. Recipient atopic predisposition, as demonstrated by higher total IgE and IgE specific for aeroallergens such as pollens, has been associated with increased allergic reactions on receiving blood in general, but not necessarily with anaphylactic reactions.1,12
IgE-mediated reactions are type I immediate hypersensitivity reactions. IgE has the ability to bind to mast cells and tissue basophils through Fc receptors on their cell membranes. Mast cells (armed with a surface coating of IgE) are triggered when the patient next becomes exposed to the antigen (allergen) recognized by the IgE. This leads to cross-linking of the bound IgE antibody, producing mast cell degranulation with release of preformed and new mediators of the allergic reaction.
Histamine is the most important preformed mediator. It causes vasodilation, increased vascular permeability, increased mucous secretion by nasal and bronchial glands, and smooth muscle contraction. Other granule compounds that mediate the reaction include heparin, enzymes, leukotrienes, cytokines, and activating factors such as the eosinophil and neutrophil chemotactic factors and platelet activating factor.

Investigation of patients with anaphylactic transfusion reactions

If a patient develops an anaphylactic transfusion reaction, screening tests should be done for IgA deficiency. If the patient appears to be IgA deficient, samples should be sent to Canadian Blood Services for determination of true IgA deficiency and the presence of anti-IgA.

Transfusion support for patients with a history of anaphylactic transfusion reactions

Ideally, investigation would be done to determine if anti-IgA antibodies are present. Transfusion management of patients with a history of an anaphylactic transfusion reactions and anti-IgA antibodies is outlined in Table 2. If the patient is not IgA deficient and no anti-IgA has been detected, and the patient has experienced only a single anaphylactic or anaphylactoid reaction, a trial transfusion of unwashed blood components may be performed under controlled conditions, including patient consent, premedication, and close medical supervision. If an anaphylactic reaction occurs again, the patient should be transfused using washed components1.
If there is inadequate time to perform testing for anti-IgA, the case should be discussed with the CBS medical director.

Table 2: Transfusion management of patients with a history of an anaphylactic transfusion reaction and anti-IgA
RBCs - give RBCs from unselected donors after washing with 0.9 % NaCl
- if reaction recurs, give frozen-thawed-deglycerolized RBCs
- alternatives (where available/appropriate)
- autologous RBCs or RBCs from IgA deficient donors
Platelets - use platelets, apheresis collected from IgA deficient donors
- alternatively, give platelets from unselected donors after washing with 0.9% NaCl
Fresh Frozen Plasma, Frozen Plasma and Cryoprecipitate - use components collected from IgA-deficient donors
Plasma Derivatives (IVIg, Albumin, Rh Immune Globulin) - check package inserts for instructions, cautions/contraindications for transfusion of these products
- if there is a choice, select product with lower level of IgA

Related Customer Letter

Customer Letter # 2012-09 Important Information Regarding Patient IgA/Anti-IgA Testing Requests

Patient IgA/Anti-IgA Testing Requests

References

  1. Vamvakas EC. Allergic and anaphylactic reactions. In: Popovsky M, editor. Transfusion reactions, 3rd ed. Arlington, VA: AABB Press, 2007, p. 105-156.
  2. AABB TechnicalManual, 16th Edition, 2008. Roback JD, Combs MR, Grossman BJ, Hillyer CD (eds.). Appendix 1, p.987
  3. Palmer DS, O’Toole J, Montreuil T, Scalia V, et al. Screening of Canadian Blood Services donors for severe immunoglobulin A deficiency. Transfusion 2010; 50:1524-1531.
  4. Palmer DS, O’Toole J, Montreuil T, Scalia V, Goldman M. Evaluation of particle gel imunoassays for the detection of severe immunoglobulin A deficiency and anti-human immunglobulin A antibodies. Transfusion (In press): DOI 10.111/j.1537-2995.2011.03513.x
  5. Thibault L, Beauséjour, de Grandmont MJ, Long A, et al. Establishment of an immunoglobulin A-deficient blood donor registry with a simple in-house screening enzyme-linked immunosorbent assay. Transfusion 2006; 46:2115-2121.
  6. Héma-Québec, Rapport du comité d’hemovigilance, 2008. Website : http://publications.msss.gouv.qc.ca/msss/fichiers/2009/09-212-05.pdf 
  7. Serious Hazards of Transfusion 2010 Annual Report. Website: www.shotuk.org/shot-reports
  8. Sandler SG. How I manage patients suspected of having had an IgA anaphylactic transfusion reaction. Transfusion 2006; 46:10-13.
  9. Lilic D, Sewell WAC. IgA deficiency: what we should – or should not – be doing. J Clin Pathol 2001; 54:337-338.
  10. Sandler SG, Vassallo RR. Anaphylactic transfusion reactions. Transfusion 2011; 51:2265-2266.
  11. Public Health Agency of Canada, Transfusion Transmitted Injuries Surveillance System – Program reports. Website: www.phac-aspc.gc.ca, reports and publications, Transfusion Transmitted Injuries Surveillance reports.
  12. Savage WJ, Tobian AA, Fuller AK, Wood RA, et al. Allergic transfusion reaction to platelets are associated more with recipient and donor factors than with product attributes. Transfusion 2011; 51:1716-1722.