Continuing Education Activity

The majority of patients with selective IgA deficiency undergoing transfusion of blood products are asymptomatic. However, in the subset of patients in whom anti-IgA antibodies are formed, anaphylactic reaction to blood products may occur. This activity reviews the etiology, pathophysiology, and treatment of transfusion selective IgA deficiency and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Describe the pathophysiology of transfusion selective IgA deficiency.
• Review the appropriate evaluation of selective IgA deficiency.
• Outline the management options for selective IgA deficiency.
• Summarize the importance of collaboration amongst the interprofessional team to enhance the care of patients with selective IgA deficiency.

Introduction

Selective IgA deficiency is defined as a decrease of serum IgA in the setting of normal serum IgM and serum IgG levels. It is the most common primary immunodeficiency.[1] Although selective IgA deficiency is common, the majority of patients with selective IgA deficiency undergoing transfusion of blood products are asymptomatic. This is in part due to the fact that the majority of patients with selective IgA deficiency do not form anti-IgA antibodies. Even though anti-IgA antibodies have not been definitively proven to cause transfusion reactions, several reports demonstrate the pivotal role they play in these settings.[2] Nevertheless, in the subset of patients in whom anti-IgA antibodies are formed, anaphylactic reaction to blood products may occur.

Etiology

The definition of a selective IgA deficiency mediated anaphylactic transfusion reaction is anaphylaxis that occurs within one hour of transfusion of plasma-containing blood products in an individual who is IgA deficient and has plasma anti-IgA antibodies.[3] There is indirect evidence showing that transfusion selective IgA deficiency reactions occur due to the presence of anti-IgA antibodies in IgA deficient individuals. In a report utilizing passive hemagglutination assays for the detection of anti-IgA antibodies, anti-IgA antibodies were detected in 76.3% of IgA deficient individuals who had a history of anaphylactic transfusion reaction versus 21.7% of asymptomatic IgA deficient individuals.[4]

However, the role anti-IgA antibodies play still remains controversial. For example, blood products containing anti-IgA antibodies given to IgA deficient individuals have occurred with no adverse reactions. Additionally, it has been shown that IgA containing blood products does not always induce a reaction when exposed to anti-IgA antibodies.[5] Overall, anti-IgA antibodies have been demonstrated to be associated with transfusion reactions in IgA deficient individuals, but further research is needed.

Epidemiology

In the western world, selective IgA deficiency occurs in about 1 in 600 individuals. However, there is a great deal of variability among various ethnic groups.[6] It is estimated that the frequency of anti-IgA antibodies in IgA deficiency is about 1/1200.[4] Overall, it has been estimated that the actual incidence of blood transfusion reactions caused by anti-IgA antibodies is about 1.3 per million blood products transfused.[7]

Pathophysiology

There are several reports of anaphylactic transfusion reactions to either IgE or IgG with anti-IgA antibodies in patients with undetectable IgA levels.[2]

IgE-mediated transfusion reactions occur immediately via a type I hypersensitivity response. At first, an allergen induces the secretion of IgE by plasma cells. These IgE antibodies bind to and sensitize mast cells and basophils. Subsequent exposures to the allergen then cause crosslinking of preformed IgE on the sensitized mast cells and basophils. Ultimately, this causes degranulation of the cells and release of active mediators such as histamine, which in turn causes vasodilation and smooth muscle contraction.[8]

There are several proposed mechanisms of how IgG anti-IgA antibodies can cause anaphylactic transfusion reactions. Some reports suggest that IgG anti-IgA antibodies may be a biomarker that increases the risk of non-IgE mediated anaphylaxis. Another proposed mechanism is that IgG anti-IgA antibodies react with infused IgA; thus, blood products with higher levels of IgA would be more likely to cause a reaction.[2] However, the exact mechanism of how IgG anti-IgA antibodies cause anaphylactic transfusion reactions warrants further investigation.

History and Physical

A thorough history must be taken prior to any transfusion. Healthcare professionals must ask patients if they have ever had blood transfusions in the past, and if so, if they have had any transfusion-related reactions. Patients with selective IgA deficiency are especially at risk of transfusion-related reactions.

When an anaphylactic reaction occurs, patients present with cutaneous, pulmonary, cardiovascular, and possibly gastrointestinal symptoms. As a result, these patients generally develop hives, wheezing, hypotension, and diarrhea.[3] An anaphylactic reaction is severe and can be life-threatening. However, patients can also present with milder symptoms or no symptoms at all.

Evaluation

Currently, there are no universal guidelines for screening for anti-IgA antibodies. Since the presence of anti-IgA antibodies is not a direct predictor of anaphylactic risk, patients who test positive for anti-IgA antibodies may be unnecessarily labeled as “at risk.” These patients would be subject to a lifelong policy of IgA deficient blood products and potentially harmful delays. Therefore, one approach is to only test patients who are at high risk of developing anti-IgA antibodies prior to transfusion of blood products.[9] However, it is recommended for patients with a history of anaphylactic transfusion reaction to undergo laboratory testing for IgA and anti-IgA antibodies.

Treatment / Management

As discussed earlier, most patients with selective IgA deficiency who undergo transfusion of blood products are asymptomatic. In patients where anaphylaxis does occur, emergency intervention is important. Immediately, the transfusion should be stopped, and epinephrine is to be administered. Hypotensive patients should be adequately resuscitated with intravenous fluids. Maintenance of a patent airway is important, and oxygenation should be provided. In severe cases, intubation and vasopressors may be necessary.[10] Anaphylaxis can occur in a biphasic manner in which symptoms arise hours after the initial episode. Therefore, patients should be monitored for up to 24 hours after the resolution of symptoms.[3]

If IgA anaphylaxis is suspected in a patient with no known history of IgA deficiency, but additional transfusions are needed, there may not be enough time to confirm the presence of anti-IgA antibodies. In this situation, the safest method is to use washed red blood cells and plasma or platelets from known IgA deficient donors. If a platelet transfusion is required sooner than platelets from an IgA deficient donor can be supplied, platelets can be washed, but this requires extensive skill. If fresh frozen plasma (FFP) is required sooner than FFP from an IgA deficient donor can be supplied, then a slow transfusion can be initiated under a monitored setting. This is largely due to the fact that the benefit of the FFP transfusion outweighs the risk of an anaphylactic reaction, as anti-IgA antibodies have only been found in 18.1% of suspected IgA anaphylaxis cases. However, if a patient with confirmed IgA deficiency and anti-IgA antibodies needs platelets or FFP from an IgA deficient donor and these blood products are not readily available, then recombinant activated coagulation factor VII (rFVIIa) is a possible alternative. There have been cases in which rFVIIa has been used in systemic bleeding disorders in place of FFP or platelets. Theoretically, rFVIIa should be able to be transfused safely in IgA deficiency patients since it does not contain IgA.[3]

In patients with anti-IgA antibodies requiring immunoglobulin replacement, subcutaneous immunoglobulin (SCIG) can be used. In a retrospective study of 15 patients with side effects to blood products and/or immunoglobulins, 4 patients had reactions due to anti-IgA antibodies. When these patients were given subcutaneous immunoglobulin, no side effects were seen. Additionally, the anti-IgA antibodies had disappeared in some patients, and they were able to tolerate intravenous immunoglobulin (IVIG) administration. In this study, it was theorized that the antibodies formed complexes with IgA, and these complexes might have been removed quickly from circulation.[11] In a situation where a patient who is IgA deficient has a history of reaction to IVIG and SCIG is not recommended, then a low-IgA content IVIG can be considered.[12]

Another possible approach in these patients is desensitization to blood products. In a case report of an individual with severe IgA deficiency and anti-IgA antibodies with a history of transfusion reactions with IgA-containing blood products, standard blood products were given without complication. This was achieved through continuous infusion of gradually increasing concentrations of IgA-containing immunoglobulin preparations. Thus, the patient was successfully desensitized to IgA.[13]

Differential Diagnosis

The differential diagnosis of transfusion selective IgA deficiency comprises of the different types of acute transfusion reactions. These include:[3]

• Anaphylactic transfusion reaction
• Acute hemolytic transfusion reaction (AHTR)
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Sepsis
• Angiotensin-converting enzyme (ACE) inhibitors
• Coincident exposure to allergens
• Urticarial transfusion reaction (UTR)
• Febrile non-hemolytic transfusion reaction (FNHTR)
• Primary hypotensive reaction

Prognosis

An IgA-mediated anaphylactic transfusion reaction can be life-threatening. In the United States from 2006 to 2009, it was estimated that the case fatality for hospitalizations or emergency department presentations for anaphylaxis was 0.3%.[14] Although the case fatality for anaphylaxis is relatively low, healthcare professionals must be able to evaluate and treat patients promptly and effectively when an IgA-mediated anaphylactic transfusion reaction is suspected.

Complications

As discussed earlier, the most severe complication of IgA-mediated transfusion reactions is anaphylaxis. Anaphylaxis is an allergic reaction that can be potentially fatal. Thus, these situations must be handled promptly.

Deterrence and Patient Education

Patients with selective IgA deficiency should wear a medical alert bracelet stating their condition and that they are at an increased risk of an allergic reaction to transfused blood products. This applies to patients with or without anti-IgA antibodies. Although there is no specific guideline on how often IgA deficient patients should be tested for anti-IgA antibodies, one study did find that 11.8% of patients with IgA levels < 0.05 mg/dL had formed antibodies upon a 16 to 21-year follow-up.[9] Therefore, patients should be informed that there still poses a risk of an allergic reaction.

Enhancing Healthcare Team Outcomes

It is essential that an interprofessional approach is taken when dealing with transfusion selective IgA deficiency.[15] In a patient with confirmed IgA deficiency and anti-IgA antibodies who requires transfusion of blood products, it is crucial that the appropriate blood products are administered. This requires seamless communication between the clinician, nurse, and blood bank technologist. During the transfusion, it is important that the patient is monitored for any adverse events by the medical and nursing staff. Overall, the appropriate precautions are to be taken to prevent anaphylactic reactions. In the event of an anaphylactic reaction, the patient should be evaluated and treated quickly.