A readily available assay for anti‐immunoglobulin A: is this what we have been waiting for?

A lthough anaphylactic transfusion reactions due to underlying immunoglobulin A deficiency (IgAD) are rare, it is not uncommon for transfusion medicine physicians to encounter patients with transfusion reactions with respiratory distress or hypotension, where the specter of anaphylaxis is raised. In such cases, IgAD with associated anti-IgA as the underlying cause must be excluded. Another common scenario is a patient with a purported history of IgAD, requiring a judgment in a limited time window as to whether special IgAdeficient blood components are needed for transfusion. In the majority of such cases, IgAD is not present in the patient, nor has it been an etiologic factor in a previous transfusion reaction. However, in most urgent situations, there are no diagnostic tests readily available to help us exclude the presence of IgAD or anti-IgA. Anaphylactic transfusion reactions are acute and potentially life-threatening events, and therefore it is incumbent upon physicians to identify at risk individuals and provide them with appropriate blood components to prevent such reactions. Severe anaphylactic reactions associated with IgAD and mediated by anti-IgA have been reported since 1968. There have been more than 40 case reports in the literature, but the true incidence of IgA anaphylactic transfusion reactions is still unknown. As recently pointed out by Sandler, many of the older reports of IgA anaphylactic transfusion reactions may actually represent examples of other entities, such as unrecognized transfusion-related acute lung injury, which may only have relatively mild respiratory distress. Other cases may be secondary to a variety of blood-soluble factors, such as latex, antibiotics, activated platelet (PLT) membrane fragments or PLT-derived microparticles, or cytokines generated in stored blood components. In Japan, where IgAD is rare, anti-haptoglobin antibodies are responsible for more anaphylactic transfusion reactions than anti-IgA. Furthermore, of the 359 samples referred to the American Red Cross National Reference Laboratory for suspected IgA anaphylactic transfusion reactions between 1978 and 1998, anti-IgA was identified only in 18% of the cases, suggesting that IgAD is only one of many causes for anaphylactic transfusion reactions. If anti-IgA can be shown to be absent in such cases, then IgA anaphylactic reactions can be essentially excluded, rendering provision of IgA-deficient blood components for future transfusions unnecessary. In many ethnic populations, IgAD is the most common primary immune deficiency. Among Caucasian persons, IgAD is often quoted to have a prevalence of 1 of 500 to 700 individuals. Although most patients are asymptomatic at the time of diagnosis, up to 80 percent show a predilection for sinopulmonary and gastrointestinal infections, as well as autoimmune disorders when followed for up to 20 years. IgAD is rarely of immediate clinical concern, except in the setting of blood transfusion, and only patients with severe IgAD whose plasma contain anti-IgA are at risk for IgA-mediated anaphylaxis. Such reactions in these individuals can be prevented by providing IgA-deficient blood components. Red blood cells (RBCs) from normal donors can be rendered IgA-deficient with thorough washing to minimize the plasma content, but plasma products must be prepared from IgA-deficient donors. PLTs can be washed, but the procedures required to remove enough plasma to prevent reactions can damage PLTs, limiting their recovery and survival. Registries of IgA-deficient donors have been established in the United States, Canada, Europe, and Asia. To ensure that IgA-deficient products contain only negligible amounts of IgA, most collection centers use stringent criteria to qualify potential donors as IgA-deficient. For example, all donors in the American Rare Donor Program (ARDP) database must have IgA levels less than 0.05 mg per dL, measured twice with high-sensitivity IgA assays. In most populations, only about half of the individuals who meet the clinical criteria of IgAD (serum IgA < 7 mg/dL) would have IgA concentration low enough to be qualified as an IgA-deficient donor. The Canadian Blood Services, in addition to using the same criterion of IgA level, also excludes donors with detectable anti-IgA. As a result, only 34 eligible donors were identified after screening 38,759 donor samples in one study. Therefore, IgA-deficient components are a scarce and precious resource that should be allocated with care and reserved for patients at risk for anaphylaxis. On the other hand, the need for such rare products for patients with a reported history of IgAD or anaphylactic transfusion reaction cannot be convincingly established in many cases. The current prevailing clinical definition of IgAD (serum IgA level below 7 mg/dL in an individual older than 4 years of age) was chosen in part because IgA concentrations cannot be measured reliably below this TRANSFUSION 2008;48:2048-2050.