IgA deficiency (IgAD) is the most frequent immunodeficiency in the western population and affects approximately 1 in 600 individuals, most of whom are discovered incidentally during the screening of healthy blood donors, and are generally not further evaluated . However, recent reports indicate that on long term follow up, many suffer from an increased frequency of infections, autoimmune disorders, atopy and malabsorption syndromes .
IgAD is exemplified by serum IgA level of < 0.05 mg/dL and an attendant absence of secretory IgA in a person with normal levels of total IgG and IgM. The term 'selective IgA deficiency' is used for those without any of the above-mentioned conditions that are known to be associated with low levels of IgA. The occurrence of IgG subclass deficiency, especially of the IgG2 and IgG4 subclasses has been described in 20% of these patients, often accompanied by a deficiency of IgM and a compensatory increase in IgG1 and IgG3 levels . IgAD may be diagnosed in early childhood if the child presents with recurrent infections.
Common variable immunodeficiency (CVID), the most common form of primary panhypogammaglobulinemia, affects 1 in 50,000 Caucasians and is characterized by a marked reduction in serum levels of IgG (<0.3g/L), IgA (<0.05 g/L) and frequently IgM (< 0.3 g/L) . Affected individuals develop recurrent infections of the respiratory and urinary tracts. Granulomatous involvement of the liver and spleen and inflammatory bowel disease are commonly seen. Up to 10% of patients develop autoimmune thyroid disorders, hemolytic anemia or thrombocytopenia. Typically, CVID first manifests clinically in the second or third decades of life.
Both IgAD and CVID can follow exposure to anti-rheumatic and anti-epileptic medications. Other secondary causes include viral infections, notably rubella. Some cases of CVID develop from IgAD and occasionally IgAD has been known to develop from CVID. Moreover, anti-IgA antibodies can be detected in both diseases. Some investigators believe these disorders to represent the polar ends of a clinical spectrum of humoral immunodeficiency, reflecting a single underlying genetic defect.
Inheritance and pathogenesis:
20% of IgAD and CVID are familial, with most cases appearing to have an autosomal pattern of inheritance. Interestingly, the recurrence risk of IgAD was higher when the affected parent was the mother. IgAD has also been associated with the ataxia-telangiectasia syndrome. While the genetic factors underlying these disorders are not exactly known, the defect appears to involve immunoglobulin class switching at the stem cell level . Studies carried out on circulating B-lymphocytes in IgAD patients showed the presence of membrane-bound IgA on these cells, suggesting that the pathways involved in the initial expression of the relevant genes for IgA immunoglobulin class were intact. The development of IgA deficiency probably resulted then from a failure of these IgA-bearing lymphocytes to differentiate into plasma cells . A predisposing locus has been reported in the HLA class II or class III region and a number of abnormalities in the cytokine network are also currently under investigation .
A family history, appropriate age of onset and exclusion of secondary causes of hypoimmunoglobulinemia will help in arriving at a clinical diagnosis. Laboratory determination of the serum immunoglobulin concentrations is usually obtained by nephelometry or radial immunodiffusion methods.
Transfusion reactions in patients with IgA deficiency:
The occurrence of anti-IgA antibodies in some individuals with IgA deficiency places them at risk for developing an anaphylactic reaction when receiving blood products containing even small amounts of IgA immunoglobulin [6,7]. Anaphylactic reactions are very rare, but potentially lethal. Although, class-specific anti-IgA antibodies are detected in IgA-deficient donors at a relatively high frequency (1 in 1200), the estimated incidence of IgA anaphylactic transfusion reactions is only between 1 in 20,000 to 47,000 transfusions .
Severe anaphylactic reactions in individuals who lacked IgA were first described in 1968. The first lethal reaction associated with anti-IgA antibodies was reported in 1975. While some of these individuals were previously transfused or pregnant, others give no history of prior sensitization. IgA deficiency and/or the presence of anti-IgA must be excluded when patients develop an anaphylactic reaction during their first transfusion of blood products. Anti-IgA antibodies may be class-specific, subclass-specific (anti-IgA1 or IgA 2) or allotype-specific [anti-IgA2 m (1) or IgA2 m (2)]. The more severe reactions are usually associated with the presence of class-specific anti-IgA and the less severe anaphylactoid reactions are generally related to the subclass or allotype-specific anti-IgA. While most individuals in whom these antibodies are detected are also IgA deficient, cases of anaphylactoid reactions attributed to subclass or allotype-specific antibodies in patients with normal IgA levels have also been reported.
Laboratory testing for IgA and anti-IgA:
Screening for IgA deficiency in donors is accomplished using radial immunodiffusion methods, which can detect IgA levels as low as 0.5 mg/dL. True IgA deficiency (<0.05 mg/dL) should however be confirmed by the highly sensitive passive hemagglutination inhibition assay (PHIA) . The passive hemagglutination assay (PHA), utilizes group O red blood cells coated with multiple myeloma-derived IgA proteins as indicator cells and is considered the most sensitive assay currently available for the detection of IgA antibodies. A large study evaluating these assays in the diagnosis of IgA deficiency detected class-specific anti-IgA in 76% of IgA deficient patients with history of anaphylactic transfusion reaction and in 20% of asymptomatic IgA deficient donors. The authors estimated the frequency of IgA deficiency with class-specific anti-IgA among random donors to be 1 in 1200. They also found that the titer of antibodies did not always correlate with the severity of the reaction . There have been some reports suggesting that anti-IgA antibody of the IgE class is a more specific marker for predicting the risk of anaphylactic reactions in these patients .