Immunoglobulin A (IgA) deficiency is a common primary immunodeficiency characterized by undetectable serum amounts of IgA and a concomitant lack of secretory IgA. Other immunoglobulin levels are normal. The diagnosis is usually established in individuals older than 4 years whose blood levels of IgA are below 7 mg/dl but have normal levels of IgG and IgM. These individuals have a normal antibody response to vaccines. Nevertheless, IgA deficiency should be excluded from any other cause of hypogammaglobulinemia and defects in T lymphocytes. Patients who suffer from selective IgA deficiency may have clinical symptoms or be asymptomatic.
The worldwide prevalence of selective IgA deficiency depends on the ethnic background; it is most prevalent in Caucasians. The incidence varies from 1:143 to 1:965 in different regions, with equal distribution between the genders. However, the real rate could be higher due to the absence of routine screening programs for immunodeficiencies and the fact that many patients are asymptomatic. It is estimated that the prevalence of selective IgA deficiency is 38-fold higher in first-degree relatives of the patients with the disorder than unrelated donors and the chance to inherit the disease in the family is about 20%.
The exact pathophysiology of selective IgA deficiency is not fully elucidated. It seems that the chief defect is immunoglobulin class switching, whereas the IgA-bearing B lymphocytes cannot differentiate terminally into IgA-secreting plasma cells. The described defect could be linked to the stem cells, as the deficiency can be transmitted by bone marrow transplantation. Impaired or decreased T-helper cells which support switching, as well as the defect in B-cell signaling downstream the cytokine effect in the germinal centers of the secondary lymphoid organs, could be involved in the defective antibody production. Survival, growth, differentiation, and production of immunoglobulins, including IgA, also depend on the extent of the apoptosis of B cells. Several underlying genetic alterations are described in selective IgA deficiency, including chromosomal abnormalities, cytogenetic defects, mutations in JAK3, RAG1, RAG2, TACI, CXCR4, STAT1, among others. Researchers think that identification of the underlying genetic defects in patients with selective IgA deficiency may help avoid severe clinical complications and assist with the treatment strategies.
Most IgA patients remain asymptomatic their whole life. Coincidentally, they are often diagnosed during routine laboratory screening. However, some patients present with different complaints and clinical phenotypes, mainly with recurrent sinopulmonary infection, allergies, autoimmune diseases, gastrointestinal disorders, malignancies, and other severe complications. The most common manifestations associated with selective IgA deficiency are the recurrent pulmonary infections caused by extracellular encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. More severe symptoms occur when selective IgA deficiency is combined with IgG2 and IgG3 subclass deficiency.
A higher incidence of some autoimmune diseases has been observed in patients with selective IgA deficiency, such as celiac disease, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis, diabetes mellitus type 1, Graves disease, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, among others. Allergic conjunctivitis, eczema, rhinitis, urticaria, food allergy, and asthma are also most commonly associated with selective IgA deficiency, as well as gastrointestinal diseases and malignancies: IBD (ulcerative colitis and Crohn disease), pernicious anemia, giardiasis, nodular lymphoid hyperplasia, and gastric and colonic adenocarcinoma.
The European Society for Immunodeficiencies (ESID) new criteria for diagnosing selective IgA deficiency include the following constellation:
If specialized immunophenotyping is being performed, the results may show that some patients possess a lower percentage of switched memory B cells (below 0.4%), whereas others may have a similar profile with healthy controls percentages. The former patients classified as group I may demonstrate a higher rate of pneumonia, autoimmunity, and hepatosplenomegaly. Patients presenting over 45 years should be tested by a chest x-ray to exclude a thymoma.
Due to the heterogeneity of the selective IgA deficiency and the fact that there is no specific treatment, every patient should be managed individually. The recommended management comprises of periodic monitoring, prophylaxis, and treatment of infections with antibiotics, treatment of the associated allergic and autoimmune conditions, replacement therapy with intravenous or subcutaneous immunoglobulins, administration of polyvalent pneumococcal vaccines, patient education. Regular immunoglobulin replacement should be performed with caution to avoid an anaphylactic reaction.
The diagnosis of selective IgA deficiency often is one of exclusion. It should be distinct from common variable immunodeficiency (CVID), where both IgG and IgA decline marked significantly, although IgM is reduced in about half the patients. Single gene primary immunodeficiencies like X-linked agammaglobulinemia and X-linked hyper IgM syndrome could be easily differentiated from selective IgA deficiency. Patients with thymoma may also present with moderate hypogammaglobulinemia even though having no circulating B cells. Secondary hypogammaglobulinemia usually shows moderately low levels of IgA. However, conditions such as nephrotic syndrome, protein-losing enteropathy, chronic lymphatic leukemia, and myeloma should also be excluded.
Nevertheless, it was shown that a variety of anti-rheumatic (sulphasalazine, gold), anti-epileptic drugs (carbamazepine, valproate), ACE inhibitors have the potential to lower the IgA levels.
Selective IgA deficiency is usually a lifelong disease. However, a few patients may have normal levels of IgA. In contrast, cases progressed to CVID over time have also been recorded. These observations are valid particularly for adolescence or young adulthood. Thus, after an accidental diagnosis of selective IgA deficiency, these patients should follow-up regularly and be evaluated every 4 to 6 months.
The most common complications are associated with respiratory infections – obliterative bronchiolitis, bronchiectasis, and pneumonia – leading to pulmonary damage. An unwelcome complication is developing CVID as well. On the other hand, the most severe complications are related to the association of selective IgA deficiency and malignancies, such as adenocarcinoma of the stomach and lymphoma, which arise in particularly older patients.
Specialist consultation with Allergy/Immunologist may be required. Patients who have recurrent pulmonary infections will benefit from consultation with a pulmonologist.
Patients with selective IgA deficiency should be educated. They are recommended to wear a medical alert bracelet. Patients should be aware of potential anaphylactic reaction following transfusion of blood products. The suitable products for patients with selective IgA deficiency are those prepared from other IgA-deficient individuals or saline-washed red blood cells. However, all blood products should be given with caution, and the healthcare providers should be prepared for potential anaphylaxis. Furthermore, it is recommended for both asymptomatic and symptomatic patients to be monitored periodically for anti-IgA antibodies.
Selective IgA deficiency is a disorder that requires an interdisciplinary healthcare team to provide the best diagnostic process, management, and follow-up of the patients. Physicians including pediatricians and primary care physicians should be involved in the care of these patients. Specialist consultation from an allergist or immunologist may be required. Patients who have recurrent pulmonary infections will benefit from a consultation with a pulmonologist. Nurses should educate these patients on the importance of vaccinations and compliance with antibiotics.
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