Continuing Education Activity
Immunoglobulin A (IgA) deficiency is a common primary immunodeficiency characterized by undetectable serum IgA, a concomitant lack of secretory IgA, and normal levels of other immunoglobulins. IgA deficiency should be distinguished from any other cause of hypogammaglobulinemia or T lymphocyte defect. This activity describes the evaluation and treatment of IgA deficiency and highlights the role of the interprofessional team in managing patients with this condition.
- Identify the etiologies of Immunoglobulin A deficiency.
- Describe the management of Immunoglobulin A deficiency.
- Describe any further evaluations that should be considered in patients with Immunoglobulin A deficiency.
- Explain the role of interprofessional team members in evaluating and treating patients with Immunoglobulin A deficiency.
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.
IgA deficiency is often associated with normal CD4 and CD 8 T cells, with normal B lymphocytes in the systemic circulation. In some patients, there may be anti-IgA autoantibodies present.
Most patients with IgA deficiency are asymptomatic. There is a small percentage of patients that will go on to develop common variable immunodeficiency. Primary IgA deficiency is a permanent disorder. Secondary causes may be due to infection or medications, but these cases are reversible. Recent studies reveal that close to 20-30% of patients with IgA deficiency may develop severe respiratory tract infections and others may be at risk for developing adverse reactions to blood products. Since IgG anti-IgA antibodies may cause transfusion reactions if given whole blood, they should be administered IgA poor or washed red cells.
IgA is the 2nd most common antibody in human serum and is predominantly found in mucosal secretions. There are 2 forms of IgA. The majority of serum IgA is monomeric while the secretory IgA is a dimer that carries an extra protein fragment that makes it resistant to proteolytic enzymes found in mucosal secretions. These secretory IgA antibodies can bind to toxins, neutralize viruses and prevent bacteria from adhering to the mucosal epithelial cells.
Since the selective IgA deficiency is a heterogeneous disorder, several etiological causes and/or modifier genes are discussed, including intrinsic defects in B cells, anomalies in T-cell help, alterations of the cytokine network, and others.
Recent studies indicate that the mucosal IgA response is impaired in COPD. In addition, patients with IgA deficiency may have a higher prevalence of atopy.
IgA deficiency is also seen in ataxia-telangiectasia and other related genetic disorders.
Drugs known to cause IgA deficiency include:
- D penicillamine
- Phenytoin, valproic acid
Infections that may cause transient IgA deficiency include:
- Epstein Barr virus
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.
History and Physical
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:
- Undetectable serum IgA levels (below 0.07 g/l, measured by nephelometry), although normal serum levels of IgG and IgM (evaluated by nephelometry at least twice)
- Enhanced susceptibility to infections, especially respiratory;
- Diagnosis at an age older than 4 years
- Concomitant autoimmune diseases and/or a family member with the disease
- Excluded secondary causes of hypogammaglobulinemia
- Normal antibody (IgG) response to all vaccinations
- Exclusion of T-cell defect
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 control 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.
Pulmonary function tests are recommended to follow patients with IgA deficiency. Patients with recurrent diarrhea should undergo jejunal biopsy which may show blunting of the villi. The histopathology may reveal the absence of IgA secreting cells and the presence of IgM secretory cells in the lamina propria.
Treatment / Management
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 diet may have to be altered in patients with food allergies and those with food malabsorption.
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.
More evidence seems to indicate that IgA deficiency is common in COPD. Children with the disorder may be increasingly susceptible to respiratory tract infections. More important, these patients also seem to have a higher rate of atopy, drug allergies, and food hypersensitivity. Reports also indicate that the rates of certain cancers may be higher in patients with IgA deficiency, but the subject remains debatable. There is also a high risk of lung damage in patients with recurrent viral and bacterial infections.
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.
Deterrence and Patient Education
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.
Enhancing Healthcare Team Outcomes
Selective IgA deficiency is a disorder that requires an interprofessional 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 work with the team to educate these patients on the importance of vaccinations and compliance with antibiotics. Those with food allergies and malabsorption may benefit from a dietary consult.
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. To improve the quality of life and lower morbidity, an interprofessional team approach is vital.