INTRODUCTION AND DEFINITION — Selective immunoglobulin A (IgA) deficiency (sIgAD) (MIM 137100) is defined as the isolated deficiency of serum IgA (ie, serum levels of immunoglobulin G [IgG] and immunoglobulin M [IgM] are normal) in a patient older than four years of age in whom other causes of hypogammaglobulinemia have been excluded. It is the most common primary antibody defect in humans.
●Severe IgA deficiency refers to serum levels below 7 mg/dL, which is the lower limit of detection for most assays.
●Partial IgA deficiency refers to serum levels above 7 mg/dL but below the lower limit of normal (ie, lower than 2 standard deviations below the age-adjusted mean).
Note that some experts do not distinguish severe and partial deficiencies and reserve the diagnosis of IgA deficiency for patients with levels below 7 mg/dL [1,2].
The clinical manifestations of sIgAD range from an asymptomatic laboratory finding to recurrent infections and autoimmune disease. This topic reviews the management and prognosis of patients with sIgAD. The clinical features, pathophysiology, and diagnosis are discussed separately. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)
MANAGEMENT — All individuals with sIgAD should not only be informed about the associated conditions but also reassured that the majority of people with this laboratory finding are healthy and live normal lives.
Review medications — Several medications are associated with IgA deficiency (eg, anticonvulsants, sulfasalazine, certain nonsteroidal anti-inflammatory drugs, etc), and efforts to discontinue these medications should be made. A more detailed discussion of the drugs associated with IgA deficiency is found elsewhere. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Drug-induced immunoglobulin disorders'.)
Vaccinations — The following recommendations concern vaccination of patients with sIgAD:
●For asymptomatic individuals with partial IgA deficiency, there are no special restrictions for vaccine use.
●For patients with severe sIgAD, certain live viral vaccines are contraindicated because patients with humoral immunodeficiencies can develop disseminated infections. Specifically, oral polio vaccine, Bacille Calmette-Guérin, and yellow fever should not be given, especially in those with associated IgG subclass deficiency [3].
●In patients in whom the diagnosis of sIgAD is preliminary because an immune evaluation is incomplete, a more cautious approach is warranted, and live local vaccines (eg, intranasal influenza and live rotavirus) should also be avoided until the evaluation is complete. These additional restrictions are warranted because IgA deficiency can be a finding in other more severe immunodeficiencies (eg, ataxia-telangiectasia), which preclude a wider array of live vaccines.
●Other vaccines, such as the pneumococcal vaccine, are specifically recommended for patients with sIgAD to help reduce the risk of sinopulmonary infections [3].
Asymptomatic patients — Most people with partial IgA deficiency are asymptomatic. These individuals require no specific treatment beyond education. Patients with severe sIgAD are less likely to be entirely asymptomatic, although this is still possible. If an asymptomatic person with severe sIgAD has received blood products at any point, then he/she should be checked for anti-IgA antibodies.
Monitoring — There is no consensus about how asymptomatic patients should be monitored. The approach of the author and editors of UpToDate is to ask patients to return at periodic intervals to review the frequency of infections, as well as a thorough review of systems. We also suggest checking levels of IgA, IgG, and IgM periodically.
Symptomatic patients — Symptomatic patients with sIgAD are managed according to the disorder present.
Sinopulmonary infections — The most common clinical manifestation of symptomatic sIgAD is recurrent sinopulmonary infections or recurrent otitis media in younger children, which may impact the patient's full participation in life (school, job, social functioning). Patients may benefit from several interventions to prevent or reduce the frequency of these illnesses, such as treatment of concomitant rhinitis or asthma, prophylactic antibiotics, or if these measures are insufficient, immune globulin therapy.
Treat concomitant disorders — The finding of sIgAD in a patient with recurrent infections does not exclude other causes of sinopulmonary infections. Patients with sIgAD may also have chronic rhinosinusitis, allergic rhinitis/asthma, or chronic nonallergic rhinitis. These other conditions could be more important causes of recurrent infection. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis" and "An overview of asthma management" and "Chronic nonallergic rhinitis".)
Prophylactic antibiotics — For patients with continued infections despite management of underlying conditions, a six-month course of daily prophylactic antibiotics can be instituted. Maintenance prophylactic antibiotics may be continued if the initial course is successful. It may also be possible to administer these antibiotics only during the winter, depending upon the patient's historic pattern of infections. The use of prophylactic antibiotics in immunodeficiency disorders is reviewed in more detail separately. (See "Primary immunodeficiency: Overview of management", section on 'Prophylactic antimicrobial therapy'.)
Immune globulin — A trial of immune globulin replacement therapy may occasionally be warranted in patients with recurrent infections if prophylactic antibiotics fail to diminish the number of infections, particularly if there is an associated antibody deficiency and/or subclass deficiency. In our experience, only a small minority of patients with sIgAD require immune globulin to control infections. This therapy does not replete IgA in the serum or secretions but rather provides pathogen-specific IgG pooled from the general adult population.
Immune globulin replacement may be administered intravenously or subcutaneously (table 1). Anaphylaxis to subcutaneous immune globulin (SCIG) is rare. A potential complication of intravenous therapy in sIgA-deficient patients is the presence of anti-IgA antibodies that may cause anaphylaxis [4-9]. To reduce this risk, intravenous preparations with the lowest content of IgA should be utilized whenever possible (table 1). The use of immune globulin in patients with immunodeficiency is reviewed in detail separately. (See "Subcutaneous and intramuscular immune globulin therapy" and "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects", section on 'Preparation'.)
Giardia infection — Patients with sIgAD can become infected with Giardia lamblia from contaminated private wells, public sources, and bottled water. The clinical manifestations and diagnosis of acute and chronic infection are reviewed separately. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis".)
Measures to reduce Giardia exposure through drinking water are discussed separately. (See "Giardiasis: Treatment and prevention", section on 'Counseling and prevention'.)
COVID-19 infection — It is unclear whether sIgAD patients experience a more severe illness course with infection of coronavirus disease 2019 (COVID-19). One small study looking at 11 patients with sIgAD and COVID-19 infection showed a 7.7 fold higher risk of severe disease compared with controls [10]. This may have been due to a diminished mucosal IgA presence, although larger studies are necessary [11].
Autoimmune disorders — The management of patients with sIgAD and autoimmune disease is dictated by the autoimmune disorder present. Associated autoimmune disorders are reviewed elsewhere. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Autoimmune disorders and autoantibodies'.)
The management of autoimmune diseases is discussed in various topic reviews. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults" and "General principles and overview of management of rheumatoid arthritis in adults" and "Systemic juvenile idiopathic arthritis: Treatment".)
Reactions to blood products — Patients with severe sIgAD (ie, undetectable serum IgA) can experience infusion reactions to blood products containing small amounts of IgA, typically in plasma, including the following:
●Whole blood
●Red blood cells
●Platelets
●Fresh frozen plasma
●Cryoprecipitate
●Granulocytes
●Intravenous gammaglobulin (although immune globulin contains very low amounts of IgA compared with other products above)
Anti-IgA antibodies have been identified in severely IgA-deficient patients who experienced infusion reactions to blood products and have been implicated as the cause of these infusion reactions, although it has not been conclusively demonstrated that these antibodies cause the reactions [12]. Indirect evidence in support of the role of anti-IgA antibodies includes the finding that these antibodies are more prevalent in patients with sIgAD who have experienced anaphylaxis compared with those who have not (76 compared with 22 percent in one study of approximately 200 patients) [13].
There are two types of anti-IgA antibodies, which are IgG and IgE, and both may be implicated in adverse reactions to blood products [9,12,14,15]. IgE anti-IgA is much less common than IgG anti-IgA. IgE anti-IgA was demonstrated in only 1 individual in a series of 46 IgA-deficient patients, and this individual had life-threatening anaphylaxis in response to intravenous gammaglobulin [6]. Despite these uncertainties, the diagnosis of IgA-related anaphylaxis is usually assumed if a patient experiences infusion-related anaphylaxis and has undetectable serum IgA combined with anti-IgA antibodies of either type.
Most patients with sIgAD do not form anti-IgA antibodies. These antibodies are usually only found in patients with undetectable serum IgA. Even among severely IgA-deficient individuals, antibodies to IgA are rare. In studies of blood donors, anti-IgA antibodies where detected in severely IgA-deficient patients at a frequency of approximately 1 in 1200 to 1600 [13,16]. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Anaphylactic reactions to blood products'.)
In the past, assays for anti-IgA antibodies were time consuming and limited to research or blood bank laboratories [17]. However, a commercial assay is available for the detection of IgG against IgA [18,19]. There is no commercial test for IgE anti-IgA, but a positive test for the IgG isotype assumes that the patient might also be capable of producing IgE against IgA.
Indications for screening for anti-IgA antibodies — We suggest screening for anti-IgA antibodies in all patients with severe sIgAD and in patients with partial sIgAD who have experienced an infusion reaction to a blood product in the past. Screening for anti-IgA antibodies allows clinicians to identify patients at risk for infusion reactions and helps these patients become informed about the potential risks of receiving blood products.
Preparation for future treatment — Patients with severe sIgAD, either with or without positive screening tests for anti-IgA antibodies (as patients with negative screens can become sensitized over time), are advised to obtain a medical alert bracelet/necklace inscribed with the following information:
●The patient has sIgAD.
●The patient is at risk for an allergic reaction to any injected plasma-containing blood products, and testing for anti-IgA antibodies should be performed before such blood products are administered.
Safe administration of blood products — All blood products should be used with caution in IgA-deficient patients, and appropriate staff and medication should be available to treat anaphylaxis [20].
Patients who have already experienced an infusion reaction to plasma-containing blood products should be tested for anti-IgA antibodies prior to receiving any additional blood products. If positive, a strategy should be devised for safe administration of future blood products. The approach will differ depending upon the blood product needed. Consultation with a transfusion medicine specialist should be considered [21]. Examples include the following:
●Patients who require transfusions of red blood cells can receive cells that have been washed to remove as much of the contaminating IgA as possible [17,18,22]. (See "Immunologic transfusion reactions".)
●Patients who require immune globulin therapy can receive products that are low in IgA content or receive the therapy subcutaneously. (See "Subcutaneous and intramuscular immune globulin therapy", section on 'IgA-deficient patients'.)
Desensitization to blood products is another approach that may be appropriate in specific circumstances. A case report described desensitization of a patient with sIgAD who experienced anaphylaxis to blood products but subsequently required numerous infusions of various blood products in the context of liver transplant. The patient was successfully desensitized to a gammaglobulin preparation, which was then administered weekly to maintain the desensitized state [23].
PROGNOSIS — The prognosis of sIgAD is not well-studied, although studies have found the following:
●Severe sIgAD in children usually persists, whereas partial sIgAD in children may resolve over time, particularly if no other primary immune disorder is present [24-26]. This was demonstrated in a study that followed 40 children with severe sIgAD and 40 with partial deficiency [26]. At four years after initial diagnosis, serum levels remained low in those with severe deficiency but had risen to normal in one-half of those with partial deficiency.
●sIgAD can progress to common variable immunodeficiency [27-32]. This tended to occur in adolescence or young adulthood in the available case reports. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Pathophysiology of IgA deficiency'.)
●The prognosis of IgA deficiency diagnosed in adulthood is not well-studied, and it is not known if the condition spontaneously remits in a subset of individuals.
Data indicating that the severity of sIgAD (ie, serum IgA levels) impacts prognosis are lacking. Ultimately, prognosis probably depends largely upon the presence and severity of associated disorders or progression of the immunodeficiency.
Risk of malignancy — Patients with sIgAD have been determined to have a moderately increased risk of cancer, particularly involving the gastrointestinal tract. The risk was found more significant in adults than children [33].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
INFORMATION FOR PATIENTS — Information for patients about sIgAD is available online through the Immune Deficiency Foundation [34].
SUMMARY AND RECOMMENDATIONS
●Definition – Selective immunoglobulin A (IgA) deficiency (sIgAD) (MIM 137100) may be defined as the selective deficiency of serum IgA (ie, serum levels of immunoglobulin G [IgG] and immunoglobulin M [IgM] are normal) in a patient older than four years of age in whom other causes of hypogammaglobulinemia have been excluded. (See 'Introduction and definition' above.)
●Most patients are asymptomatic – The majority of patients with sIgAD are asymptomatic. These patients require only education about the condition and periodic monitoring. (See 'Asymptomatic patients' above.)
●Disorders in symptomatic patients – Symptomatic patients with sIgAD most commonly suffer from recurrent sinopulmonary infections, autoimmune disorders, gastrointestinal disorders, and/or associated immunodeficiencies. Anaphylactic transfusion reactions to plasma-containing blood products can occur, although these are rare. (See 'Symptomatic patients' above.)
●Evaluation and management of sinopulmonary infections – Patients with recurrent sinopulmonary symptoms should be evaluated and treated for other conditions predisposing to upper respiratory tract infections (eg, allergic rhinitis/asthma, chronic rhinosinusitis). (See 'Treat concomitant disorders' above.)
•In patients who continue to have sinopulmonary infections despite aggressive management of predisposing conditions (eg, allergic rhinitis/asthma, chronic rhinosinusitis), we suggest a trial of prophylactic antibiotics (Grade 2C). (See 'Prophylactic antibiotics' above.)
•For patients with recurrent sinopulmonary infections, clearly impaired vaccine responses, and no improvement with prophylactic antibiotics, we suggest a trial of immune globulin replacement therapy to reduce the number and severity of infections (Grade 2C). An intravenous or subcutaneous preparation that is low in IgA content is preferred. (See 'Immune globulin' above.)
●Caution with blood products – In patients with undetectable levels of serum IgA and in those with past infusion reactions to plasma-containing blood products, we perform a baseline screening test for anti-IgA antibodies to better assess patients' risk for future infusion reactions to blood products. If these antibodies are identified, various steps can be taken to prevent recurrent reactions, depending upon the blood product needed. (See 'Reactions to blood products' above.)
●Prognosis – Severe sIgAD appears to be a lasting condition, while partial sIgAD sometimes resolves, particularly in children. The risk of malignancy is moderately increased in adults with IgA deficiency. The prognosis of patients with sIgAD probably depends largely upon the presence and severity of associated disorders. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
