Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis

INTRODUCTION — Selective immunoglobulin A (IgA) deficiency (sIgAD; MIM 137100) may be defined as the isolated deficiency of serum IgA (ie, in the setting of normal serum levels of immunoglobulin G [IgG] and immunoglobulin M [IgM]) in an individual older than four years of age in whom other causes of hypogammaglobulinemia have been excluded [1].

The clinical manifestations of sIgAD are variable, ranging from no symptoms to recurrent infections and autoimmune disease. This topic will review the epidemiology, clinical manifestations, diagnosis, and pathophysiology of sIgAD. The management and prognosis of patients with this disorder are discussed separately. (See "Selective IgA deficiency: Management and prognosis".)

The structure and normal functions of IgA are reviewed separately. (See "Structure and biologic functions of IgA".)

NORMAL BIOLOGY OF IgA — IgA accounts for more than 70 percent of total immunoglobulin in the body. The normal functions of IgA are mentioned briefly here and discussed in detail separately. (See "Structure and biologic functions of IgA".)

IgA exists in two distinct forms:

●Monomeric IgA in the serum – This type of IgA interacts with the phagocytic arm of the immune system. IgA molecules bind foreign antigens through their Fab portions, while the Fc portion binds to the Fc-alpha receptor (CD89) located on the cell surface of neutrophils, eosinophils, and macrophages [2,3]. IgA binding to the receptor initiates ingestion and destruction of the microorganism by the phagocyte. (See "Overview of therapeutic monoclonal antibodies".)

●Dimeric secretory IgA in secretions – This form of IgA is found in saliva, milk, colostrum, tears, and mucosal secretions from the respiratory tract, genitourinary tract, and prostate. It is called secretory IgA and is believed to be important in mucosal immunity. Its actions include coating of microbes to prevent adherence to epithelial cells and neutralization of microbial toxins, as well as dampening of inflammatory pathways that could lead to autoimmune processes. In addition, secretory IgA promotes intestinal homeostasis between the host and commensal bacteria by regulating bacterial communities, favoring commensal organisms in biofilms, and preventing pathogen overgrowth.

PATHOPHYSIOLOGY OF IgA DEFICIENCY — sIgAD is believed to be a heterogeneous disorder that probably arises through several pathogenic mechanisms. The precise molecular defects are unknown. However, most humoral immunodeficiencies arise from either defects in B cells or defective interactions between B and T cells. A brief review of normal B cell development and antibody production is helpful in understanding the theories of pathogenesis.

Despite the apparent importance of IgA in mucosal immunity, the vast majority of patients with IgA deficiency do not experience more frequent or severe infections or overt autoimmune disease. This disconnect between the presumed role of IgA and clinical observations of IgA deficiency is probably explained by the presence of redundant immunologic mechanisms that protect the host. For example, secretory IgM may perform many of the same functions and may compensate for lack of IgA in normal neonates and in patients with IgA deficiency [4]. For example, most IgA-deficient patients (although not all [5]) appear to have increased production of secretory IgM [6,7], and IgA and IgM have evolutionary, structural, and functional similarities [8-10].

B cells in IgA deficiency — In patients with sIgAD, B cells expressing surface IgA are present but appear to be developmentally blocked. Theoretically, the defect resides after the surface coexpression of IgM and IgA, although this has not been established with certainty. Based on animal studies, the failure of B cells to terminally differentiate into plasma cells that secrete IgA may be due to the lack of effects from various cytokines, such as interleukin (IL) 21, IL-4, IL-6, IL-7, or IL-10, although other mechanisms have also been proposed [11-17]. B cells found in IgA-deficient patients show a decrease in the frequency of switched memory B cells, transitional cells, and plasmablasts, as well as an increase in CD21^low CD38^low subset [18].

T regulatory cells — The mean percentage of T regulatory cells (CD4⁺, CD25^high, FoxP3⁺ T cells) was significantly lower in 26 children (ages 4 to 17 years) with sIgAD compared with normal controls [19]. When patients with sIgAD were classified into two groups based on the percentages of T regulatory cells, a greater proportion of those with lower T regulatory cells had autoimmune disorders, pneumonia, and evidence of class-switching defects. These findings await replication and evaluation in other age groups.

Genetic factors — IgA deficiency is associated with several types of genetic abnormalities, although none are known to be causative, and there may be other, more relevant defects that have not been identified.

●Associated molecular defects – The first genetic defect to be identified in patients with sIgAD was a mutation in the tumor necrosis factor (TNF) receptor family member "transmembrane activator and calcium-modulator and cyclophilin ligand interactor" (TACI), a molecule that mediates isotype-switching in B cells. However, TACI mutations/polymorphisms have been identified in only a small subset of patients with sIgAD, as well as in some patients with common variable immunodeficiency (CVID), and it is not clear that these mutations/polymorphisms are directly related to pathogenesis [20]. B cells in these patients expressed TACI but did not produce IgG and IgA in response to the TACI ligand, suggesting impaired isotype switching [21,22]. (See "Pathogenesis of common variable immunodeficiency".)

●Large chromosomal abnormalities – There are conflicting findings concerning the presence or absence of large chromosomal abnormalities. Some studies have reported abnormalities involving chromosomes 16 and 18, while other studies have not found consistent abnormalities within IgA-deficient families [23-31]. Long- or short-arm deletion and ring formation have been described in some patients who are also intellectually disabled and exhibit additional dysmorphic features [28]. These findings are probably not relevant to asymptomatic IgA-deficient patients.

●Major histocompatibility complex (MHC) loci associations – Associations have also been identified between sIgAD and several genes of the MHC [31-39].

●Abnormalities in genes associated with autoimmunity – Genome-wide association studies revealed an association between sIgAD and genetic variants in the genes for interferon-induced helicase C domain-containing protein (IFIH1) and for C-type lectin domain family 16 (CLEC16A) [40]. Mutations in these loci are also associated with autoimmune disorders [38]. In a European genome-wide association study, four loci in a rare IFIH1 variant were found in patients with sIgAD and may lead to the conclusions that sIgAD may be due to a complex network of gene effects. These loci also overlapped with autoimmune markers [41]. These findings draw a loose connection between sIgAD and an autoimmune diathesis, although further studies are necessary to show causality.

EPIDEMIOLOGY OF IgA DEFICIENCY — sIgAD is the most common immunologic defect in humans [42]. It is considered to be a primary humoral immunodeficiency, even though most affected individuals are asymptomatic. Estimates of prevalence are typically obtained through studies of healthy blood donors. Prevalence ranges from 1 in 100 to 1 in 1000 in White, Black, and Middle Eastern populations [43-54]. The condition is less common in Asian populations, with prevalence rates ranging from 1 in 1615 to 1 in 19,000 in different regions of China and Japan [55-57].

Risk factors — The most significant risk factor for having IgA deficiency is a family history of either IgA deficiency or the more profound defect in antibody function, common variable immunodeficiency (CVID). First-degree relatives of affected individuals are 50 times more likely to be affected themselves compared with unaffected people. Affected mothers are more likely than affected fathers to transmit the disorder to their offspring [58,59]. In the Swedish population, a higher frequency of IgA deficiency was found more commonly in monozygotic twins (1 in 241) and dizygotic twins (1 in 198), as compared with the normal population (1 in 600) [60]. However, the exact pattern of inheritance of IgA deficiency remains unclear [23].

CLINICAL MANIFESTATIONS IN SYMPTOMATIC PATIENTS

Overview — The majority of individuals with sIgAD are asymptomatic. Less than one-third come to medical attention and usually present with one or more of the following disorders [61-63]:

●Recurrent sinopulmonary infections

●Autoimmune disorders

●Giardia lamblia infections and other intestinal disorders

●Allergic disorders

●Anaphylactic transfusion reactions

Serum levels of IgA in deficient patients do not necessarily correlate with the occurrence or severity of these disorders, and the pathophysiologic relationship between the deficiency of IgA and the disorders listed above has not been clearly delineated. (See 'Pathophysiology of IgA deficiency' above.)

As with other immune disorders, lymphomas and gastrointestinal malignancies have been reported, but it has not been established that patients with sIgAD are at increased risk for neoplastic disease [64].

Recurrent infections — Some patients with sIgAD suffer from recurrent infections, most often affecting the sinopulmonary tract. Gastrointestinal infections are seen to a lesser degree. Sinopulmonary infections may be more common than gastrointestinal infections in sIgAD because secreted IgM, which may partially compensate for the deficiency of IgA, is more prominent in the gut than the respiratory tract [65].

Sinopulmonary — Children with sIgAD may experience recurrent otitis media, sinusitis, and/or pneumonia. Adults with sIgAD may also suffer from recurrent sinusitis and pulmonary infections, although otitis media is less common [66,67]. These infections are most commonly caused by encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae). There have been several reports of patients presenting with end-organ damage, such as bronchiectasis, due to chronic and recurrent infections [68,69]. There is evidence to suggest that local airway acquired secretory sIgAD of patients with chronic obstructive pulmonary disease may allow chronic bacterial colonization, leading to inflammation and progressive destructive remodeling [70].

Common viral respiratory tract infections (colds), laryngitis, and infectious conjunctivitis were also more common in a case-control study of 32 adults with sIgAD compared with age- and sex-matched controls [66].

It can be difficult to know what constitutes an excessive number of sinopulmonary infections, although immunologic societies have estimated that four or more sinus or ear infections or two or more episodes of pneumonia within a single year is concerning for the presence of an inborn error of immunity (IEI) [71,72]. However, not all patients with this number of infections will be found to have an immune defect. An individual's susceptibility to these common infections can vary tremendously from year to year, depending on multiple factors, such as exposure to children (for adults), variations in the incidence and virulence of common respiratory viruses, stress levels, and other transient fluctuations in health status. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

Gastrointestinal — Some IgA-deficient patients suffer from gastrointestinal infections due to Giardia lamblia [73-76]. (See "Giardiasis: Epidemiology, clinical manifestations, and diagnosis".)

Individuals with IgA deficiency appear to have adequate defenses against other types of gastrointestinal infections. As an example, patients were shown to clear rotavirus infections normally and generate higher levels of total IgG and IgG1 subclass antibodies compared with normal controls [77].

Gastrointestinal disorders (noninfectious) — Celiac disease and inflammatory bowel disease occur with increased prevalence in patients with sIgAD [38,78]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Gastrointestinal manifestations in primary immunodeficiency".)

Celiac disease — Screening programs have detected celiac disease in up to 8 percent of patients with sIgAD [38,79], and 1 to 2 percent of all patients with celiac disease have sIgAD [80]. Patients with celiac disease may present with classic symptoms related to malabsorption, including diarrhea, steatorrhea, weight loss, and nutrient or vitamin deficiencies. However, many patients with celiac disease exhibit only minor gastrointestinal complaints, have nongastrointestinal manifestations, or are asymptomatic. Testing strategies are discussed below. (See 'Patients with symptoms of autoimmune/allergic diseases' below.)

Inflammatory bowel disease — Inflammatory bowel diseases, including ulcerative colitis and Crohn disease, are associated with sIgAD, although the pathophysiologic relationship is unclear [81-84].

●In children and adolescents, inflammatory bowel diseases should be considered in those presenting with loose stools or bloody diarrhea, abdominal pain, weight loss or growth failure, perianal disease, anemia, arthritis, or delayed onset of puberty. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

●Adults with ulcerative colitis usually present with diarrhea that is associated with blood. Accompanying symptoms include colicky abdominal pain, urgency, and tenesmus. Patients may also have fever, fatigue, and weight loss. Ulcerative colitis primarily involves the intestine but may be associated with several extraintestinal manifestations. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)

●Adults with Crohn disease usually present with persistent diarrhea accompanied by abdominal pain with or without gross bleeding, fatigue, and weight loss. Symptoms may be present for years before the diagnosis is made. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

Nodular lymphoid hyperplasia — Nodular lymphoid hyperplasia, also known as follicular lymphoid hyperplasia, is a benign finding in the small intestine that is associated with sIgAD, common variable immunodeficiency (CVID), and gastrointestinal lymphoma (picture 1) [85-88]. It is discussed separately. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Predisposing conditions'.)

Anaphylactic reactions to blood products — Anaphylactic reactions to blood products have been reported in patients with sIgAD, as well as in those with CVID [89-99]. These reactions have been theorized to be due to the presence of antibodies directed against IgA, which can form in some patients with undetectable levels of serum IgA. Reactions occur when anti-IgA antibodies react to small amounts of IgA in plasma or immunoglobulin products. Plasma- or IgA-containing blood products include whole blood, red blood cells, platelets, fresh frozen plasma, cryoprecipitate, granulocytes, or intravenous immune globulin (IVIG) preparations containing IgA. However, only a minority of IgA-deficient patients forms anti-IgA antibodies, and there are several other reasons for anaphylactic reactions to blood products, which are reviewed separately. (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions'.)

Antibodies to IgA are generally only formed in patients whose serum IgA levels are below the limit of detection. The evaluation of such individuals and the evaluation of a patient with sIgAD who has experienced an anaphylactic reaction to a blood product are discussed separately. (See "Selective IgA deficiency: Management and prognosis".)

Allergic diseases and asthma — Food allergies and respiratory allergies (ie, allergic rhinitis and allergic asthma) are prominent in patients with sIgAD, although the true prevalence is not well studied [66,100].

Autoimmune disorders and autoantibodies — Among patients followed in immunology clinics, approximately 20 to 30 percent of patients with sIgAD develop autoimmune disorders [38,66,101,102]. In particular, systemic lupus erythematosus (SLE), Graves' disease, type 1 diabetes, vitiligo, both juvenile- and adult-onset rheumatoid arthritis, immune thrombocytopenia, and myasthenia gravis are associated with sIgAD, although there are some conflicting evidence for the association with myasthenia gravis [38,103-115].

Individuals with sIgAD have an increased prevalence of autoantibodies without symptoms of overt autoimmune disease [101,116-120]. In one series comparing 60 sIgAD patients with a normal control population, 90 percent had detectable autoantibodies, and 40 percent had six or more autoantibodies [116].

False-positive pregnancy tests have been reported in IgA-deficient females, a phenomenon that has been attributed to the presence of heterophile antibodies [121]. Heterophile antibodies are discussed separately. (See "Infectious mononucleosis".)

Theories concerning autoimmunity — At first glance, it appears paradoxical that an autoimmune disorder could develop in the individual with a humoral immunodeficiency disease since this would require the emergence of self-reactive antibodies in a host with defective antibody production. Theories about the relationship between autoimmunity and IgA deficiency include the following:

●Autoimmunity is seen in several types of humoral immunodeficiencies, including sIgAD and CVID. The immune system is normally prevented from damaging self-tissues by the elimination (or negative selection) of cells that strongly react against self-antigens. These mechanisms are believed to be compromised in some humoral immunodeficiencies. (See "Normal B and T lymphocyte development" and "Primary humoral immunodeficiencies: An overview".)

●An alternative theory is that individuals with IgA deficiency have underlying genetic factors that independently predispose to autoimmunity, without there being a direct causal relationship between the IgA deficiency and autoimmune disease. The observation that the prevalence of autoimmune disorders is increased among first-degree relatives of patients with IgA deficiency supports this theory [38,122].

●A third theory posits that the compromised mucosal barrier in sIgAD allows for abnormal passage of food antigens through the gut wall. In some patients, this may lead to the formation of autoreactive antibodies and autoimmune disease due to molecular mimicry between large food proteins, such as milk, and host antigens. One study showed the presence of antibodies against milk in patients with IgA deficiency correlated with an increased frequency of serum autoantibodies [123].

ASSOCIATED DISORDERS

Other inborn errors of immunity — IgA deficiency is associated with several inborn errors of immunity (IEI; previously "primary immunodeficiencies") [124]:

●Humoral deficiencies – Some cases of sIgAD may progress to common variable immunodeficiency (CVID) [125-130]. In addition, families have been described in which affected individuals progress from a normal immunologic state to IgA deficiency with and without IgG subclass deficiency or CVID [23,24,131]. The propensity to progress to CVID may be stronger in familial and major histocompatibility complex (MHC) associated sIgAD or in patients with 18q deletion syndrome [128,132]. In these cases, genetic testing may assist in defining specific humoral deficiencies. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

●IgG2 subclass deficiency – Deficiency in IgG2 has been described both as an isolated finding and in combination with IgG4 and/or IgA deficiency. (See "IgG subclass deficiency", section on 'IgG2 deficiency'.)

●Ataxia-telangiectasia – This is a disorder that presents in early childhood with progressive cerebellar ataxia, abnormal eye movements, other neurologic abnormalities, oculocutaneous telangiectasias, and immunodeficiency. (See "Ataxia-telangiectasia".)

●DiGeorge syndrome – This presents with conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia, often in the setting of developmental delay and frequent infections. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●Recombination-activating gene (RAG) 1 and 2 deficiency – This is a form of severe combined immunodeficiency (SCID) involving a defect in lymphocyte gene rearrangement [133]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'RAG complex (initiation of recombination)'.)

Risk for cancer — Individuals with IgA deficiency have been found to have a moderately increased risk of developing cancer, particularly involving the gastrointestinal tract. This relationship has only been found in adults [134].

EVALUATION AND DIAGNOSIS

Indications for evaluation — An evaluation for sIgAD is appropriate in the following patients:

●A child with recurrent otitis media, sinusitis, and/or pneumonia

●An adult with recurrent/chronic sinusitis or pulmonary infections

●A patient of any age with one or more of the following:

•Absence or low level of IgA on routine immunoglobulin examination

•Celiac disease

•Gastrointestinal infection with Giardia lamblia

•Unexplained and recurrent autoimmune phenomena

•A family history of IgA deficiency or common variable immunodeficiency (CVID)

•A past anaphylactic reaction to blood products

Initial laboratory evaluation — The initial evaluation should include the measurement of serum concentrations of IgA, IgG, and IgM. A repeat level of IgA should be done to confirm the initial test to ensure accurate diagnosis. In sIgAD, only IgA is low. Serum levels of IgG and IgM levels must be normal. In contrast, patients with CVID have low levels of IgG plus low levels of IgA, IgM, or both.

Diagnosis — The diagnosis of sIgAD is based on the finding of an isolated deficiency of serum IgA in the presence of normal IgG and IgM levels in a patient older than four years of age in whom other causes of hypogammaglobulinemia have been excluded.

The evaluation of any serum immunoglobulins in children is best undertaken after the age of six months since maternal immunoglobulins (particularly IgG) are present until this age, although maternal IgA does not cross the placental barrier to a significant degree under normal circumstances. For this reason, children with antibody defects do not generally present with recurrent infections until this age, when maternal antibodies have been cleared and the child's underlying deficiency is unmasked.

In children younger than four years, the diagnosis should be considered preliminary, and the child should be monitored over time to see if IgA levels normalize. IgA levels may normalize as late as adolescence [135]. Observations about the natural history of sIgAD are reviewed separately. (See "Selective IgA deficiency: Management and prognosis", section on 'Prognosis'.)

Two severities of sIgAD have been distinguished, which correlate with the certainty of the diagnosis [136]:

●Severe deficiency/definitive diagnosis – A patient greater than four years of age with a serum IgA concentration of less than 7 mg/dL (the lower limit of detection for most assays) and normal serum levels of IgG and IgM. Other causes of hypogammaglobulinemia must be excluded.

●Partial deficiency/probable diagnosis – A patient greater than four years of age with a serum IgA concentration higher than 7 mg/dL but below the lower limit of normal (defined as two standard deviations below the age-adjusted mean value). Serum levels of IgG and IgM must be normal, and other causes of hypogammaglobulinemia must be excluded.

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 [137,138].

Functional testing of the patient's humoral immune response using vaccine challenge is not part of the diagnostic criteria for sIgAD. However, this evaluation is indicated in a patient with recurrent sinopulmonary infections, as discussed in the next section.

IgA deficiency with recurrent sinopulmonary infections and poor antibody response, particularly to polysaccharide antigens, may suggest that the underlying diagnosis of specific antibody deficiency or CVID is more appropriate. The evaluation may then progress to B cell phenotyping or immune genetic evaluation to define other humoral deficiencies.

Further evaluation — Further evaluation depends on the patient's clinical presentation. This may include a complete blood count (CBC) with differential, chemistry panel, screening tests for autoimmunity (antinuclear antibodies and thyroid autoantibodies), and screening tests for chronic infection or inflammation (erythrocyte sedimentation rate [ESR] and/or a C-reactive protein [CRP]). A total serum immunoglobulin E (IgE) is also appropriate as a screen for allergic disease.

The measurement of IgA in specific bodily fluids is considered a research tool and is not recommended, since IgA levels in secretions are highly variable. Patients with measurable serum IgA levels have sufficient secretory IgA, and patients with low serum IgA levels (<7 mg/dL) can be assumed to have little or no secretory IgA. There is also no need to measure IgA isotypes (IgA1 and IgA2).

Patients with recurrent infections — Sinus imaging and chest radiography should be considered if there is a history of lower or upper respiratory infection. In addition to serum levels of IgA, IgG, and IgM, a CBC with differential and total hemolytic complement (THC or CH50) assay should be obtained to screen for other immunologic causes of recurrent infections. If the serum IgG level is normal, then IgG subclasses should be measured as IgG2 subclass deficiency may coexist with IgA deficiency (which is designated IgA deficiency with IgG subclass deficiency) [139]. (See "Laboratory evaluation of the immune system" and "IgG subclass deficiency".)

Patients with sIgAD may have normal or impaired responses to protein and polysaccharide antigens, although antibody function is not part of the diagnostic criteria. Still, assessment of vaccine responses is clinically useful because, if it is impaired, then the cause of the patient's recurrent infections has been identified and immune globulin replacement therapy is sometimes indicated. In addition, patients with impaired antibody function should be monitored for evolution to CVID. IgA-deficient patients with immune abnormalities are more likely to suffer from severe and progressive infections [102]. (See "Assessing antibody function as part of an immunologic evaluation" and "Selective IgA deficiency: Management and prognosis".)

Patients with symptoms of autoimmune/allergic diseases — Patients with sIgAD have a higher incidence of celiac disease, rheumatoid arthritis, Graves' disease, type 1 diabetes, myasthenia gravis, asthma, upper respiratory allergy, and food allergy [38,66]. Suggestive clinical clues should be followed up by appropriate investigations. When screening for celiac disease in patients with sIgAD, IgG-antigliadin antibodies or an IgG test for tissue transglutaminase is preferable to IgA-based assays, as the latter may be falsely negative [104]. (See "Diagnosis of celiac disease in adults", section on 'Negative serology'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of sIgAD includes other inborn errors of immunity (IEI) and secondary IgA deficiency due to medications.

Other inborn errors of immunity — IgA deficiency may be detected in a patient with another, more severe immunodeficiency, as discussed previously (see 'Associated disorders' above). In particular, the disorders below should be excluded in infants and older patients, respectively:

●Transient hypogammaglobulinemia of infancy (THI) – THI may be defined as a prolongation of the "physiologic" hypogammaglobulinemia of infancy, which is normally observed during the first three to six months of life. Vaccine responses are normal in children with THI. The diagnostic criteria for THI vary somewhat worldwide. Most definitions require that IgG be reduced, with or without reductions in other immunoglobulin classes, but some criteria accept an isolated low IgA level as sufficient for the diagnosis. Because of the changing nature of immunoglobulin levels in young children, THI is an appropriate diagnosis for children under four years of age with low immunoglobulin levels, whereas the diagnosis of sIgAD is best deferred until the child is older than four. (See "Transient hypogammaglobulinemia of infancy".)

●Evolving common variable immunodeficiency (CVID) and other humoral immunodeficiencies – Patients with sIgAD who developed CVID over time have been reported [126]. Therefore, patients who continue to suffer from repeated infections and develop conditions associated with CVID, such as autoimmune hemolytic anemia or thrombocytopenia, should have IgG levels and vaccine responses assessed periodically. The diagnosis of CVID requires low IgG and low IgA or low IgM, in conjunction with impaired vaccine response. In these cases, B cell phenotyping or immune genetic testing may elucidate the humoral etiology that is responsible for the deficit. (See 'Associated disorders' above and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Drug-induced immunoglobulin disorders — Several medications can cause low levels of IgA, usually in combination with reductions in serum levels of other immunoglobulin classes. Most of these are reversible with discontinuation of the responsible medication, although cyclosporine A has been reported to cause permanent IgA deficiency even after the drug has been stopped [140].

Examples of drugs that may cause reversible reductions in serum IgA levels include the following:

●Antiseizure medications [141], including phenytoin [142-145], valproic acid [108], lamotrigine [146], carbamazepine [147], and zonisamide [148]

●D-penicillamine [149-151]

●Aurothioglucose [152]

●Captopril [153,154]

●Sulfasalazine [155]

●Fenclofenac [156]

●Gold [157]

●Thyroxine [158]

●Cyclosporine [140]

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)".)

SUMMARY

●Definition and role of IgA – 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. IgA is concentrated in mucosal secretions and is believed to be important in the immune functioning of the mucosal barrier. (See 'Introduction' above and 'Normal biology of IgA' above.)

●sIgAD is usually asymptomatic – The vast majority of individuals with sIgAD do not suffer from increased infections or other disorders, possibly because there are redundant immune mechanisms that can compensate in most IgA-deficient individuals. The pathophysiology is largely unknown and may result from several different mechanisms. (See 'Pathophysiology of IgA deficiency' above.)

●sIgAD is common – sIgAD is considered the most common immunodeficiency in humans, with prevalence ranges from 1 in 100 to 1 in 1000 in White, Black, and Middle Eastern populations. It is less common in Asian populations. (See 'Epidemiology of IgA deficiency' above.)

●Disorders in symptomatic patients – A minority of individuals with sIgAD are symptomatic. These patients may develop recurrent sinopulmonary infections, autoimmune disorders, gastrointestinal disorders, allergic diseases, and rare anaphylactic reactions to blood products. (See 'Clinical manifestations in symptomatic patients' above.)

●sIgAD is a diagnosis of exclusion – Evaluation begins with measurement of serum levels of IgA, immunoglobulin G (IgG), and immunoglobulin M (IgM). Serum levels of IgG and IgM levels must be normal to consider the diagnosis of sIgAD. A low level of IgA must be confirmed with a repeat measurement. Two severities of sIgAD are distinguished. A serum IgA level <7 mg/dL is considered severe deficiency. Partial deficiency refers to a level above 7 mg/dL but below the lower limit of age-adjusted normal. Further evaluation depends upon the patient's clinical presentation. (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – Other disorders in which serum IgA may be low include several other immune disorders and secondary IgA deficiency due to medications. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.