Selective IgA Deficiency - Clinical Manifestations, Pathophysiology, and Diagnosis - UpToDate

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Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis
Author: Robert W Hostoffer, DO, FACOP, FAAP, FACOI, FCCP

Section Editor: E Richard Stiehm, MD
Deputy Editor: Anna M Feldweg, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2017. | This topic last updated: Aug 31, 2015.
INTRODUCTION Selective IgA deficiency (sIgAD) (MIM 137100) may be defined as the isolated deficiency of
serum immunoglobulin A (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 elsewhere. (See "Structure and biologic functions of
IgA".)
DEFINITION Selective IgA deficiency (sIgAD) is defined as decreased serum immunoglobulin A (IgA) levels in
the context of normal serum levels of immunoglobulin G (IgG) and immunoglobulin M (IgM) and in the absence
of any other immunodeficiency disorder. The diagnosis should only be made after four years of age, since
antibody levels in younger children can be depressed in the absence of any immune dysfunction. (See
'Diagnosis' below.)
NORMAL BIOLOGY OF IgA Immunoglobulin A (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 "Function
and clinical applications of immunoglobulins".)
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 overgrown.
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PATHOPHYSIOLOGY OF IgA DEFICIENCY Despite the apparent importance of immunoglobulin A (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 immunoglobulin M (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]. Most IgA-
deficient patients (although not all [5]) appear to have increased production of secretory IgM [6,7]. IgA and IgM
have evolutionary, structural, and functional similarities. These include homologies between the primary constant
chain domains and the tail pieces, the presence of a J chain in both, the formation of polymers, and the ability to
bind the basolateral polymeric immunoglobulin receptor on mucosal epithelial cell, thereby forming secretory
immunoglobulin molecule that contains the epithelial secretory component. The glycan moieties are also similar
in IgA and IgM molecules [8-10].
Selective 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.
Normal B cell development The initial steps in B cell maturation are independent of antigen stimulation and
take place in the liver during gestation and in the bone marrow after birth. (See "Normal B and T lymphocyte
development".)
While in the bone marrow, hematopoietic stem cells normally progress to pre-B cells, which do not demonstrate
surface immunoglobulin receptors, but contain a cytoplasmic mu () heavy chain [11]. These mu chains are
eventually expressed on the cell surface in association with a pseudolight chain. Failure to progress beyond the
pre-B cell stage results in agammaglobulinemia [12,13]. (See "Agammaglobulinemia", section on
'Pathophysiology'.)
Subsequent steps in B cell maturation occur after B cells interact with exogenous antigen and/or regulatory T
cells. These constitute the antigen-dependent phase and correspond to the generation of the humoral immune
response. Further, normal B cell development results in the cell surface expression of IgM followed by surface
expression of IgG, IgA, IgD, or IgE, together with IgM [14]. The specific immunoglobulin isotype found with IgM
determines the antibody isotype the individual cell eventually secretes. (See "The humoral immune response".)
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 upon 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-21 (IL-21), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-7 (IL-7), or interleukin-10 (IL-
10), although other mechanisms have also been proposed [15-21]. B cells found in IgA deficiency patients show
a decrease in the frequency of switched memory B cells, transitional cells, and plasmablasts, as well as an
increase in CD21low CD38low subset [22].
T regulatory cells The mean percentage of T regulatory cells (CD4+, CD25high, FoxP3+ T cells) was
significantly lower in 26 children (ages 4 to 17 years) with sIgAD compared with normal controls [23]. When
patients 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 is
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 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 [24]. B cells in these patients expressed TACI,
but did not produce IgG and IgA in response to the TACI ligand, suggesting impaired isotype-switching
[25,26]. (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 [27-35].
Long- or short-arm deletion and ring formation have been described in some patients who are also
intellectually disabled and exhibit additional dysmorphic features [32]. These findings are probably not
relevant to asymptomatic IgA-deficient patients.
MHC loci associations Associations have also been identified between sIgAD and several genes of the
major histocompatibility complex (MHC) [35-43].
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 (1IFIH1) and the C-type lectin domain family 16 gene (CLEC16A) [44]. Mutations in these
loci are also associated with autoimmune disorders [42]. These findings draw a loose connection between
sIgAD and an autoimmune diathesis, although further studies are necessary to show causality.
EPIDEMIOLOGY OF IgA DEFICIENCY Selective IgA deficiency (sIgAD) is the most common immunologic
defect in humans [45]. 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 Caucasian, Black, and Middle Eastern populations [46-
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 immunoglobulin A (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 [27].
CLINICAL MANIFESTATIONS IN SYMPTOMATIC PATIENTS
Overview The majority of individuals with selective IgA deficiency (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
Gastrointestinal infections and other intestinal disorders
Allergic disorders
Anaphylactic transfusion reactions
Serum levels of immunoglobulin A (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 immunoglobulin M (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].
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 gender-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 a primary immunodeficiency [70,71]. 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
[72-75]. (See "Epidemiology, clinical manifestations, and diagnosis of giardiasis".)
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 immunoglobulin G (IgG) and IgG1 subclass antibodies compared with normal controls [76].
Gastrointestinal disorders (noninfectious) Celiac disease and inflammatory bowel disease occur with
increased prevalence in patients with sIgAD [42,77]. (See "Pathogenesis, epidemiology, and clinical
manifestations of celiac disease in adults".)
Celiac disease Screening programs have detected celiac disease in up to 8 percent of patients with sIgAD
[42,78], and 1 to 2 percent of all patients with celiac disease have sIgAD [79]. 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 [80-83].
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) [84-87]. It is discussed elsewhere. (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 [88-98]. 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 gammaglobulin (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 elsewhere. (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 [66,99].
Autoimmune disorders and autoantibodies Among patients followed in immunology clinics, approximately
20 to 30 percent of patients with sIgAD develop autoimmune disorders [42,66,100,101]. 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 [42,102-114].
Individuals with sIgAD have an increased prevalence of autoantibodies without symptoms of overt autoimmune
disease [100,115-119]. 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 [115]. Subjects were evaluated for
21 different autoantibodies, and reactivity to the following antigens was identified:
Sulfatide (32 percent of patients)

Jo-1 (28 percent)
Cardiolipin (21 percent)
Phosphatidylserine (20 percent)
Asialo-GM1 (21 percent)
Sm (15 percent)
Sulfoglucuronyl paragloboside (11 percent)
Collagen type I (10 percent)
False-positive pregnancy tests have been reported in IgA-deficient women, a phenomenon that has been
attributed to the presence of heterophile antibodies [120]. Heterophile antibodies are discussed elsewhere. (See
"Infectious mononucleosis in adults and adolescents".)
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 [42,121].
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 [122].
Other immunodeficiencies IgA deficiency is associated with:
Common variable immunodeficiency Some cases of sIgAD may progress to CVID [123-128]. 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 [27,28,129]. 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 [126,130]. (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 [131]. (See "T-B-NK+ SCID:
Pathogenesis and genetics", section on 'Recombination-activating gene (RAG) complex'.)
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 is only found in adults but not
in the pediatric population [132].
EVALUATION AND DIAGNOSIS
Indications for evaluation An evaluation for selective IgA deficiency (sIgAD) should be considered in the
following patients:
A child with recurrent otitis media, sinusitis, and/or pneumonia. The evaluation of serum immunoglobulins in
children is best undertaken after the age of six months, since maternal immunoglobulins (particularly IgG)
are present until this age. 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.
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 upon the finding of an isolated deficiency of serum IgA (ie, IgG
and IgM levels are normal) in a patient older than four years of age in whom other causes of
hypogammaglobulinemia have been excluded. 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 [133]. Observations about the natural history of sIgAD are reviewed
elsewhere. (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 [134]:
Severe deficiency/definitive diagnosis 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 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 2 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.
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).
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.
Further evaluation Further evaluation depends upon 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 IgE is also appropriate as a screen
for allergic disease.
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) [135]. (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
immunoglobulin 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 [101]. (See "Assessing the immunologic response to
vaccination" 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 [42,66]. 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 [103]. (See
"Diagnosis of celiac disease in adults", section on 'Suggestive clinical features but negative serologic tests'.)
DIFFERENTIAL DIAGNOSIS The differential diagnosis of selective IgA deficiency (sIgAD) includes other
primary immunodeficiencies and secondary IgA deficiency due to medications.
Other primary immunodeficiencies The following alternative diagnoses should be excluded in patients with
isolated deficiency of serum IgA:
Transient hypogammaglobulinemia of infancy Transient hypogammaglobulinemia of infancy (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 Patients with sIgAD who developed common variable
immunodeficiency (CVID) over time have been reported [124]. 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.
(See 'Other immunodeficiencies' above and "Clinical manifestations, epidemiology, and diagnosis of
common variable immunodeficiency in adults".)
IgA deficiency may be detected in a patient with another more severe immunodeficiency, as discussed
previously. (See 'Other immunodeficiencies' above.)
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 [136].
Examples of drugs that may cause reversible reductions in serum IgA levels include the following:
Anticonvulsants [137], including phenytoin [138-141], valproic acid [107], carbamazepine [142], and
zonisamide [143]
D-penicillamine [144-146]
Aurothioglucose [147]
Captopril [148,149]
Sulfasalazine [150]
Fenclofenac [151]
Gold [152]
Thyroxine [153]
Cyclosporine [136]
SUMMARY
Selective IgA deficiency (sIgAD) (MIM 137100) may be defined as the selective deficiency of serum
immunoglobulin A (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' above.)
IgA is concentrated in mucosal secretions and is believed to be important in the immune functioning of the
mucosal barrier. However, the vast majority of patients with sIgAD do not suffer from increased infections,
possibly because there are redundant immune mechanisms that can compensate in most IgA-deficient
individuals. (See 'Normal biology of IgA' above and 'Pathophysiology of IgA deficiency' above.)
IgA deficiency is considered the most common immunodeficiency in humans, with prevalence ranges from 1
in 100 to 1 in 1000 in Caucasian, Black, and Middle Eastern populations. It is less common in Asian
populations. The pathophysiology is unknown. (See 'Epidemiology of IgA deficiency' above and
'Pathophysiology of IgA deficiency' above.)
Only a minority of IgA-deficient individuals 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.)
Evaluation begins with measurement of serum levels of IgA, IgG, and 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. Further evaluation depends upon the patient's clinical presentation. (See 'Evaluation and
diagnosis' above.)
Two severities of IgA deficiency 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. (See 'Diagnosis' above.)
sIgAD is a diagnosis of exclusion. Other disorders which must be considered include several other immune
disorders and secondary IgA deficiency due to medications. (See 'Differential diagnosis' above.)
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Topic 3963 Version 16.0
GRAPHICS
Nodular lymphoid hyperplasia
Nodular mucosa of the terminal ileum seen at colonoscopy in a patient later

proven to have common variable immunodeficiency (CVID). Nodularity was also
visible in the proximal colon.
Reproduced with permission from: Eric D Libby, MD.
Graphic 80570 Version 3.0
Contributor Disclosures
Robert W Hostoffer, DO, FACOP, FAAP, FACOI, FCCP Nothing to disclose E Richard Stiehm,
MD Consultant/Advisory Boards: ADMA Biologics [Infections of respiratory syncytial virus in organ transplants
(Respiratory syncytial virus immune globulin)]. Anna M Feldweg, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

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7/25/2017 Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis - UpToDate

Official reprint from UpToDate

Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis

Author: Robert W Hostoffer, DO, FACOP, FAAP, FACOI, FCCP

IgA exists in two distinct forms:

PATHOPHYSIOLOGY OF IgA DEFICIENCY Despite the apparent importance of immunoglobulin A (IgA) in

Abnormalities in genes associated with autoimmunity Genome-wide association studies revealed an

CLINICAL MANIFESTATIONS IN SYMPTOMATIC PATIENTS

Recurrent sinopulmonary infections

Sulfatide (32 percent of patients)

Other immunodeficiencies IgA deficiency is associated with:

Recombination-activating gene (RAG) 1 and 2 deficiency This is a form of severe combined

EVALUATION AND DIAGNOSIS

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

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

Transient hypogammaglobulinemia of infancy Transient hypogammaglobulinemia of infancy (THI) may

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1. Yel L. Selective IgA deficiency. J Clin Immunol 2010; 30:10.

Topic 3963 Version 16.0

Nodular lymphoid hyperplasia

Nodular mucosa of the terminal ileum seen at colonoscopy in a patient later

Reproduced with permission from: Eric D Libby, MD.

Graphic 80570 Version 3.0

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