Selective immunoglobulin A deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Synonyms and keywords:

Overview

Selective Immunoglobulin A( IgA) deficiency is the most common primary immunodeficiency and is defined as "serum level of IgA equal or below 7mg/dl in the presence of normal level of other immunoglobulins in individuals older than four years of age and in which other causes of hypogammaglobulinemia have been excluded.

Historical Perspective

• Immunoglobulin A was first discovered in the serum by Graber and Williams in 1953.
• Within 10 years, the first cases with selective IgA deficiency were identified in healthy as well as in patients with ataxia telangiectasia.

Classification

Selective IgA deficiency can be classified based on either the laboratory values of B-cells subsets or the clinical phenotype of individuals with the condition.

Classification Based on Memory B cell Population

SIgAD can be classified based on the laboratory values of the B-cell subsets such as naive, IgM memory, switched memory or IgM+CD21- B cells in patients as compared to healthy individuals.

Percentage of switched Memory B cells(CD 19+, CD 21+, IgD-

SIgAD1 Less than 0.4% of switched memory B cells( CD19+, CD21+, IgD-)

SIgAD2 Greater than 0.4% of switched memory B cells( CD19+, CD21+, IgD-)

Classification Based on the Clinical Phenotype

• Health related quality of life(HRQL)can be compromised by the severity of symptoms in patients with selective IgA deficiency. It is classified based on the clinical presentation of the patients suffering from it.

Clinical Phenotypes	Description
Asymptomatic	About 60% of the patients have no clinical findings. Care should be taken while transfusing blood or blood products Regular monitoring i.e every 4-6 months is required as the disease may progress Patient should be educated but no therapeutic intervention is required ]]
Minor Infections	About 12% of the patients have minor infection phenotype. Quality of life ( QoL) both in physical and mental components are significantly decreased in patients with this phenotype. Infections are usually caused by viral or bacterial agents that normally resolves without any sequel but few patients have severe infections and need investigations for secondary immune defects such as IgG2 subclass deficiency or mannan-binding lectin.]]
Allergy	About 15% of the patients fall under this category. QoL is severely affected in patients of this group, particularly in the mental component. Allergic manifestations in this group of patients are more severe than in the general population so special consideration should be given to the prevention and treatment of these patients. Evaluations of serum IgE level, skin prick test and lung function test are suggested in these patients.
Autoimmune	There is an evidence of reduced proper mental and physical function affecting the QoL in patients with SIgAD. Among the autoimmune disorders, idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia are more common in patients with IgA deficiency requiring blood or blood product administration frequently which should be performed with caution. Based on the concurrence of autoimmune disorders with SIgAD, screening of IgA levels should be considered. In patients with SIgAD, IgA-based serological diagnosis of autoimmunity is difficult, since these assays may usually be negative leading to underestimation of the prevalence of these diseases. Other autoantibodies could be found in the serum of some patients with SIgAD without any clinical autoimmune manifestations such as antibodies against thyroglobulin, thyroid microsomal antigens, red blood cells, basement membrane, smooth muscle cells, pancreatic cells, cardiolipin, human collagen, and adrenal cells. Although the presence and certain level of these antibodies donot predict the development of disorders but could be suggestive of future disease.
Severe symptoms	A few percent of the patient with SIgAD develop both recurrent or severe infections and autoimmune disorders fall into severe symptoms phenotype. there is an association with HLA predisposing haplotype, reduced memeory B cells and decrease Treg counts. Severe phenotype of selective IgA deficency and Combined variable immunodeficiecny share common clinical feature, eviddence of development of both the disease in a single family and progression of SIgAD into CVID propose a common genetic background. Mortality rate for this group is twice as compared to the general population. It is proposed that the patient with this phenotype and the family history of both SIgAD and CVID perform the basic clinical and immunologic evaluation and regular follow-up examinations.

Pathophysiology

Pathogenesis

• Several studies were carried out to establish the mechanism involved in selective IgA immunodeficiency but the exact pathogensis is still not clear.
• SIgAD has been attributed to an intrinsic B cell lymphocyte defect, T cell abnormalities and most recently an impairment in cytokine regulation indicating that it is a heterogenous dysfunction.
• The most common pathological process involved in patients with selective immunoglobulin A deficiency is a maturation defect in B cells to produce IgA.
• Normally, the surface immunoglobulins are acquired in a sequential manner in B- cell differentiation. The first surface immunoglobulin to appear on B cells is IgM, as the cells mature they acquire surface IgD and sometimes IgA or IgG. A fully differentiated B cell performs a specfic function which means it would bear a specfic surface immunoglobulin.It is found that Patients with sIgAD have B cells arrested at a stage where they coexpress surface IgM, IgD as well as IgA and donot develop into IgA secreting plasma cells..
• The abnormality appears to involve stem cells as it can be passed on by bone marrow transplantation.
• Cytokine dysregulation such as lack of IL-4, IL-6, IL-7, IL-10, TGF-b and most recently IL-21 is suggested to play a role in SIgAD

Genetics

• Several genetic mutations are associated with SIgAD which suggest its polygenic nature but whtether and how they imply causation is yet to be established.
• MHC susceptibilty genes associated with SIgAD
  • HLA class I A1, A28, B8 and B14.
  • HLA class II HLA-DR1, DR3, DR7..
  • MHC class III C2, C4A, C4B and MSH5.
• Non MHC susceptibiliy genes associated with SIgAD
  • IFIH1 and CLEC16A.
• Mutation in tumor necrosis factor(TNF) family member "transmembrane activator and calcium-modulator and cyclophilin ligand interactor"(TACI), a molecule responsible for isotype switching in B-cells is also found in this condition.

Associated Conditions

• Combined Variable Immunodeficiency
  • Common genetic basis has been proposed for IgA deficiency and common variable immunodeficiency by their existence in the members of the same family and the underlying B cell defect.
• IgA deficiency may progress into combined variable immundeficinecy.
• Autoimmune disorders
• Several autoimmune diseases have been associated with SIgAD.
• The most common of them are:
  • Celiac disease
  • Type 1 diabetes myelitis
  • Inflammatory bowel disease
• Other less common conditions associated are:
  • Graves Disease
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Mysthenia gravis
  • Ulcerative colitis
  • Hyperthyreosis
  • Idiopathic juvenile arthritis
  • Hypothyreosis
  • Idiopathic Pulmonary Hemosiderosis
• Ataxia Telangiectasia
• Carcinomas
• There is an increased risk of cancer specifically of the gastrointestinal tract in adults.Though children with IgA deficiency are not at increased risk for cancers.

Causes

Disease name] may be caused by [cause1], [cause2], or [cause3].

OR

Common causes of [disease] include [cause1], [cause2], and [cause3].

OR

The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].

OR

The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here.

Differentiating IgA Deficiency from Other Diseases

IgA defieciency should be differentiated from other disorders leading to hypogammaglobulinemia and defects of humoral immunity. The following conditions may be considered as differentials:

Disorder	Defect (Mechanism of Development)	Characteristic Features	Clinical Presentation	Laboratory Findings
X-Linked (Bruton) Agammaglobulinemia	Defect in tyrosine kinase gene (BTK) B cells fail to mature	X-linked recessive pattern of inheritance Increased prevalence in males	Recurrent bacterial and enteroviral infections after 6 months of age Pre-disposition to development of infections by encapsulated organisms Pre-disposition to development of Giardia infections Absent lymph nodes and tonsils	Normal CD19+ B cell count Decreased pro-B cells Increased pre-B cells Decreased immunoglobulins of all classes
Selective IgA Deficiency	Stem cell defect (Transferrable with marrow transplant) Lack of IL-4, IL-6, IL-7, IL-10, TGF-β, and IL-21 Mutations in transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI, TNFRSF13B)	Most common primary immune deficiency	Majority of the cases are asymptomatic Respiratory and gastrointestinal infections (mucosal infections) Associated with autoimmune diseases Atopy Anaphylaxis to IgA containing products	Serum IgA < 7 mg/dl Normal IgG and IgM levels
Common Variable Immunodeficiency	Defective B cell differentiation	May be acquired in 20-30 years of age	May present with other autoimmune diseases Associated with bronchiectasis Associated with lymphoma Associated with sinopulmonary infections (Bacterial, enteroviral and parasitic such as Giardia)	Decreased plasma cells Decreased immunoglobulins
Autosomal dominant hype IgE syndrome (Job's Syndrome)	Defieciency of Th17 cells due to STAT3 mutation Impaired neutrophils to sites of infection	Distinctive coarse facies Cold (non-inflammatory) Staphylococcal abscesses Retained primary teeth Eczema		Increased levels of IgE Decreased levels of interferon gamma (IFN-gamma)
Severe combined immunodeficiency (SCID)	Defective interleukin-2 receptor gamma chain Adenosine deaminase deficiency Reg 1 and Reg 2 nonsense mutations	IL-2R disease is X-linked ADA deficiency and reg mutations are typically autosomal recessive	Failure to thrive Chronic diarrhea Thrush Recurrent bacterial, viral and protozoal infections Treatment is bone marrow transplant	Decreased T cell receptor excision circles (TRECs) Abscence of thymic shadow on chest X-Ray Absent germinal centers of lymph node biopsy Absent T cells on flow cytometry
Ataxia Telangiectasia	Defect in ATM gene DNA double stranded breaks leading to cell cycle arrest	Hypersensitivity to X-Rays	Triad of: Ataxia Spider angiomas (Nests of distended capillaries) IgA deficiency	Increased alpha fetoprotein (AFP) Decreased IgA, IgG and IgE Lymphopenia Cerebellar atrophy
Hyper IgM Syndrome	Defective CD40L (CD40 ligand) on Th cells leading to class switching defect	X-linked recessive pattern of inheritance	Severe pyogenic infections in early life Opportunistic infection with: Pneumocystis jiroveci Cryptosporidium Cytomegalovirus (CMV)	Increased IgM Decreased IgG, IgA and IgE No germinal centers
Wiskott-Aldrich Syndrome	Mutation in WAS gene T cells unable to reorganize actin microfilaments (microfilament defect)	X-linked recessive pattern of inheritance Increased risk of autoimmune disease and malignancy	Thrombocytopenic purpura Eczema Recurrent infections	Decreased to normal IgG and IgM Increased IgE and IgA Fewer and smaller platelets

• Malignancy: can cause the reduction in the immunoglobulin production.

• Viral infections: such as Epstein-Barr virus, HIV, cytomegalovirus are other causes of hypogammaglobulinemia..
• Side effect of certain medications: Some drugs include systemic glucocorticoids, phenytoin, and carbamazepine, have been associated with IgG deficiency.
• Other causes of primary humoral immunodeficiencies.
• Smoking: may cause IgG2 subclass deficiency.
• Protein-losing conditions: enteropathies, nephrotic syndrome, burns, and other traumas may cause abnormal loss of immunoglobulins.

fferential dx3].

Epidemiology and Demographics

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

OR

In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

OR

In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.

Patients of all age groups may develop [disease name].

OR

The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

OR

[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

OR

[Chronic disease name] is usually first diagnosed among [age group].

OR

Selective IgA is more common in caucasians with the prevalence of 1/600

OR

[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].

[Disease name] affects men and women equally.

OR

[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.

The majority of [disease name] cases are reported in [geographical region].

OR

[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Risk Factors

• Positive family history

There are no established risk factors for [disease name].

OR

The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

Screening

Most of the patients are asymptomatic but as there is an increse risk of progression to CVID so routine screening is recommended in patients with family history of combined variable immunodeficiency or selective IgA deficiency. There is insufficient evidence to recommend routine screening for [disease/malignancy].

OR

According to the [guideline name], screening for [disease name] is not recommended.

OR

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Selective IgA is diagnosed based on serum levels of IgA in individuals older than 4 years of age. As high rate of familial inheritance can be seen in families with SIgAD, so It is recommended to do the screening in first-degree relatives of such patients.

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

OR

The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

OR

The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

• serum IgA less than 0.7 mg/dl with normal levels of IgM and IgG.

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

• There is no specific treatment for selective IgA deficiency. Individuals can be treated based on their symptoms as the presentation varies from patient to patient.
• There are several aspects of care in patients with selective IgA deficiency:
  • Patient Education
  • Vaccination
  • Use of Antibiotics
  • Use of Immunoglobulins
  • Management of associated conditions

• Patient Education
  • Patient with severe IgA deficiency can have anaphylactic reactions secondary to blood transfusion or its products.
  • It is specifically seen in patients with undetectable serum IgA levels.
  • These patients develop anti IgA antibodies so they should be advised to wear medical alert bracelet.
  • IgA levels should be periodically monitored in asymptomatic patients.
• Vaccination:
  • Pneumococcal vaccine is recommended in patients with SIgAD to reduce the risk of sino-pulmonary infections.
• Use of antibiotics:
  • A trial of antibiotic prophylaxis is usually given to patients with SIgAD who are not taking immunoglobulins.

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

References

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