Immunoglobulin A Deficiency

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Immunoglobulin A Deficiency
Article Last Updated: Jul 13, 2006
AUTHOR AND EDITOR INFORMATION
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Author: Rebecca Bascom, MD, MPH, Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Pennsylvania State College of Medicine, Milton S Hershey Medical Center

Rebecca Bascom is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Physicians, American Industrial Hygiene Association, American Public Health Association, and American Thoracic Society

Coauthor(s): Marina Y Dolina, MD, Staff Physician, Division of Pulmonary, Allergy, and Critical Care Medicine, Milton S Hershey Medical Center, Penn State University; Bettina C Hilman, MD, Consulting Staff, The Asthma and Allergy Center

Editors: Zuhair Ballas, MD, Director, Program Director, Department of Internal Medicine, Division of Allergy-Immunology, Professor, University of Iowa College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael R Simon, MD, MA, Professor, Departments of Pediatrics and Internal Medicine, Department of Allergy and Immunology, Wayne State University School of Medicine; Consulting Staff, Henry Ford Health System; Timothy D Rice, MD, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Associate Professor, Saint Louis University School of Medicine; Michael A Kaliner, MD, Clinical Professor of Medicine, Section of Allergy and Immunology, Washington Hospital Center, George Washington University School of Medicine; Chief, Medical Director, Institute for Asthma and Allergy

Author and Editor Disclosure

Synonyms and related keywords: immunoglobulin A deficiency, IgA deficiency, immunodeficiency, selective IgA deficiency, SIgAD, selective immunoglobulin A deficiency, sIgA, primary antibody deficiencies, primary antibody deficiency, antibody deficiency, IgAD, immunodeficiency disease, sinopulmonary infection, sinus infection, otitis media, stomach cancer, Giardia lamblia, G lamblia, Escherichia coli, E coli, Helicobacter pylori, H pylori, GI cancer, gastrointestinal disease, GI disease, Crohn disease, upper respiratory tract infection, lower respiratory tract infection, chronic diarrhea, transfusion complication, blood product reaction, adverse transfusion reaction
INTRODUCTION
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* Miscellaneous
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Background

Selective immunoglobulin A deficiency (SIgAD) is a primary immunodeficiency disease and is the most common of the primary antibody deficiencies (Bonilla, 2005). Total immunoglobulin A deficiency (IgAD) is defined as an undetectable serum immunoglobulin A (IgA) level at a value of 5 mg/dL (0.05 g/L) in humans. Partial IgAD refers to detectable but decreased IgA levels that are more than 2 standard deviations below normal age-adjusted means (Daele, 2000).

IgAD is commonly associated with normal B lymphocytes in peripheral blood, normal CD4+ and CD8+ T cells, and, usually, normal neutrophil and lymphocyte counts. Anti-IgA autoantibodies may be present. Peripheral blood may also be affected by autoimmune cytopenias, eg, autoimmune thrombocytopenia (Spickett, 1991; Longhurst, 2002).

IgA was first identified by Graber and Williams in 1952; ten years later, the first patients with IgAD were described.

IgAD is a complex disorder, and the results of intensive study are beginning to elucidate the genetic loci and molecular pathogenesis of this disorder. Several lines of evidence support a common pathogenesis for IgAD and common variable immunodeficiency (CVID), which is discussed further in Pathophysiology. Family studies show variable inheritance patterns. Familial inheritance of IgAD occurs in approximately 20% of cases (Hammarstrom, 2000), and, within families, IgAD and CVID are associated (Vorechovsky, Am J Hum Genet, 1999; Vorechovsky, J Immunol, 1999).

Associated conditions reported in some IgAD patients include (1) deficits in one or more immunoglobulin G (IgG) subclasses (20-30% of IgA-deficient patients) and (2) a deficient antibody response to pneumococcal immunization. Some patients with IgAD later develop CVID.

Primary IgAD is permanent, and below-normal levels have been noted to remain static and persist after 20 years of observation (Koskinen, 1994).

Environmental factors such as drugs or infections can cause IgAD, but this form is reversible in more than half the cases (see Causes).

Although individuals with IgAD have largely been considered healthy, recent studies indicate a higher rate of symptoms. A 20-year follow-up study that compared 204 healthy blood donors with incidentally identified IgAD to 237 healthy subjects with normal IgA levels demonstrated that 80% of IgAD donors and 50% of control subjects had episodes of infections, drug allergy, or autoimmune or atopic disease. Severe respiratory tract infections occurred in 26% of IgAD subjects, in 24% of subjects with decreased IgA levels, and in 8% of control subjects; however, the incidence of life-threatening infections was not increased. IgAD is more common in adult patients with chronic lung disease than in healthy age-matched control subjects (International Union of Immunological Societies, 1999).

Patients with IgAD are at a high risk of developing severe reactions after receiving blood products (Sazama, 1990; Rogers, 1998; Sanz, 1999). IgA-deficient patients with immunoglobulin E (IgE)–class anti-IgA antibodies are at risk for anaphylaxis if they receive blood or intravenous immunoglobulin. Only intravenous immunoglobulin depleted of IgA should be used in patients with confirmed or probable IgE anti-IgA antibodies. A history devoid of previous blood product administration does not exclude the possibility of anti-IgA antibodies or adverse reactions. Fortunately, appropriate precautions can significantly reduce morbidity (see Treatment).

Pathophysiology

IgA is the second most common immunoglobulin in human serum (after IgG) and is the predominant immunoglobulin found in mucosal secretions.

Structurally, IgA has 2 different forms. Serum IgA is a monomer, and secretory IgA is a dimer; it is this property that makes this unique immunoglobulin resistant to the proteolytic enzymes found in many human secretions.

Secretory IgA antibodies can neutralize viruses, bind toxins, agglutinate bacteria, prevent bacteria from binding to mucosal epithelial cells, and bind to various food antigens, thus preventing their entry into the general circulation. The role of serum IgA is unclear.

IgAD is a primary immunodeficiency disease presumed to result from a failure of terminal differentiation in IgA-positive B cells. Multipotent hematopoietic stem cells give rise to progenitors of T cells, B cells, and natural killer cells.

The development of B-lineage cells begins in the fetal liver. B-lineage cell development then transfers to the bone marrow when it becomes the major hematopoietic organ. Pre–B cells become immature immunoglobulin M (IgM)–positive B cells and then migrate from the bone marrow to lymph node germinal centers. After leaving the bone marrow, the B cells mature and express immunoglobulin D receptors, respond to antigens, and, with the help of T cells (CD4+), undergo proliferation and plasma cell differentiation (International Union of Immunological Societies, 1999).

In germinal centers, antigen is presented by follicular dendritic cells with help from CD4+ T cells and stimulates B cells to proliferate and undergo somatic mutation and immunoglobulin class-switching. B cells that produce high antigen affinity antibodies are selected to develop into plasma cells that produce different immunoglobulin isotypes (ie, IgM, IgG, IgA, or IgE) or become recirculating memory B lymphocytes. These processes are regulated by cell interaction molecules (eg, CD40 on B cells, CD40 ligand on activated T cells), and cytokines (ie, interferon-gamma and interleukin [IL]–2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-14, and IL-15) and their cell surface receptors (International Union of Immunological Societies, 1999).

Patients with IgAD have a normal number of B cells expressing surface IgA in their blood, but the amount of surface IgA on each B cell is markedly decreased. Based on animal studies, the failure of B cells to terminally differentiate into IgA-secreting plasma cells may be due to the lack of effects caused by cytokines such as IL-4, IL-6, IL-7, or IL-10.

Molecular analysis of B-cell differentiation in a small number of patients with selective or partial IgA deficiency indicated that a decreased expression level of alpha germline transcripts before a class switch might be critical for the pathogenesis of some patients with SIgAD. However, in patients with a partial IgA deficiency, B-cell differentiation might be disturbed after a class switch (Asano, 2004). Missense mutations in one allele of the tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) were found in 4 of 19 unrelated individuals with common variable immunodeficiency and in 1 of 16 individuals with SIgAD. The B cells from individuals with the TACI mutations expressed TACI but did not produce IgG and IgA in response to a TACI ligand, a finding thought to reflect impaired isotype switching (Castigli, 2005).

IgAD has been noted to evolve into CVID and is often observed in pedigrees containing individuals with CVID (Buckley, 1992). Evidence for a common pathogenesis of CVID and IgAD include shared susceptibility alleles major histocompatibility complex class III genes (D locus) (Cucca, 1998), a similar spectrum of IgG subclass deficiencies, a gradual decline of immunoglobulin levels in concordant siblings, and the development of CVID in some patients with IgAD.

Previous studies of multiple-case families of patients with IgAD showed a higher prevalence of CVID among close relatives than in the general population. In multiple-case families with dominant transmission of CVID and IgAD, CVID was usually present in parents, followed by IgAD in the descendants. That study indicated the presence of a predisposing locus in the proximal part of the major histocompatibility complex. The recurrence risk was found to depend on the sex of the parents transmitting the defect. Affected mothers were more likely to produce offspring with IgAD than affected fathers (Vorechovsky, Am J Hum Genet, 1999; Vorechovsky, J Immunol, 1999; Vorechovsky, 2000; Vorechovsky, 2001).

IgAD has been reported in patients with constitutional chromosome 18 abnormalities, and a case series of 83 cases of 18p- syndrome showed an increased frequency of IgAD; however, attempts to identify a specific locus on chromosome 18 have not been successful (Vorechovsky, J Immunol, 1999).

Structural lung disease such as chronic obstructive pulmonary disease (COPD) was previously thought not to impair the ability to generate antigen-specific IgA. Studies of acute exacerbations of chronic bronchitis show that new mucosal IgA to surface-exposed epitopes of the infecting Moraxella catarrhalis isolate developed in sputum supernatants after 42% of exacerbations (Bakri, 2002), and significant increases in mycoplasmal-specific IgA occurred in 85% of a group of 34 patients hospitalized for acute exacerbations of COPD. In a prospective study of 250 hospitalizations for acute exacerbations of COPD, the geometric mean serum titer for IgG and IgA against Chlamydia pneumoniae was higher, with 33% meeting criteria for chronic infection (Lieberman, 2001). In another series from India, serum and sputum IgA levels were higher in subjects with COPD than in control subjects (Chauhan, 1990).

Recent studies, however, suggest that the mucosal IgA response is impaired in COPD with deficient transport of IgA across the bronchial epithelium, possibly involving degradation of the Ig receptor involved in transepithelial routing (Pilette, 2004).

Observations that SIgAD is associated with an increased prevalence of atopy suggest a role for IgA in asthma pathogenesis. A protective role of IgA has been seen in murine models of asthma (Pilette, 2004).

Frequency
United States

At a minimum, an estimated 250,000 individuals have IgAD in the United States (Gustafson, 1997). In African Americans, the prevalence of IgAD is 1 case per 6000 persons.
International

* Factors associated with the prevalence of IgAD include a family history of IgAD and the country of origin. Family studies using IgAD blood donors as probands show that first-degree relatives have a 7.5% prevalence rate of IgAD, which is 38-fold higher than that of unrelated donors (Oen, 1982). The serological prevalence of IgAD varies 100-fold among populations. Prevalences, in decreasing order, are as follows:

o Arabian peninsula - One in 142 persons.


o Spain - One in 170 persons


o Eastern Nigeria - One in 255 persons


o Finland - One in 396 persons


o Czech Republic - One in 408 persons


o Basque regions of Spain and France - One in 521 persons


o Iceland - One in 533 persons


o England - One in 875 persons


o Brazil - One in 965 persons


o France - One in 3040 persons


o China (Han) - One in 2600 persons


o China (Zhuang) - One in 5300 persons


o Japan - One in 14,850-18,500 persons


o Sweden - Approximately 20,000 persons affected


o United Kingdom - Approximately 120,000 persons affected (Gustafson, 1997)

Isolated IgAD is present in a minority of cases of transient hypogammaglobulinemia of infancy. Of a series of 40 patients presenting with recurrent responsive infections, otitis media, bronchitis or bronchial asthma, or recurrent gastroenteritis when aged 4-29 months, only 1 had isolated IgAD, 10 had reduced IgG and IgA levels, and 6 had diminished IgA and IgM levels. The majority recovered immunoglobulin levels by age 3 years, but 3 had persistently low IgG and IgA levels.

A study performed by Weber-Mzell et al (2004) on 7293 healthy white volunteers demonstrated an IgAD prevalence of 0.21% (definition of IgAD was level <0.07g/L). The same study showed seasonal fluctuations of serum IgA (SIgA) concentration; levels of SIgA increased in winter.

Mortality/Morbidity

IgAD is more frequent in adult subjects with chronic lung disease than in a healthy, age-matched control subjects (International Union of Immunological Societies, 1999).

The 20-year longitudinal study of healthy blood donors with incidental findings of IgAD used questionnaires and medical record reviews to demonstrate a 3-fold increase in rates of severe childhood respiratory conditions (9% vs 3%), a 4-fold increase in rates of severe adult respiratory conditions (16% vs 4%), a similar increase in recurrent mild respiratory tract infections, and a significant increase in rates of recurrent viral infections (16% vs 1%).

This study also noted a 4-fold increase in the rate of autoimmune conditions (23% in subjects with SIgAD vs 5% in control subjects); a 2.5-fold increase in the rate of abdominal symptoms caused by milk (16% vs 6%); and slight increases in the rates of atopic eczema (8% vs 5%), drug allergy (9% vs 5%), and food hypersensitivity (3% vs 1%). A slight decrease was observed in the rate of allergic rhinitis and/or eczema (11% vs 17%).

In previous reports, most individuals with IgAD (ie, 60-90%) were asymptomatic. A longitudinal design may have been needed to appreciate the cumulative burden of this disorder.

Patients with SIgAD commonly present with anaphylactic transfusion reactions (patients with anti-IgA antibodies) or autoimmune antibodies, autoimmune disorders, or both.

When IgAD is associated with one or more IgG subclass deficiencies or an impaired polysaccharide responsiveness, some individuals with IgAD may develop recurrent sinopulmonary infections, especially in patients with concurrent IgG type 2 subclass deficiency; GI tract infections and disorders in patients with absent secretory IgA; or an increased incidence of cancer. Lack of secretory IgA has been hypothesized to compromise the defense against infection with Helicobacter pylori, which is thought to be a cause of stomach cancer.

The risk for cancer among 562 Danish and Swedish subjects with CVID or IgA was compared with that of 2017 relatives for the period 1958-1996. Among 176 subjects with CVID, the incidence of cancer (all sites) was increased (standardized incidence ratio [SIR], 1.8; 95% confidence interval [CI], 1-2.9). Stomach cancer was increased (SIR, 10.3; 95% CI, 2.1-30.2), and malignant lymphoma was increased (SIR, 12.1; 95% CI, 3.3-31). Among 386 subjects with IgAD, the incidence of cancer (all sites) was not increased (SIR, 1); however, the incidence of stomach cancer was increased, albeit to an insignificant degree (SIR, 5.4; CI, 0.7-19.5) (Mellemkjaer, 2002). The same study did not show an increase in lymphoid malignancies (non-Hodgkin lymphoma, Hodgkin disease) in IgAD subjects, even though some evidence in the literature indicates that the risk of developing a lymphoid malignancy is increased (Cunningham-Rundles, 1993).

Patients with IgAD who have a compensatory increase in secretory monomeric IgM in their upper respiratory tract secretions and GI fluids tend to be less symptomatic. Note that patients with total IgAD are more symptomatic than patients partial IgAD.

A previously unrecognized clear association of SIgAD with recurrent parotitis of childhood (PTC) was demonstrated by Fazekas et al (2005) in an Austrian pediatric clinic population. The prevalence of PTC in IgA-deficient patients (22%) was much higher than in a large population of healthy Austrian volunteers (0.3%; Weber-Mzell, 2004).

* Recurrent sinopulmonary infections are reported. IgAD usually manifests as recurrent otitis (in children), tonsillitis, sinusitis, and bronchitis with extracellular encapsulated bacteria (eg, Haemophilus influenzae, Streptococcus pneumoniae). Severe respiratory tract infections occur more often in adult subjects with IgAD than in normal control subjects, with a cumulative prevalence rate over 20 years of 16% (see Images 1-3).

The substantial risk of developing lung damage, which is often reported in patients with CVID, is not a major threat to individuals who only have SIgAD. Lung function is significantly impaired among patients who have a combination of IgAD and a deficiency of one or more IgG subclasses. A few recently published cases reported the occurrence of hypersensitivity pneumonitis in patients with SIgAD and the authors suggest that SIgAD is a risk factor for a more severe course of the disease and increased susceptibility to develop extrinsic allergic alveolitis. (Yalein, 2003; Sennekamp, 2004)


* Autoimmune disease is reported in approximately 20% of patients with CVID and is associated with IgAD. Autoantibodies are often produced but may be difficult to detect. The sera of individuals with IgAD may contain various autoantibodies that cause no disease or cause myasthenia gravis or thyroid disease. Other selective case reports indicate an association between SIgAD and type 1 diabetes mellitus, vertigo, vitiligo, and alopecia. Rheumatoid arthritis and systemic lupus erythematosus are the diseases most commonly connected with IgAD. In a survey of serum specimens from 60 healthy subjects with SIgAD, 16 of 21 different autoantibody levels were higher in IgAD subjects than in healthy control subjects (Barka, 1995).

The prevalence rate of anti-IgA antibodies among white persons with IgAD is 30-40%. In patients with combined IgA-IgG type 2 deficiency, the rate is 50-60 %.

IgA-deficient patients with anti-IgA antibodies may develop severe anaphylactic reactions when they are transfused with blood components that contain IgA. These autoantibodies are typically of the IgE class; however, IgG class anti-IgA antibodies can also cause anaphylactic-type reactions (Bjorkander, 1987). Although anaphylactic reactions occur in 1 in 20,000-47,000 transfusions, they constitute one of the frequent nonhemolytic causes of transfusion-related mortality.


* GI tract infections and disorders are reported. Patients with SIgAD have a 10-fold increased risk of celiac disease. Milk intolerance is common in patients with primary IgAD. Reports indicate that patients with IgAD may have IgG antibodies against cow milk and ruminant serum proteins. Patients with a high titer of antibodies to cow milk reportedly are more likely to have other autoantibodies (Cunningham-Rundles, 1981).

Other conditions, such as ulcerative colitis, inflammatory bowel disease, Crohn disease, and pernicious anemia, have been described in IgA-deficient individuals. Friman et al (Microb Pathol, 2002) showed that individuals with SIgAD have an increased risk of becoming a carrier of E coli strains that have increased proinflammatory properties, and hypothesize that this may contribute to the development of gastrointestinal disorders in SIgAD patients. Mucosal infections include acute diarrhea caused by viruses, bacteria, or Giardia lamblia parasites. A higher occurrence of serum antibodies to milk antigens in patients with IgAD suggests that normal serum IgA responses protect the host from continuing exposure to environmental antigens.

Race

IgAD occurs in Asian persons at a rate of 1 case per 14,840-18,500 persons, in Arab persons at a rate of 1 case per 142 persons, in white persons at a rate of 1 case per 500-700 persons, and in African American persons at a rate of 1 case per 6000 persons.
Sex

A study of 7293 Austrian volunteers showed a greater frequency of SIgAD in men than in women (0.19% vs 0.014%) and a greater frequency of subnormal serum IgA levels (0.07-0.7 g/L) in men (2.66%) than in women (0.93%; Weber-Mzell, 2004).
Age

This disease can be diagnosed in persons of any age.

Average serum IgA levels increase 0.2 ±0.06 g/L per decade of life (Weber-Mzell, 2004).

* Those older than 6 months who have recurrent upper and lower respiratory tract infections with encapsulated bacteria (eg, H influenzae, S pneumoniae) should be evaluated for IgAD. Patients with humoral deficiencies do not usually present with recurrent infections in the first few months of life because they have circulating immunoglobulins due to placental transfer of maternal immunoglobulins.


* Children and adults present with recurrent sinopulmonary infections or GI infections or diseases. Case reports exist of severe life-threatening infections in patients with SIgAD (Gomez-Carrasco, 1994; Lantz, 2001; Chen, 2002).


CLINICAL
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History

Previous studies based on analysis of blood donor banks have suggested that up to 90% of patients with SIgAD are asymptomatic. However, recent follow-up studies demonstrate that 80% of individuals with IgAD developed symptoms later in their life (Koskinen, 1996). Symptomatic patients have a history significant for recurrent otitis media, sinusitis, bronchitis, pneumonia, GI tract infections, severe allergic reaction following infusions with immunoglobulins or blood transfusions, or, in children, failure to thrive.

* Recurrent sinopulmonary infection is the most common illness associated with IgAD. Most upper and lower respiratory tract infections are caused by bacterial or viral pathogens characteristic of community-acquired pneumonia. Patients with concomitant IgG type 2 subclass deficiency may have a higher risk for recurrent infections from S pneumoniae, H influenzae, M catarrhalis, or Staphylococcus aureus.


* Various GI tract infections with viruses, bacteria, and G lamblia parasites manifest as chronic diarrhea with or without malabsorption. Biopsy specimens may show nodular lymphoid hyperplasia with flattened villi.


* Food allergy and other atopic disorders, such as allergic conjunctivitis, rhinitis, urticaria, atopic dermatitis, and asthma, are common in patients with IgAD.


* Of patients with IgAD, 10-44% have anti-IgA antibodies, and these patients may have severe adverse reactions to IgA-containing materials such as blood, plasma, or immunoglobulin.

Physical

Patients present with various signs of recurrent respiratory tract infections, including swelling, pain, or tenderness upon palpation over the maxillary and frontal sinuses; nasal discharge; fever; nonproductive or productive cough; and dyspnea. GI findings may include abdominal distention, focal tenderness to direct palpation (without rebound), diffuse pain, and increased peristalsis.

Causes

The underlying cause of this disease remains unknown. Familial inheritance has been recognized in 25% of affected individuals, suggesting a strong genetic influence.

* Case reports of some affected families indicate that inheritance may be autosomal dominant or recessive. In other families in which multiple members are affected, the pattern of inheritance does not conform to strict mendelian rules.
*
o In some families, the immunodeficiency can appear to skip generations; in others, one family member may have IgAD, while another may have CVID, suggesting variable expressivity and penetrance of a disease susceptibility gene.

o Recent studies have shown that susceptibility to either CVID or IgAD may be linked to specific alleles of the major histocompatibility complex, suggesting that these alleles, or alleles of closely linked genes with which they are in linkage disequilibrium, are somehow involved in the pathogenesis of CVID and IgAD.

* In his 1991 report of 2 mothers with IgAD, de Laat suggests that transplacental passage of anti-IgA antibodies can also cause IgAD in an infant by inducing excessive IgA-specific T-cell suppressor activity.
*

* Certain drugs may also cause IgAD, but this form usually resolves once the medication is stopped. The following drugs have been implicated:
*
o D-penicillamine

o Sulfasalazine

o Aurothioglucose

o Fenclofenac

o Gold

o Captopril

o Zonisamide

o Phenytoin

o Valproic acid

o Thyroxine

o Chloroquine

o Carbamazepine

o Hydantoin

o Levamisole

o Ibuprofen

o Salicylic acid

o Cyclosporin A

* Infections may cause a transient IgAD. The following have been recognized as causes:
*
o Rubella

o Cytomegaloviruses

o Toxoplasma gondii

o Congenital rubella and Epstein-Barr virus infection - May result in persistent IgAD

* IgAD can follow bone marrow transplantation from an IgA-deficient donor into a histocompatible sibling not previously deficient in IgA.


DIFFERENTIALS
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Combined B-Cell and T-Cell Disorders
Severe Combined Immunodeficiency
Wiskott-Aldrich Syndrome

Other Problems to be Considered

Primary immunodeficiencies include agammaglobulinemia, hypoglobulinemia, selective deficiency of IgG subclasses with or without IgAD, X-linked agammaglobulinemia, autosomal recessive agammaglobulinemia, impaired polysaccharide responsiveness, B-cell disorders, T-cell disorders, combined B- and T-cell disorders, CVID, severe combined variable immunodeficiency, transient hypogammaglobulinemia of infancy, and Wiskott-Aldrich syndrome.

Acquired immunodeficiencies include drug-induced hypogammaglobulinemia (most commonly, long-term therapy with anticonvulsants and steroids), AIDS, and postinfectious hypogammaglobulinemia.

Recurrent sinopulmonary infections include cystic fibrosis, immotile cilia syndrome, endobronchial obstruction, and recurrent aspiration.

WORKUP
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Lab Studies

* IgAD is defined as an undetectable serum IgA level, traditionally measured using the low-level radial immunodiffusion method (lower limit of detection is 50 mg/mL [5 mg/dL]). The lower limit of detection differs depending on the sensitivity of the method used. It is 0.2 g/L for nephelometry, 0.05 g/L (5 mg/dL) for low-level radial immunodiffusion plates, and 0.0016 g/L for hemaglutination inhibition techniques (Booth, 1995).


* Almost all patients with IgAD also exhibit loss of both secretory IgA type 1 and secretory IgA type 2 in their external secretions, but these are not routinely measured.


* Low serum IgA levels in children aged 6 months to 4 years should be confirmed to be persistently low at age 4 years before making a lifetime diagnosis of IgAD. Some children with a low level when aged 6 months to 4 years progress to CVID, whereas others completely normalize.


* Normal serum levels of IgG and IgM are necessary for a diagnosis of SIgAD. Other causes of hypogammaglobulinemia should be excluded (see Differentials). Repeat tests for low IgA serum values in children younger than 5 years. Some children with low levels progress to CVID, but levels can normalize by age 4-5 years.


* The most common mistake clinicians make is when they diagnose IgAD or transient hypogammaglobulinemia of infancy in children using the adult reference range for serum IgA levels.

Imaging Studies

* Perform chest radiography together with CT scans of the sinuses to investigate for structural lesions or chronic disease, and perform CT scans of the chest for a sensitive assessment of possible bronchiectasis.

o

In patients with primary humoral immunodeficiency and chronic productive cough, high-resolution computed tomography (HRCT) is helpful in evaluating the extent of lung damage (Rusconi, 2003).
o In a Mayo Clinic series, 95% of 50 patients with a late onset of adult hypogammaglobulinemia had grossly abnormal findings on sinus films but did not necessarily have symptoms of purulent sinusitis (Hermans, 1976).


o

In Denver, Colo, 28 (98%) of 30 patients had abnormal sinus films (Kohler, 1984).
* Patients who are first diagnosed with immunodeficiency after age 45 years should undergo an imaging study to rule out thymoma.

Other Tests

* Pulmonary function tests may show an obstructive pattern in patients with IgAD and hypogammaglobulinemia.
*

* Jejunal biopsy specimens of patients with IgAD who have chronic diarrhea and malabsorption may show blunting of the villi. IgM-secreting plasma cells are observed in the lamina propria, instead of IgA-secreting plasma cells. Otherwise, lymph node architecture is normal.


TREATMENT
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Medical Care

The approach to treatment includes identification of comorbid conditions, preventive measures to reduce the risk of infection, and prompt and effective treatment of infections.
Surgical Care

Some patients with recurrent sinusitis require surgical interventions to promote drainage.
Consultations

* Rheumatologist
*

* Otolaryngologist
*

* Allergist/immunologist

Diet

Dietary modifications may be necessary to manage chronic diarrhea and malabsorption or food allergy. A gluten-free diet and, possibly, other restricted diets are important for treatment in patients with celiac disease.

MEDICATION
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IgAD has no specific treatment. Replacement therapy is not practical for IgAD because of the short half-life of IgA and the relative paucity of IgA in commercial immunoglobulin preparations.

Antibiotic therapy is the first line of treatment, specific to respiratory or GI tract infection. Associated sinopulmonary infections are treated according to treatment protocols used for community-acquired respiratory tract infections in healthy persons.

Immunization with pneumococcal polysaccharide vaccine is important; however, not all patients are able to mount an immune response. Postvaccination IgG titers can be obtained to confirm the presence of an age-appropriate protective level of antipneumococcal IgG. Patients with CVID may be unable to mount a response to polysaccharide antigens; therefore, pneumococcal vaccination in CVID patients is ineffective.

Use of IV IgG is warranted in patients with CVID. Previously, prophylactic IgG replacement therapy was contraindicated in patients with IgAD because of the risk of a severe systemic adverse reaction or the development of anti-IgA antibodies. Reports now indicate safe and effective prophylactic IgG replacement therapy with SC administration to patients with SIgAD, including those with IgA antibodies (Gustafson, 1997; Sundin, 1998).

Patients with known or possible anti-IgA antibodies are still at high risk of anaphylaxis.

Precautions must be used in the administration of IV immunoglobulin for replacement of IgG subclass deficiency in patients with IgAD because IV immunoglobulin preparations contain small amounts of IgA.

Drug Category: Vaccines, inactivated bacteria

Used to induce active immunity.
Drug Name Pneumococcal vaccine 23-valent (PPV23; Pneumovax 23; Pnu-Imune 23)
Description Contains capsular polysaccharides of 23 pneumococcal types, which comprise 98% of pneumococcal disease isolates. For use in children >2 y and adults at increased risk of pneumococcal disease and its complications because of other underlying health conditions. Also benefits adults >65 y.
Adult Dose 0.5 mL IM/SC
Following bone marrow transplant (use of PCV7 under study): One dose PPV23 at 12 mo and 24 mo following procedure
Pediatric Dose <2 years: Not recommended (see PCV7)
>2 years: Administer as in adults; PPV23 can be given to children >2 y and offers protection not covered with PCV7; can be given to children with newly recognized SIgAD
Serum can be obtained to determine if protective levels are achieved; if IgG pneumococcal antibody levels in the PCV7 remain low after children >2 y are given the PPV23, the authors give an additional PCV7; the authors see some children who have specific IgG pneumococcal antibody deficiency and lose immunologic memory (Sorensen, 1996)
Previously vaccinated with PCV7 vaccine, children >2 years, and adults with sickle cell disease, asplenia, immunocompromise, or HIV infection: 0.5 mL at age 2 y and then 2 mo after last dose of PCV7; revaccination with PPV23 administered 3-5 y after previous dose of PPV23 for children <10 y and, for children >10 y, every 3-5 y; revaccination should not be administered <3 y after previous PPV23 dose
Chronic illness: 0.5 mL in children >2 y and then 2 mo after last dose of PCV7; revaccination with PPV23
Contraindications Documented hypersensitivity to vaccine or any component; active infection, Hodgkin disease, 10 d prior to or during treatment with immunosuppressive drugs or radiation; children <2 y (children <2 y do not respond satisfactorily to capsular types of 23 pneumococcal vaccine); pregnancy (safety of vaccine has not been evaluated; do not administer during pregnancy unless risk of infection is high)
Interactions Effects decrease with immunosuppressive agents (eg, immunosuppressive doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents); globulin preparations may interfere with immune response to pneumococcal vaccine and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Epinephrine injection (1:1000) must be immediately available in case of anaphylaxis; use caution in individuals who have had episodes of pneumococcal infection within preceding 3 y (preexisting pneumococcal antibodies may result in increased reaction to vaccine); may cause relapse in patients with stable idiopathic thrombocytopenia purpura

Drug Name Pneumococcal 7-valent conjugate vaccine (PCV7; Prevnar)
Description Pneumococcal conjugate vaccine approved for infants and toddlers. Contains 7 purified capsular polysaccharides of S pneumoniae serotypes, accounting for 71% of infection among children <24 m, each coupled with a nontoxic variant of diphtheria toxin, CRM 197.
Licensed for use in infants and young children in Feb 2000. Recommended for children aged 2-23 mo and for children aged 24-59 mo who are at increased risk for pneumococcal disease (eg, with sickle cell disease, HIV infection, other immunocompromising or chronic medical conditions). Licensed for infants aged >6 wk.
Adult Dose Not recommended; see PPV23
Pediatric Dose 0.5 mL IM at ages 2, 4, 6, and 12-15 mo
Contraindications Documented hypersensitivity to any component or diphtheria toxoid; severe or moderate febrile illness; infants or children with thrombocytopenia or coagulation disorder contraindicating IM injection (unless benefits outweigh risks)
Interactions Effects may decrease with immunosuppressive agents (immunosuppressive doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents); pneumococcal 7-valent conjugate vaccine may increase effects of anticoagulant therapy; globulin preparations may interfere with immune response to pneumococcal vaccine and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Concurrent administration of PCV7 and PPV23 not recommended because safety and efficacy of concurrent vaccination have not been studied; epinephrine injection (1:1000) must be immediately available in the case of anaphylaxis; caution in individuals who have moderate or severe illness with or without fever, or delay vaccination until child has recovered


FOLLOW-UP
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* Authors and Editors
* Introduction
* Clinical
* Differentials
* Workup
* Treatment
* Medication
* Follow-up
* Miscellaneous
* Multimedia
* References


Deterrence/Prevention

* Primary prevention for IgAD has not been developed. If a medication is under consideration as the cause of the IgAD, it should be discontinued.


* Secondary prevention is vaccination (see Medication). The role of prophylactic antibiotics is controversial because they increase the hazard of infection with fungi or other resistant organisms.


* Tertiary prevention includes (1) prompt antibiotic treatment for respiratory tract infections, (2) microbial identification of diarrheal pathogens, (3) dietary modification for malabsorption syndromes, and (4) screening for anti-IgA antibodies if reactions to blood products occur (not routinely performed).

Complications

* Severe anaphylactic reactions to blood products
*

* Bronchiectasis
*

* Recurrent sinopulmonary infections
*

* Chronic diarrhea
*

* Severe otitis media resulting in hearing loss; case reports of deaths
*

* Malabsorption syndrome
*

* Growth retardation secondary to malabsorption and chronic infection

Prognosis

* In children aged 6 months to 4 years, IgAD may be transient and resolve permanently by age 5 years; in others, the syndrome may progresses to CVID.


* Adults with SIgAD are often asymptomatic; however, up to 90% have frequent bacterial respiratory tract infections.

Patient Education

* Educate patients to recognize early signs of respiratory tract infections, such as increased phlegm, discolored phlegm, cough, or dyspnea.


MISCELLANEOUS
Section 9 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page Click here to go to the next section in this topic

* Authors and Editors
* Introduction
* Clinical
* Differentials
* Workup
* Treatment
* Medication
* Follow-up
* Miscellaneous
* Multimedia
* References


Medical/Legal Pitfalls

* Advise patients with SIgAD that they have a 10-44% chance of having anti-IgA antibodies. Patients with IgE anti-IgA antibodies are at increased risk of anaphylactic transfusion reactions. They should discuss their condition with their doctor before receiving blood or blood-derived products. Recent recommendations address the identification of an IgA-mediated mechanism for transfusion-associated anaphylaxis and qualification of patients to receive IgA-deficient plasma-containing products (Vassallo, 2004).


* IgAD has no specific treatment, but patients need prompt and vigorous treatment of infections.


* Except in children or if drug-induced IgAD is diagnosed, IgAD is usually permanent.


* While uncommon, drug-induced SIgAD is a possibility; clinicians should review the patient's medication list.


* The inheritance patterns are variable, and clinicians cannot easily predict whether offspring will be affected. In rare cases, inheritance patterns are known for specific families.


* Avoid the diagnosis of SIgAD in children younger than 6 months.


* SIgAD cannot be regarded as asymptomatic; however, it is usually not life-threatening.


* False-positive beta human chorionic gonadotropin (beta-HCG) test results have been reported in patients with IgAD (Knight, 2005). Consider that possibility before recommending medical and surgical procedures for the evaluation of elevated beta-HCG levels.


* Transfusion of apheresis platelets from IgA-deficient donors with anti-IgA is not associated with an increase in transfusion reactions (Winters, 2004).

Special Concerns

* Importantly, patients with total IgAD are at high risk of developing a severe anaphylactic reaction upon receiving IgA-containing blood and blood products. In many cases, these reactions are associated with anti-IgA antibodies; however, they may occur in patients naive to blood products. As a precaution, super-washed normal donor erythrocytes or blood products from other IgA-deficient individuals should be used in these patients. Case reports exist of successfully avoiding transfusion reactions in such patients by using IgA-deficient and washed blood components. One case report described this method in a bone marrow transplant recipient who received IgA-reduced intravenous immunoglobulin.


MULTIMEDIA
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* Authors and Editors
* Introduction
* Clinical
* Differentials
* Workup
* Treatment
* Medication
* Follow-up
* Miscellaneous
* Multimedia
* References


Media file 1: Chest radiograph of a 50-year-old man with immunoglobulin A deficiency and severe bilateral pneumonia. He also had congenital heart disease. Serum immunoglobulin G and immunoglobulin M levels were normal.
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Media type: X-RAY

Media file 2: Lateral chest radiograph of a 50-year-old man with immunoglobulin A deficiency and severe bilateral pneumonia.
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Media type: X-RAY

Media file 3: Portable chest radiograph of a 50-year-old man with acute respiratory distress syndrome as a complication of severe bilateral pneumonia. The patient died from respiratory failure 2 days after this x-ray film was taken.
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Media type: X-RAY


REFERENCES
Section 11 of 11 Click here to go to the previous section in this topic Click here to go to the top of this page

* Authors and Editors
* Introduction
* Clinical
* Differentials
* Workup
* Treatment
* Medication
* Follow-up
* Miscellaneous
* Multimedia
* References


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Immunoglobulin A Deficiency excerpt

Article Last Updated: Jul 13, 2006