Continuing Education Activity

Immunoglobulin A (IgA) deficiency is a common primary immunodeficiency characterized by undetectable serum IgA, a concomitant lack of secretory IgA, and normal levels of other immunoglobulins. IgA deficiency should be distinguished from any other cause of hypogammaglobulinemia or T lymphocyte defect. This activity describes the evaluation and treatment of IgA deficiency and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiologies of immunoglobulin A deficiency.
• Review the evaluation that should be considered in patients with immunoglobulin A deficiency.
• Describe the management of immunoglobulin A deficiency.
• Identify interprofessional team strategies for improving care coordination and outcomes in patients with immunoglobulin A deficiency.

Introduction

Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency characterized by a decreased amount of serum IgA and a concomitant lack of secretory IgA. Other immunoglobulin levels are normal. By the International Consensus definition, the diagnosis is established in individuals older than four years whose blood levels of IgA are below 7 mg/dl but have normal levels of IgG and IgM. (IgE is  normal too.) These individuals have a normal antibody response to vaccines. Nevertheless, IgA deficiency should be excluded from other causes of hypogammaglobulinemia and defects in T lymphocytes. Patients who suffer from selective IgA deficiency may have clinical symptoms, but most are largely asymptomatic.[1][2]

IgA deficiency is often associated with normal CD4 and CD8 T cells, with normal B lymphocytes in the systemic circulation. Some patients, though,  may harbor anti-IgA autoantibodies.

Patients with IgA deficiency could also suffer from concurrent autoimmune disease. Secondary causes may be due to infection or medications, but these cases are reversible. Recent studies reveal that close to 20-30% of patients with IgA deficiency develop severe respiratory and gastrointestinal tract infections and others are at risk for developing adverse reactions to blood products. Since IgG and IgE anti-IgA antibodies may cause transfusion reactions if given whole blood, they should be administered IgA poor or washed red cells.

Without direct signs or symptoms on presentation, the diagnosis of IgA deficiency may require an initial intuitive approach with a clinical suspicion based on indirect findings. 

Etiology

Like other similar immunodeficiencies, IgA deficiency appears to be a common destination to many pathogenic routes.[3]  At birth, IgG immunoglobulins are transferred across the placenta from mother to child.[4]  In contrast, none of the other immunoglobulins, including IgA, are transported.  IgA is secreted, in large amounts, into breast milk and functions to protect the newborn from enteric infections.  In adults, IgA is found in the secretions from the gastrointestinal and respiratory tracts in the form of saliva, tears, and breast milk; comparatively, serum levels are low. 

Most cases of IgA deficiency appear to be sporadic.  Those cases of primary IgA deficiency that appear familial in nature have no common Mendelian pattern.  Secondary IgA deficiency can result from a myriad of factors.  Many drugs are causative agents for IgA deficiency, including, for example, cyclosporine, gold, penicillamine, and antiepileptics.[5][6][7][8] With the cessation of the medication, the effects are often readily reversible.  Viral infections, such as Hepatitis C, Epstein-Barr virus, and congenital Rubella have a more pronounced effect.  Their deficiency states may develop post-infection and persist for a greater period of time. 

No matter the causative agent, the target remains the same; it is either B-cell proliferation, B-cell maturation (IgA switching), or Plasma cell production of IgA.[9][10] Targeting one or more of these mechanisms has the propensity to cause IgA deficiency. 

Epidemiology

The worldwide prevalence of selective IgA deficiency depends on the ethnic background; it is most prevalent in White-race individuals. The incidence varies from 1:143 to 1:965 in different regions, with equal distribution between the genders.[11] However, the real rate could be higher due to the absence of routine screening programs for immunodeficiencies and because many patients are asymptomatic. It is estimated that the prevalence of selective IgA deficiency is 38-fold higher in first-degree relatives of the patients with the disorder than unrelated donors, and the chance to inherit the disease in the family is about 20%.[1][11]

Pathophysiology

IgA deficiency has been likened to a "Heterogenous Disease" due to its variety of mechanisms, a disease with a common result to a multitude of pathogenic approaches.[12]  The major areas so affected that lead to IgA deficiency center around B-cell proliferation, maturation, and the production of immunoglobulin.[1][13] B-cell proliferation can often be affected by medications. Rituximab, an anti-CD20 monoclonal antibody, has been shown to cause an immunodeficient state by depleting the B-cell population.[14] 

Another physiologic target is B-cell maturation, the "IgA class-switching" that converts the B-cell into an IgA-secreting plasma cell. There are two subclasses of IgA known as IgA1 and IgA2. Monomeric IgA1 is foremost within the serum. There are monomeric and dimeric forms of both IgA1 and IgA2 that are linked by a J-chain (a polypeptide responsible for complex formation and transmural transport) located on mucosal surfaces. [15][16]  Here they neutralize toxins, bacteria, and viruses. IgA1 predominates within the airways, whereas IgA2 is dominant in the colon. IgE can demonstrate a compensatory increase in concentration to the low IgA. This increase is felt to be the reason behind the increased prevalence of atopic disease in IgA deficiency. Roughly one-fourth to a half of patients with IgA deficiency have concurrent allergic diseases. Although the lack of serum IgA provokes no compensatory response, the decrease in secretory IgA has been found to incite a compensatory increase in secretory IgM.[17]  This is believed to be why some patients with IgA deficiency have fewer problems with infections than others. However, the IgM response does not fully relieve the IgA deficient patient of problems. A deficiency of IgA results in a distortion of the microflora within the gut. The IgM response only partially restores the micro population. (IgG itself is unaffected by this situation). Primary IgA deficiency is thought to result from a lack of B-cell maturation. The other literature has suggested that T-cell suppression of B-cell maturation occurs to a degree.[17][18] 

Familial studies have been inconsistent; some cases appear to be autosomal dominant, while others are autosomal recessive. Chromosome mutations have been noted in JAK3, RAG1, RAG2, TAC1, CXCR4, and STAT1.[19]  This causes abnormal cytokines/inflammatory signaling in regulators such as BAFF and TAC1 that, amongst others, promote immunoglobulin switching and production. The quality of life for the IgA deficient patient seems most affected by the disease's indirect effects. Many patients are asymptomatic, but for others, the IgA defect remains hidden behind a facade of comorbidities. 

History and Physical

Most IgA patients remain asymptomatic their whole life. Coincidentally, they are often diagnosed during routine laboratory screening. However, some patients present with different complaints and clinical phenotypes, mainly with recurrent sinopulmonary infection, allergies, autoimmune diseases, gastrointestinal disorders, malignancies, and other severe complications.[1] The most common manifestations associated with selective IgA deficiency are the recurrent pulmonary infections caused by extracellular encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. More severe symptoms occur when selective IgA deficiency is combined with IgG2 and IgG3 subclass deficiency.[11]

Autoimmune diseases have been observed in roughly 20 to 30% of patients with selective IgA deficiency. With selective IgA deficiency, allergic conjunctivitis, eczema, rhinitis, urticaria, food allergy, and asthma are commonly noted. There is an association of IgA deficiency with type 1 diabetes.[20] Type 1 diabetes, SLE, celiac disease, and Graves disease can share the same 8.1 haplotype as IgA deficiency. Scores of other autoimmune maladies also share an association.[4][21]  It is thought that the overlap of genetic loci contributes to this association. Celiac disease shares a specific significance with IgA deficiency in that the paucity of IgA antibodies can lead to the misdiagnosis of celiac disease (See Evaluation - Special Note). The prevalence of IgA deficiency in celiac disease is about 2 to 2.5%.[22]  Generally speaking, autoimmune disease is associated with IgA deficiency through various HLA markers such as A1, B8, DR1, DR3, DR7, DQ2 (8.1 haplotype), and DQ5. Celiac disease is associated with IgG deficiency, the 8.1 haplotype, and the HLA-DQBO2 allele. Incidentally, patients with concurrent celiac disease and IgA deficiency have a greater incidence of other autoimmune illnesses when compared to individuals with celiac disease alone. 

Some autoimmune diseases can have manifestations that can cloud or cover IgA deficiency necessitating an additional workup. Certain conditions like ataxia-telangiectasia can be problematic based on their multiple immunoglobulin deficiencies (IgA, IgG, and IgE are all decreased, unlike in IgA deficiency, where the IgG is normal). Patients with Hyper-IgM syndrome will present with decreased IgA as part of a hypergammaglobulinemia where only the IgM is elevated. These patients present with severe infections and hyperviscosity (due to the increased IgM) and are inherited in either an X-linked or autosomal recessive format.[23]  Selective IgA deficiency should be a possibility in every workup of an autoimmune disease. 

Evaluation

The European Society for immunodeficiencies (ESID) new criteria for diagnosing selective IgA deficiency include the following constellation:

• Undetectable serum IgA levels (below 0.07 g/l, measured by nephelometry), although normal serum levels of IgG and IgM (evaluated by nephelometry at least twice)
• Enhanced susceptibility to infections, especially respiratory
• Diagnosis at an age older than four years (reportedly the age at which nephelometry can measure IgA with precision). 
• Concomitant autoimmune diseases or a family member with the disease
• Excluded secondary causes of hypogammaglobulinemia
• Normal antibody (IgG) response to all vaccinations
• Exclusion of T-cell defect

If specialized immunophenotyping is being performed, the results may show that some patients possess a lower percentage of switched memory B cells (below 0.4%), whereas others may have a similar profile with healthy control percentages. The former patients classified as group I may demonstrate a higher rate of pneumonia, autoimmunity, and hepatosplenomegaly.[18] Patients presenting over 45 years should be tested by a chest X-ray to exclude a thymoma.[11]

Pulmonary function tests are recommended to follow patients with IgA deficiency. Patients with recurrent diarrhea should undergo jejunal biopsy, which may show blunting of the villi. The histopathology may reveal the absence of IgA secreting cells and the presence of IgM secretory cells in the lamina propria.

Special Note: Celiac Disease

Patients with concomitant celiac disease and IgA deficiency can display laboratory incongruencies.[22] The difficulty is that the labs to screen for celiac disease look specifically for IgA-autoantibodies such as anti-tissue transglutaminase (anti-tTG), Endomysial antibodies (EMA), Anti-Gliadin antibody, and antibody to deaminated gliadin peptides. An IgA deficiency, coexistent state, may give a false negative test. Therefore, it is important to check the TOTAL serum IgA levels during the screen. Sources also recommend checking IgG and IgM levels as well. It is also known that a falsely positive beta-HCG occurs due to a heterophile auto-antibody production. 

Treatment / Management

Due to the heterogeneity of the selective IgA deficiency and the fact that there is no specific treatment, every patient requires individual management. The recommended management comprises periodic monitoring, prophylaxis, and treatment of infections with antibiotics (sometimes empirically), treatment of the associated allergic and autoimmune conditions, replacement therapy with intravenous or subcutaneous immunoglobulins (rare), and patient education.[11] Many sources recommend directing empiric antibiotic therapy specifically toward Streptococcus pneumoniae and Haemophilus influenza. Immunoglobulin replacement should be performed judiciously and cautiously to avoid an anaphylactic reaction.[1] The diet may need to be altered in patients with food allergies and food malabsorption syndromes. 

All IgA deficient patines, even if asymptomatic, should receive polyvalent pneumococcal and influenza vaccines; patients must avoid attenuated or live vaccines. Specifically, live vaccines such as oral polio, Bacille-Calmette-Guerin, and yellow fever, should be considered contraindicated due to the threat of subsequent severe infection. 

Differential Diagnosis

The diagnosis of selective IgA deficiency is often is one of exclusion. The following conditions are examples of what must be excluded while making a diagnosis of IgA deficiency:

• Common variable immunodeficiency (CVID), where both IgG and IgA decline significantly, although IgM is also reduced in about half the patients. The IgA deficiency can be seen early in the development of CVID. Memory B-cells decrease in number, and responses to vaccines are defective. CVID and IgA deficiency patients also share mutations in transmembrane activators, Calcium modulators, and Cyclophilin ligand interactions (TCL1, TNFRSF 13B). 
• Single gene primary immunodeficiencies like X-linked hyper IgM syndrome could be easily differentiated from selective IgA deficiency (For hyper-IgM syndrome, see 'History and Physical'). Low levels of IgA can be seen with deficiencies of one or more IgG subclasses. A normal response is seen to some vaccinations. Infections by encapsulated bacteria (Hemophilus influenza and Streptococcus pneumoniae) are seen here in recurrent sinopulmonary infections as they are in IgA deficiency. 
• Patients with thymoma may also present with moderate hypogammaglobulinemia and may have no circulating B cells. Thymoma can present with immunodeficiency (AKA Good Syndrome).[24]  Patients manifest low to absent B-cells, a CD4 positive T-cell decrease, and hypogammaglobulinemia. Those afflicted have problems with recurrent infections by bacteria, viruses, fungi, and opportunistic agents. Resection of the thymoma doesn't herald the resolution of the immune defect. 
• Chronic lymphocytic leukemia (CLL) and lymphoma can have a decreased level of IgA but at the more advanced stages of the disease and typically as part of a pan-hypogammaglobulinemic format.[3] 
• Myeloma; Patients with multiple myeloma can manifest an immunoparetic state where the levels of the uninvolved immunoglobulins decrease due to increasing T and B-cell dysregulation.[25] This finding portends a poor prognosis in terms of overall and progression-free survival (OS and PFS). 
• A variety of anti-rheumatic (sulphasalazine, gold), antiepileptic drugs (carbamazepine, valproate), and ACE inhibitors have the potential to lower the IgA levels (See 'Etiology'). 

With its lack of direct signs and symptoms, IgA deficiency can be overshadowed by other ailments. The presence of clinical acumen, supplemented by suspicion, might be the only and best diagnostic weapon. 

Prognosis

The prognosis, overall, is typically good. Some patients with IgA deficiency may resolve spontaneously. For others, the repeated bouts of infection and/or inflammation, whether compounded by cancer or autoimmune disease, lead to varying rates of decline in health and a cause for trepidation.

Complications

The most common complications are associated with respiratory infections and malignancies. Following complications are associated with IgA deficiency:

• Obliterative bronchiolitis; In this entity, pulmonary damage is more pronounced than in bronchiectasis. There is obstruction of the smallest airways in the lung due to inflammation.[26]  Roentgenographically, this appears as "popcorn lung." 
• Bronchiectasis;  Recurrent lower respiratory infections in IgA deficient patients can result in chronic lung damage, eventually resulting in bronchiectasis. Bronchiectasis is the irreversible dilation of bronchial airways caused by inflammatory damage. This is particularly true with repeated sinopulmonary infections with Haemophilus influenzae and Streptococcus pneumoniae.[27] Bronchiectasis can also lead to colonization by Pseudomonas aeruginosa or non-tuberculous Mycobacterium. This compounds the damage and worsens respiratory function. 
• Pneumonia; Some sources have considered daily prophylactic antibiotics for patients with recurrent sinopulmonary infections. 
• The most severe complications are related to the association of selective IgA deficiency and the development of malignancies, such as adenocarcinoma of the stomach and lymphoma, which arise in particularly older patients.[1][28] Gastric adenocarcinomas have a higher frequency in IgA deficient (and CVID) patients than in the general population.[29]  It is believed that IgA deficient patients have less gastric IgA to contend with toxins. Additionally, specific IgA antibody levels against Helicobacter pylori were decreased. This microbe is related to the development of gastrointestinal malignancies. IgA deficiency increases the risk of gastrointestinal infections due to Giardia lamblia. Patients manifest chronic diarrhea, malabsorption, and nodular lymphoid hyperplasia (NLH). Patients with symptomatic giardiasis have decreased secretory IgA from the small intestine, but serum IgA levels were not a factor. The typical antibiotic treatment is metronidazole, but patients may have refractoriness in IgA deficiency. NLH is a benign finding in the small intestine commonly seen in immunodeficient states and associated with Giardia or Helicobacter infections. NLH is a risk factor for the development of gastrointestinal lymphoma; given this, IgA deficient patients should be screened with endoscopy. 
• Transfusions; Anti-IgA antibodies, according to various sources, have been found in 20 to 40% of IgA deficient patients. The increased risk of transfusion reactions is due to IgG/IgE antibodies.[12][30] The incidence of anaphylaxis is between 1:20,000 and 1:47,000 transfusions. Anti-IgA antibodies are found in blood products, including whole blood, platelets, fresh frozen plasma, cryoprecipitate, granulocytes, and IgA-containing intravenous immunoglobulin (IV-IgG). It is advocated to transfuse IgA deficient patients with washed red blood cells or give them blood products from an IgA-deficient donor. Afflicted patients are also urged to wear a medical alert bracelet denoting their IgA deficiency. 
• COVID; IgA deficiency is felt to be a risk factor for severe COVID-19 infection.[31] With the lack of IgA lining the gastrointestinal tract, viruses can slip by the 'open' mucosal border leading to a cytokine storm syndrome. This is a flooding of the body system with large amounts of inflammatory cytokines that subsequently damage organ systems and leads to acute respiratory distress syndrome (ARDS). The lack of anti-SARS-COV2 IgA and secretory IgA represents a probable cause for the severity of the COVID-19 infection.[32] It is likely responsible for their vaccine failures and their prolonged viral shedding. 

Deterrence and Patient Education

Patients with selective IgA deficiency should be educated. They are recommended to wear a medical alert bracelet. Patients should be aware of potential anaphylactic reactions following transfusion of blood products. The suitable products for patients with selective IgA deficiency are those specially prepared from other IgA-deficient donors or saline-washed red blood cells. However, all special blood products should still be given with great caution, and the healthcare providers should be prepared for potential anaphylaxis. Furthermore, it is recommended that both asymptomatic and symptomatic patients be monitored periodically for anti-IgA antibodies.[1]

Enhancing Healthcare Team Outcomes

Selective IgA deficiency is a disorder that requires an interprofessional healthcare team to provide the best diagnostic process, management, and patient follow-up. Providers, including pediatricians and primary care providers, should be involved in the care of these patients. Specialist consultation from an allergist or immunologist may be required. Patients who have recurrent pulmonary infections will benefit from a consultation with a pulmonologist. Nurses should work with the team to educate these patients on the importance of vaccinations and compliance with antibiotics. Those with food allergies and malabsorption may benefit from a dietary consult.

Selective IgA deficiency is usually a lifelong disease. However, a few patients may have normal levels of IgA. In contrast, cases that progressed to CVID over time have also been recorded. These observations are valid, particularly for adolescence or young adulthood.[1] Thus, after an accidental diagnosis of selective IgA deficiency, these patients should follow up regularly and be evaluated every 4 to 6 months. An interprofessional team approach is vital to improve the quality of life and lower morbidity. Recall, though, that IgA deficiency is a silent disease, requiring more diagnostic suspicion than a direct examination. The presence of certain infections (e.g., recurrent sinopulmonary), the (co-)existence of autoimmune disease, and the reaction to blood products can help to guide the way. However, in the end, it may require more of one's intuition than just observation.