Hypogammaglobulinemia · What Is It, Causes, Treatment, and More

Hypogammaglobulinemia refers to a group of immunodeficiencies characterized by low levels of immunoglobulins (Ig), or antibodies. Immunodeficiencies can be classified according to the defective immune system cell type, such as B- and T-cell disorders, which lead to deficiencies in antibody-mediated and cell-mediated immune responses, respectively.  

Antibodies are proteins produced by the immune system that recognize and help neutralize foreign substances, such as bacteria, viruses, and allergens. Five classes of antibodies exist: IgM, IgD, IgG, IgA, and IgE. Each of these classes has a different function and is responsible for a specific type of antibody-mediated immunity.  

Hypogammaglobulinemias are classified into primary and secondary depending on the underlying cause. Primary hypogammaglobulinemias are inherited disorders caused by genetic mutations or chromosomal abnormalities, which often remain unknown. In adults, the two most common forms of primary hypogammaglobulinemia are common variable immune deficiency (CVID) and selective IgA deficiency. In children, a common form is X-linked agammaglobulinemia,  caused by a mutation in the BTK gene (which is located on the X chromosome). Finally, severe combined immunodeficiency (SCID) is a severe form of primary immunodeficiency caused by genetic mutations that affect immune cells development and function. In SCID, the immune system is severely dysfunctional and almost completely absent, as both antibody-mediated and cell-mediated immune responses are lacking.  

On the other hand, secondary hypogammaglobulinemias are acquired conditions that occur as a result of extrinsic factors affecting the immune system. Secondary hypogammaglobulinemias can be caused by either deficient antibody production or increased antibody loss. Antibody production is decreased in individuals with hematological malignancies, such as chronic lymphocytic leukemia (CLL), lymphoma, and multiple myeloma. Malnourished or immunosuppressed individuals are also at risk of decreased antibody production. Immunosuppressant medications include corticosteroids and non-corticosteroid treatments, such as cyclosporine and tacrolimus, azathioprine, methotrexate, and monoclonal antibodies targeting B-cells (e.g., rituximab). Conversely, increased antibody loss can be due to gastrointestinal losses (e.g., malabsorption or protein-losing enteropathy) and renal losses (e.g., nephrotic syndrome). Finally, secondary hypogammaglobulinemia can also result from states of physical stress, like extreme physical activity, sleep deprivation, and harsh climates.  

Individuals with hypogammaglobulinemia are more prone to developing recurrent infections caused by encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, and Pseudomonas aeruginosa). These bacterial infections most often affect the respiratory tract, causing recurrent sinusitis, otitis media, pharyngitis, bronchitis, and pneumonia. Over time, if lung infections are not properly treated, they can lead to the development of bronchiectasis (i.e., an abnormal enlargement of the bronchi due to chronic inflammation). In addition, individuals may also develop viral gastrointestinal infections as well as infections from intestinal parasites, like Giardia lamblia. 

In addition to recurrent infections, IgA antibody deficiency is connected with increased frequency of atopic conditions (e.g., asthma, rhinitis, and atopic dermatitis) and autoimmune diseases, like rheumatoid arthritis and celiac disease. In selective IgA deficiency, individuals may develop severe anaphylactic reactions when receiving blood transfusions. Anaphylaxis can occur because the IgA in the transfused blood is recognized as a foreign antigen and attacked by the recipient’s immune system. For unknown reasons, individuals with common variable immune deficiency (CVID) are at increased risk of developing malignancies (especially lymphomas) as well as autoimmune conditions, such as autoimmune anemia, thrombocytopenia, or rheumatoid arthritis. 

Treatment of hypogammaglobulinemia depends on the underlying cause. For primary disorders, treatment often involves immunoglobulin replacement therapy with lifelong monthly intravenous immunoglobulin (IVIG) infusions. Intravenous immunoglobulin is a concentrate of pooled immunoglobulins from healthy donors, which provides passive immunity to people with hypogammaglobulinemia to help boost their immune system. In addition, individuals with associated autoimmune conditions may require immunosuppressive therapy with corticosteroids and immunomodulators.  

Treatment of secondary hypogammaglobulinemias depends on the underlying cause. However, treating the specific cause is rarely possible; therefore, supportive measures are generally necessary. Supportive treatment may include prophylactic vaccination with non-live vaccines and preventive antibiotic therapy in individuals undergoing chemotherapy or other immunocompromising treatments. It’s important to note that all individuals with hypogammaglobulinemia should avoid live attenuated vaccines, as the lack of antibodies can hamper the elimination of the weakened pathogen, leading to potentially life-threatening infections.  

Finally, in severe cases of immunodeficiency, such as severe combined immunodeficiency (SCID), treatment may involve hematopoietic stem cell transplantation, as well as antimicrobial prophylaxis and isolation to prevent infections.