What Is It, Causes, Treatment, and More
Author:Anna Hernández, MD
Editors:Alyssa Haag,Lily Guo,Kelsey LaFayette, DNP, ARNP, FNP-C
Illustrator:Jessica Reynolds, MS
Copyeditor:David G. Walker
What is hypogammaglobulinemia?
Hypogammaglobulinemia refers to a group of immunodeficiencies characterized by low levels of immunoglobulins (Ig), or antibodies. Immunodeficiencies can be classified according to the cell of the immune system that is defective, like B- and T-cell disorders, which respectively lead to a deficiency in antibody-mediated and cell-mediated immune responses.Antibodies are proteins produced by the immune system that recognize foreign substances, like bacteria and viruses, and help to neutralize them. There are five types of antibody classes: IgM, IgD, IgG, IgA, and IgE. Each of these antibodies has a different function and is responsible for a specific type of antibody-mediated immunity.
What causes hypogammaglobulinemia?
Hypogammaglobulinemias are classified into primary and secondary depending on the underlying cause. Primary hypogammaglobulinemias are inherited disorders caused by genetic mutations or chromosomal abnormalities often with an unknown underlying cause. 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, which is caused by a mutation in the BTK gene (which is located on the X chromosome). Finally, there is severe combined immunodeficiency (SCID), a severe form of primary immunodeficiency caused by a genetic mutation that affects the development and function of immune cells. With SCID, the immune system is so dysfunctional that it is considered almost completely absent as there is a lack of both antibody-mediated and cell-mediated immune responses.On the other hand, secondary hypogammaglobulinemias are acquired conditions that occur as a result of some extrinsic factor affecting the immune system. Causes of secondary hypogammaglobulinemia can be categorized into deficient antibody production and increased antibody loss. Antibody production is decreased in individuals with hematological malignancies, such as chronic lymphocytic leukemia (CLL), lymphoma, and multiple myeloma. Individuals who are malnourished or who undergo immunosuppressive treatment are also at risk of decreased antibody production. Immunosuppressant medications include corticosteroids and non-corticosteroid treatments, including cyclosporine and tacrolimus, azathioprine, methotrexate, and monoclonal antibodies targeting B-cells. 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.
What are the signs and symptoms of hypogammaglobulinemia?
Signs and symptoms of hypogammaglobulinemia include an increased tendency to develop recurrent infections that are typically caused by encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, and Pseudomonas aeruginosa). Most often, these bacterial infections 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, which is when the bronchi become abnormally enlarged due to chronic inflammation. In addition, individuals may also develop viral gastrointestinal infections as well as infections from intestinal parasites, like giardia lamblia.Next, some individuals with antibody deficiency (specifically of IgA) may experience increased frequency of atopy that mainly manifests as asthma, rhinitis, and dermatitis; as well as autoimmune diseases, like rheumatoid arthritis and celiac disease. In selective IgA deficiency, individuals may develop severe anaphylactic reactions when they are transfused with blood. Anaphylaxis can occur because the IgA in the transfused blood is recognized as a foreign antigen and attacked by the immune system. For unknown reasons, individuals with common variable immune deficiency are at an increased risk of developing malignancies (especially lymphomas) as well as autoimmune conditions, like autoimmune anemia, thrombocytopenia, or arthritis.
How is hypogammaglobulinemia diagnosed?
Diagnosis of hypogammaglobulinemia is suspected in individuals with recurrent infections of the respiratory and gastrointestinal tract and may be confirmed with blood tests, revealing decreased immunoglobulin levels of all or some of the Ig classes. If initial antibody levels are found to be low, IgG antibodies to previously administered vaccines may be measured to determine responsiveness to vaccination. For primary disorders with known genetic mutations, like with X-linked agammaglobulinemia, genetic testing can be conducted to confirm the diagnosis.
How is hypogammaglobulinemia treated?
Treatment of hypogammaglobulinemia depends on the underlying cause. For primary disorders, treatment often involves immunoglobulin replacement therapy with lifelong monthly IVIG infusions. Intravenous immunoglobulin (IVIG) is a concentrate of pooled immunoglobulins from healthy donors that provides a diverse set of antibodies, which gives people with hypogammaglobulinemia passive immunity to help boost their immune system. In addition, individuals with associated autoimmune conditions may require immunosuppressive therapy with corticosteroids and immunomodulators. The recurrent bacterial infections experienced by individuals with hypogammaglobulinemia can be treated with antibiotics.
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, all individuals with hypogammaglobulinemia should avoid live attenuated vaccines because the lack of antibodies can make the weakened pathogen difficult to destroy and could lead to potentially life-threatening infections.
Finally, in severe cases of immunodeficiency, like those with severe combined immunodeficiency (SCID), treatment may involve hematopoietic stem cell transplantation as well as antimicrobial prophylaxis and isolation to prevent catching an infection.
What are the most important facts to know about hypogammaglobulinemia?
Hypogammaglobulinemia is a type of immune deficiency characterized by low levels of immunoglobulins or antibodies. Primary hypogammaglobulinemias are relatively rare, genetic, and typically inherited defects of the immune system that lead to decreased antibody-mediated immunity. The most common primary hypogammaglobulinemias are common variable immune deficiency (CVID), selective IgA deficiency, and X-linked agammaglobulinemia. On the other hand, secondary hypogammaglobulinemias are much more common acquired disorders that occur as a result of some extrinsic factor affecting the immune system (e.g. hematologic malignancies, gastrointestinal disorders). Treatment of hypogammaglobulinemia may include lifelong IVIG infusions and supportive treatments, depending on the underlying cause.
Watch related videos:
Related linksAntibody classes
Introduction to the immune system
Immunodeficiencies: T-cell and B-cell disorders: Pathology review
Resources for research and reference
American Academy of Allergy, Asthma, and Immunology. Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency. American Academy of Allergy, Asthma, and Immunology. Published December 2011. Accessed 2023. https://www.aaaai.org/Aaaai/media/Media-Library-PDFs/Practice%20Management/Practice%20Tools/IVIG-guiding-principles.pdf
McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy, Asthma & Clinical Immunology.
Otani IM, Lehman HK, Jongco AM, et al. Practical guidance for the diagnosis and management of secondary
hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and
Altered Immune Response Committees. Journal of Allergy and Clinical Immunology.
Patel SY, Carbone J, Jolles S. The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis,
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Review, 20th Edition. McGraw Hill Professional; 2021.