What is hypogammaglobulinemia?

From the Guidelines

Hypogammaglobulinemia is a condition characterized by abnormally low levels of immunoglobulins, specifically IgG, in the blood, which can lead to recurrent infections and increased morbidity and mortality if left untreated. This disorder can be primary, resulting from genetic or congenital defects, or secondary, acquired due to other medical conditions, treatments, or medications such as those used in chronic lymphocytic leukemia (CLL) 1. The condition compromises the immune system's ability to fight off pathogens, making patients more susceptible to severe and recurrent infections, particularly of the respiratory and gastrointestinal tracts.

Key Characteristics and Treatment

• Hypogammaglobulinemia is identified by low IgG levels, often below 400-500 mg/dL, although recent studies suggest that levels as low as 650 mg/dL during certain treatments, like ibrutinib for CLL, could be indicative of increased risk for secondary hypogammaglobulinemia 1.
• Immunoglobulin replacement therapy (IgRT) is the cornerstone of treatment, aiming to restore normal immunoglobulin levels and reduce the frequency and severity of infections 1.
• IgRT can be administered intravenously (IVIG) or subcutaneously (SCIG), with recent evidence suggesting that SCIG may offer benefits in terms of increased IgG levels and reduced infectious episodes 1.
• The goal of IgRT is to achieve a target trough level of 600-800 mg/dL, which has been associated with improved clinical outcomes, including a reduction in major and clinically documented infections 1.

Clinical Considerations

• Patients with hypogammaglobulinemia should be monitored closely for signs of infection and receive prompt treatment when infections occur.
• Vaccination strategies are crucial, with recommendations to receive all non-live vaccines as scheduled and to avoid live vaccines due to the risk of vaccine-related infections in immunocompromised individuals.
• The management of hypogammaglobulinemia, especially in the context of CLL and other hematologic malignancies, requires a multidisciplinary approach, considering the underlying disease, current treatments, and the patient's overall health status 1.

From the Research

Definition of Hypogammaglobulinemia

• Hypogammaglobulinemia is defined as a reduced immunoglobulin level, which can be either primary due to inborn errors of immunity or acquired in the setting of poor antibody production or increased antibody loss 2.
• It can be secondary, resulting from various conditions such as immunosuppressive therapy, transplant, protein loss syndromes, certain autoimmune conditions, and malignancies 2, 3.

Causes and Associations

• Secondary hypogammaglobulinemia (SHG) can be associated with increased infectious risk and should be considered in patients with a history of immunosuppressive therapy, transplant, protein loss syndromes, certain autoimmune conditions, and malignancies 2.
• SHG can also occur in patients with hematological malignancies, such as lymphoproliferative diseases and multiple myeloma, as an intrinsic aspect of the disease or following chemo-immunotherapy regimens 4.
• The use of immunotherapy, such as rituximab, and immune-suppressive therapy, including steroids, sulfasalazine, and mycophenolate mofetil, can also lead to iatrogenic hypogammaglobulinemia 4.

Diagnosis and Management

• Appropriate history and lab-based screening can identify SHG, allowing for treatment and close monitoring as appropriate 2.
• Treatment focuses on control of the underlying condition or removal of iatrogenic causes of SHG, but in many cases, treatment of the underlying condition does not reverse SHG or immunosuppressive therapy cannot be discontinued without significant risk to the patient 2.
• Strategies for risk mitigation against infectious complications include vaccination, antibiotic prophylaxis, and immunoglobulin replacement therapy 2, 4, 5.
• Immunoglobulin replacement therapy has been shown to reduce the rate of infectious events in patients with SHG, particularly those with hematological disorders and solid organ transplantation 4, 5.