Combined immunodeficiency

Combined Immunodeficiency (CID) is a group of rare immune system disorders characterized by a block in the development of T lymphocytes and, in some forms, B lymphocytes and natural killer (NK) cells. This results in a severely compromised immune response, making individuals susceptible to a wide range of infections. CID is considered more severe than Selective Immunodeficiency Disorders but less severe than Severe Combined Immunodeficiency (SCID).

Etiology

Combined Immunodeficiency disorders can be caused by mutations in various genes that are crucial for the development and function of immune cells. These genetic defects can be inherited in an Autosomal Recessive or Autosomal Dominant manner, depending on the specific type of CID. Some well-known genes involved include RAG1, RAG2, IL2RG, and JAK3.

Pathophysiology

The pathophysiology of CID involves the defective development or function of several components of the immune system. In T cells, this can lead to impaired cell-mediated immunity, while B cell defects can compromise humoral immunity. The absence or dysfunction of NK cells further diminishes the body's ability to combat certain viral and fungal infections. The combined effect of these deficiencies leads to a broad vulnerability to infections, including opportunistic infections that are typically harmless to individuals with a normal immune system.

Clinical Manifestations

Patients with CID present with a wide range of clinical manifestations, often from early childhood. These include:

• Recurrent, severe infections by bacteria, viruses, fungi, and protozoa
• Failure to thrive or poor growth
• Autoimmune disorders
• Increased susceptibility to malignancies, particularly lymphoma and leukemia
• Chronic skin conditions, such as eczema

Diagnosis

Diagnosis of CID involves a combination of clinical evaluation and laboratory tests. Key diagnostic tests include:

• Complete blood count (CBC) with differential to assess lymphocyte counts
• Quantitative immunoglobulin levels to evaluate humoral immunity
• Flow cytometry to analyze T, B, and NK cell populations
• Genetic testing to identify specific genetic mutations

Treatment

Treatment of CID focuses on managing infections, preventing new infections, and, when possible, correcting the underlying immune defect. Approaches include:

• Prophylactic antibiotics and antifungals to prevent infections
• Immunoglobulin replacement therapy to boost antibody levels
• Hematopoietic stem cell transplantation (HSCT) as a potential cure by providing the patient with healthy immune cells from a donor

Prognosis

The prognosis for individuals with CID varies widely depending on the specific type, severity of the disorder, and timing of diagnosis and treatment initiation. Early diagnosis and appropriate treatment can significantly improve outcomes.

Prevention

As most cases of CID are genetic, there are no known measures to prevent the condition. Genetic counseling may be beneficial for families with a history of CID to understand their risks and options.