What is a Combined Immunodeficiency?

Understanding Combined Immunodeficiency: A Guide for Families

In Combined Immunodeficiency (CID), patients have genetic disorders that affect T and B cells, which are part of the adaptive immune system. In contrast to patients with severe combined immunodeficiency (SCID), those with CID commonly have some T-cells present, but their activity is limited.

CID can range from a mild weakening of the immune system to possibly life-threatening infections and inflammation. Although these diseases can be severe, diagnosing and treating them early, along with stem cell transplantation when needed, gives people a better chance of recovery.

Keep reading to learn more about combined immunodeficiency.

What are the types of CID?

Genetic mutations in T and B cells cause Combined Immunodeficiency (CID). Here are some of the major types:

X-linked CID

• Caused by mutations in the IL2RG gene.
• Mostly affects males.
• Results in significant immune system issues.

Adenosine Deaminase (ADA) Deficiency

• Results from mutations in the ADA gene.
• Causes toxic metabolite buildup, harming immune cells.
• Causes severe illnesses and problems related to growth.

JAK3 Deficiency

• They result from alterations in the JAK3 gene.
• Causes faulty signalling in the immune cells.
• Results in an increased risk of infections.

RAG1/RAG2 Deficiency

• Modifications in the RAG1 or RAG2 genes affect the development of immune cells.
• Lowers the amount of antibodies produced.
• Causes recurrent infections.

Other Genetic Variants

• Mutations in the IL7R, CD3, and other genes may also cause CID.
• Immune dysfunction may manifest as mild or severe symptoms.

What Causes Combined Immunodeficiency?

CID stems from genetic mutations impacting immune cell development or function. The following are the major causes:

Genetic Mutations

• IL2RG, ADA, JAK3, RAG1, and RAG2 mutations disrupt immune cell development.
• These impair the body's ability to fight infections.

Defective Immune Signalling

• Faulty cytokine signalling prevents immune cells from functioning correctly.
• This leads to reduced immune responses and vulnerability to infections.

Impaired DNA Rearrangement

• The immune system recombines V(D)J to create diverse antibodies.
• Defects in this process result in poor immune defence.

Toxic Metabolite Accumulation

• Adenosine Deaminase (ADA) Deficiency causes harmful substances to build up, damaging immune cells.

What are the symptoms of CID?

Clinical presentation of combined immunodeficiency includes:

Frequent Infections

• Recurring respiratory infections, including sinus and lung infections
• Ear infections
• Skin infections

Digestive Issues

• Chronic diarrhoea may lead to malnutrition.
• Slow growth or weight gain, especially in infants

Fungal and Opportunistic Infections

• Thrush (oral yeast overgrowth) or severe diaper rash
• Infections that don't respond well to treatment
• Less common are autoimmune symptoms or lymphoproliferative disorders

How is CID diagnosed?

Healthcare providers diagnose combined immunodeficiency through the following:

1. Blood tests show low lymphocyte counts (T and B cells).
2. Immunoglobulin tests evaluate antibody levels (IgG, IgA, IgM) to check the immune response. Low antibody levels may indicate CID.
3. Flow cytometry to assess T, B, and NK cell numbers.
4. Genetic testing of genes like IL2RG, ADA, JAK3, RAG1, and RAG2 to identify causative mutations.
5. The newborn screening T-cell receptor excision circle assay (TREC test) can detect SCID at an early stage.

What is the treatment for CID?

Treatment depends on the severity and specific diagnosis. It generally includes:

Antibiotics and Antiviral Medications

• Prophylactic antibiotics and antifungals.
• Intravenous immunoglobulin (IVIG) replacement to support antibody function.

Immunoglobulin Replacement Therapy

• Provides antibodies to support the immune system.
• Given through intravenous (IV) or subcutaneous injections.

Bone Marrow or Stem Cell Transplant

• Haematopoietic stem cell transplantation (HSCT) offers a potential cure, particularly when intervention occurs early.
• For ADA-SCID, enzyme replacement therapy may be an effective treatment option.

Gene Therapy (Experimental)

• Investigational gene therapies are emerging for select genetic defects.

What are the risks and complications of CID?

Potential complications of combined immunodeficiency include:

Frequent and Severe Infections

• Individuals with CID are highly susceptible to bacterial, viral, fungal, and parasitic infections.
• Even mild infections can become life-threatening without proper treatment.

Autoimmune Disorders

• CID can lead to immune dysregulation, causing the body to attack its tissues.
• This may result in autoimmune anaemia, arthritis, or inflammatory bowel disease.

Increased Cancer Risk

• People with CID have a higher chance of developing lymphomas and other malignancies.
• This is due to faulty immune surveillance, which typically helps prevent the growth of cancerous cells.

Growth and Development Issues

• Infants and children with CID may experience failure to thrive, meaning poor growth and weight gain.
• Chronic infections and malnutrition can further impact development.

Complications from Treatments

• Bone marrow transplants and gene therapy can be life-saving but come with risks like graft-versus-host disease (GVHD).
• Immunoglobulin therapy may cause allergic reactions in some individuals.

What is the care and prevention strategy for CID?

Ongoing care for combined immunodeficiency involves:

• Immune Support: Continue IVIG and prophylactic antimicrobials.
• Regular Monitoring: Check blood counts and organ function.
• Vaccination Precautions: Avoid live vaccines in CID patients.
• Genetic Counselling: Recommended for families affected by inherited CID.

Although CID is rare, early identification can be life-saving, often via newborn screening. Timely treatments, such as HSCT, have survival rates exceeding 90% in early-detected SCID.

What is the Role of Health Insurance in Treating Combined Immunodeficiency?

Combined immunodeficiencies often require costly interventions like HSCT, lifelong IVIG, diagnostics, and ongoing care.

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