Combined Immunodeficiency

Combined immunodeficiencies are a group of rare genetic disorders that affect both major types of infection-fighting white blood cells, making it difficult for the body to defend itself against infections.

Table of contents

• What is combined immunodeficiency?
• How the immune system is affected
• Causes and genetic factors
• Signs and symptoms
• Diagnosis and testing
• Treatment approaches
• Outlook and prognosis

What is combined immunodeficiency?

Combined immunodeficiency (CID) is a group of rare genetic disorders of the immune system that results in impaired immunity. The condition is referred to as ‘combined’ because both T cells (white blood cells that identify and attack invaders) and B cells (white blood cells that produce antibodies against infection) are affected^[1].

Unlike severe combined immunodeficiency (SCID), T cells are usually detectable in CID, and their function can be variably affected. This means that people with CID may have some immune cells present, but these cells don’t work properly^[1].

There are many different genetic variants that can cause CID. These variants lead to moderate to severe susceptibility to infections, and they can sometimes also cause inflammatory disease or autoimmune manifestations due to immune dysregulation (dysfunction of the immune system in which lymphocytes may be present but not work well, allowing for the development of excessive autoreactivity and resultant autoimmune disease and inflammation)^[1].

How the immune system is affected

The immune system is like your body’s built-in security system. It constantly patrols, protects, and defends the body from all types of harmful invaders, including bacteria, viruses, parasites, and fungi^[4].

In a developing baby, the immune system first takes root in the bone marrow. Some stem cells there eventually mature into the two cell types that play the biggest role in warding off infection: T cells and B cells. T cells not only directly attack cells infected with viruses, bacteria, or other microorganisms, but they also cause B cells to produce antibodies^[4].

In combined immunodeficiency, both of these infection-fighting white blood cells are either low in number or function poorly. Without properly functioning T cells and B cells, people with CID have trouble defending their bodies against infections^[1].

Causes and genetic factors

Combined immunodeficiency is caused by genetic mutations that affect the immune system. These are inherited genetic disorders, meaning they are passed from biological parents to their children^[1].

There are many different genetic variants that can cause CID. Each form of CID is caused by a different genetic defect, but all types affect how the immune system develops and functions^[1].

Even though CID is a genetic condition, having one child with CID does not necessarily mean other family members, including siblings, will develop the disease. However, it is a good idea to ask your doctor about genetic counseling for you and your other children^[4].

Signs and symptoms

Individuals with CID often present in the first two years of life with recurrent infections and specific findings associated with the different syndromes. Individuals with milder defects, however, may not present until later in childhood or even early adulthood^[1].

The most common signs include repeated infections that keep coming back or do not go away. People with CID are at risk for infections from many types of organisms, including bacteria, viruses, fungi, and protozoa^[1].

In addition to frequent infections, CID can cause immune dysregulation. This means that even though lymphocytes may be present, they don’t work well. This can lead to inflammatory complications and autoimmune disease, where the immune system mistakenly attacks the body’s own tissues^[1].

Diagnosis and testing

A diagnosis of combined immunodeficiency is usually based on a complete medical history and physical examination. In addition, multiple blood tests may be ordered to help confirm the diagnosis^[4].

The diagnosis can also be made before the baby is born through prenatal diagnosis if there has been a previously affected infant in the family and the genetic variant responsible for their condition has been identified^[7].

Laboratory tests are essential for diagnosing CID. It takes time to perform a thorough evaluation. Some laboratory tests come back quickly, while others, like genetic tests, may take weeks or months. Sometimes doctors want to repeat tests over time to find any trends in cell counts, especially if the numbers are borderline low^[7].

Treatment approaches

Treatment for combined immunodeficiency depends on the specific type and severity of the condition. Preventative treatments such as immunoglobulin (Ig) replacement therapy (infusions of infection-fighting antibodies) and prophylactic antibiotics (antibiotics given to prevent infections) can be helpful^[1].

Immunosuppressive and anti-inflammatory drugs may be needed to control immune dysregulation when the immune system causes inflammation or attacks the body’s own tissues^[1].

Several forms of CID require definitive therapy with hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation. This involves transplanting healthy stem cells from a donor to help restore the body’s ability to produce properly functioning immune cells^[1].

Appropriate supportive care is necessary, including early identification of opportunistic infections and nutritional support. Aggressive and prolonged antibiotic therapy may be needed to treat infections. Prophylactic antibiotic therapy has been recommended for patients with frequent infections, as it may significantly decrease the incidence of infections^[13].

Outlook and prognosis

The clinical spectrum of CID is wide, with some disorders causing mild to moderate disease and others causing severe susceptibility to infections. Unfortunately, the prognosis of CID is not always easy to determine at the level of the affected individual. This becomes important when considering the relative potential risks versus the potential benefits of a particular treatment strategy^[1].

Fortunately, the success rate of HSCT, particularly for those without an HLA-matched sibling donor, has improved substantially over the past few years. This means the risk of this treatment has become much more acceptable for less severely affected individuals^[1].

With proper treatment and management, many people with CID can lead full and active lives. The key is early diagnosis, appropriate treatment, and ongoing monitoring by healthcare professionals who specialize in immunodeficiency disorders^[1].