Severe Combined Immunodeficiency (SCID) – Overview

Description – SCID

Severe combined immunodeficiency (SCID) is the name given to a group of rare, inherited disorders that cause major abnormalities of the immune system. They form part of a larger group of conditions known as primary immunodeficiencies. The immune system abnormalities in SCID lead to greatly increased risks of infection and other complications that are life-threatening. Affected infants become unwell within the first few months of life, and before modern medication and treatments were available, most affected babies did not survive beyond their first year. Today, doctors understand much more about SCID. Treatment is now available that can reduce the risk of serious infection, and in many cases, cure the disorder.

Types of SCID

X-Linked SCID (XSCID)

This is the most frequent type of SCID with approximately 50% of the incidence. Mutation in the interleukin 2 receptor gamma (IL2RG) gene on X-chromosome is the primary cause for XSCID. IL2RG play a crucial role in the development of surface receptors on lymphocytes. These receptors upon activation by cytokines help the cells to mature and multiply. X-linked inherited mutations in IL2RG disrupt its functioning, creating a faulty “common gamma chain subunit”, which is a part of several defective interleukin (IL) receptors.

IL2RG also activates an important signaling molecule, JAK3 on Chromosome 19. Mutations in JAK3 also contribute to defective IL receptors. As a result of these mutations, T-lymphocytes which play a major role in foreign body location and maintaining the natural defense mechanism of the body remain underdeveloped.

Alpha Chain of the IL-7 Receptor deficiency SCID

This is the third most common form of SCID with 11% of the incidence. It is due to the mutation in the gene that encodes the alpha chain of the IL-7 receptor (IL-7Rα). There is a deficiency of T-cells, which further leads to the non-functioning of B-cells.

Janus Kinase 3 deficiency SCID

It results due to the gene mutation that encodes an enzyme, which is present in the lymphocyte named Janus Kinase 3. The patients with this type of SCID are quite similar to X-linked SCID.

CD3 Chains deficiency SCID

Three other forms of SCID results due to genetic mutations leading to deficiency of CD3δ, ε or ζ protein chains.

CD45 deficiency SCID

It is due to mutations in the genes that are responsible for coding CD45 protein, which further is responsible for the correct functioning of T-cells.

Pathophysiology

Genetic mutations in SCID disorders preclude normal production and maturation of T-cell lymphocytes and/or B-cell lymphocyte secretion of antibodies, thus preventing the development of a normal, healthy immune system. Following birth, newborns have high levels of maternal antibodies to provide protection from pathogens until the newborn’s immune system develops over the next few months. Most infants are exposed to pathogens during this period but have some ability to fight infections as their immune system develops. Infants with SCID do not have a functional immune system response to pathogenic antigens and cannot adequately overcome infections. Parents may notice their infant has frequent, severe and long-lasting infections, and often report undergoing diagnostic odysseys until their child is eventually diagnosed with SCID, usually around four to six months later.

Causes of SCID

There are more than 15 recognized kinds of SCID, but the most common type, known as SCID-X1 (for “X-linked severe combined immunodeficiency”), involves a defect in a gene on the X chromosome. Because girls have two X chromosomes while boys have only one, SCID-X1 affects only male children. However, girls can be “carriers” and can pass the disorder on to their own sons later in life.

Different genetic defects cause each form of SCID. But all types of SCID are genetic – meaning they are caused by an error or mutation in the child’s genes.

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

Inheritance Pattern

While all forms of SCID are due to specific gene mutations, some individuals affected with the disorder have the X chromosome-linked form, XSCID. In XSCID, males inherit the X-linked gene mutation from carrier mothers. Females are not affected, although they have a 50 percent chance of being carriers of the gene mutation and may pass this mutation to any future offspring. Several autosomal recessive genetic mutations also may cause SCID.

What are the risk factors for severe combined immunodeficiency?

There are risk factors of age, sex, and ethnicity:

• Most patients with SCID present by age 3 months.
• The most common form of SCID (responsible for about 45% of all cases) is X-linked and only presents in males. Other forms, however, can present in males and females equally.
• Certain ethnic groups – including the Finnish, North Africans, Italians, Navajos, and Apaches – appear to carry a greater risk for specific forms of this condition.

Clinical presentations of SCID

Symptoms of SCID usually become apparent within the first year. The following are the most common symptoms of SCID; however, each child may experience symptoms differently. Symptoms may include:

Numerous, serious, and/or life-threatening infections that are not easily treated and do not respond to medications (as they would in children without SCID), including the following:

• An infection of the lungs.
• An infection of the brain.
• An infection in the bloodstream.

Other infections, including the following:

• Chronic skin infections
• Yeast infections in the mouth and diaper area
• Diarrhea
• Infection of the liver

Diagnosis of SCID

Severe combined immunodeficiency (SCID) is generally suspected in infants younger than one-year-old who suffer from frequent and/or serious infections (especially fungal infections that are resistant to treatment), persistent diarrhea, weight loss, and chronic (ongoing) skin infections. These patients may have an enlarged liver, spleen, and/or lymph nodes, which indicate that the body is fighting off an infection. A series of tests (listed below) are necessary to confirm a diagnosis.

Complete blood count (CBC): A complete blood count (CBC) can be conducted to determine the number of lymphocytes in the blood. Lymphocytes are special cells in the bloodstream that support the immune system and keep a patient healthy. The blood count can also show if other immune cells in the blood are absent or out of balance. During the procedure, a small sample of blood is taken and analyzed under the microscope. Decreased levels of lymphocytes may indicate the presence of SCID.

Blood smear: A blood smear is often used to measure the number of lymphocytes (a kind of white blood cell in the patient’s blood). The white blood cells, which are part of the body’s immune system, help fight against diseases and infections. Healthy patients typically have more than 1,500 lymphocytes per cubic millimeter of blood. Infants who have SCID usually have significantly decreased numbers of white blood cells.

Mitogen stimulation assay: Lymphocyte function can be tested by its reaction to specific stimulation with plant extracts called mitogens. Mitogens are added to a sample of the patient’s blood to stimulate mitosis (cell division) of lymphocytes. This allows the healthcare provider to observe the lymphocytes during mitosis. This test can detect abnormal or dysfunctional lymphocytes that cause SCID.

Immunoglobulin test: An immunoglobulin test measures the levels of antibodies (a glycoprotein that detects and binds to foreign substances that enter the body) in the blood. Patients who have SCID will have extremely low levels of immunoglobulin, especially two types called immunoglobulin A (IgA) and immunoglobulin (IgM). However, soon after birth, immunoglobulin G (IgG) levels may still be high because the newborn still has healthy maternal IgG that it received through the umbilical cord before birth.

X-ray: An X-ray may detect an absent or abnormally small thymus gland, which is associated with SCID. Some T-cells are produced in the thymus gland. If the thymus gland is abnormally small, an insufficient amount of T-cells may be produced causing SCID. An X-ray may also detect inflammation of the lung caused by pulmonary infections like interstitial pneumonitis or pneumonia.

Prenatal testing: Amniocentesis, chorionic villus sampling, or cord blood can be used to diagnose a fetus with SCID. These procedures are most often conducted in patients who have a family history of SCID. Amniocentesis is performed at about 15-18 weeks of gestation. During the procedure, a long, thin needle is inserted into the pregnant woman’s abdominal wall to the uterus. A small amount of fluid is removed from the sac that surrounds the fetus. The fluid is then analyzed for genetic abnormalities. There is a risk of infection or injury to the fetus and a chance of miscarriage.

During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the uterus during early pregnancy to screen the fetus for genetic defects. Depending on where the placenta is located, CVS can be performed through the cervix (Transcervical) or through the abdomen (Transabdominal). The risks of infections or fetal damage are slightly higher than the risks of amniocentesis. Fetal loss occurs about two percent of the time.

During a cord blood test, a sample of blood is taken from the umbilical cord at the time of birth. The sample is then analyzed in a laboratory to determine whether the newborn has genetic abnormalities that indicate SCID.

Treatment and Medications that can cure SCID.

Isolation

Your baby may need to stay away from young children. This makes it less likely they will catch an illness from another child.

Immunoglobulin Replacement Therapy

Babies with SCID should be placed on immunoglobulin replacement therapy if they are more than three months of age or have already had infections. Regular immunoglobulin replacement therapy can replace missing antibodies that help your baby fight infections.

Bone Marrow Transplant

The most effective treatment for SCID is a bone marrow transplant. Bone marrow makes cells for fighting infections and illnesses. In a bone marrow transplant, bone marrow cells from a person with a working immune system are given to a person with SCID, whose bone marrow cannot make cells to fight infections and illnesses.

Gene therapy

Gene therapy involves inserting genes into an individual’s cells and tissues to treat a hereditary (passed down from parents to children) disease. Several gene therapy clinical trials based on gene transfer to hematopoietic cells (blood-forming cells in the bone marrow) have been performed. However, further research is necessary before gene therapy can be recommended.

Integrative Therapies

Blessed thistle: Laboratory studies report that the herb blessed thistle and chemicals in blessed thistles, such as cnicin and polyacetylene, have activity against several types of bacteria and no effects on other types. Avoid if allergic to blessed thistle, mugwort, bitter weed, blanket flower, chrysanthemum, coltsfoot, daisy, dandelion, dwarf sunflower, goldenrod, marigold, prairie sage, ragweed, Echinacea, or any plants of the Asteraceae or Compositae families. Avoid in patients with a history of bleeding diseases or gastroesophageal reflux disease (GERD), or if taking drugs for blood disorders, stroke, stomach diseases, or to control stomach acid. Avoid if pregnant or breastfeeding. Stop use two weeks before surgery/dental/diagnostic procedures with bleeding risk and do not use immediately after these procedures.

Bladderwrack: Laboratory study suggests the antifungal and antibacterial activity of bladderwrack. However, there are no reliable human studies to support its use as an antibacterial or antifungal agent.

Avoid if allergic or hypersensitive to Fucus vesiculosus and iodine. Avoid with a history of thyroid disease, bleeding, acne, kidney disease, blood clots, nerve disorders, high blood pressure, stroke, or diabetes. Avoid if pregnant or breastfeeding.

Cranberry: Study results of cranberry as an antibacterial in other conditions show conflicting results. Further research is needed before a conclusion can be drawn.

Avoid if allergic to cranberries, blueberries or other plants of the Vaccinium genus. Sweetened cranberry juice can affect blood sugar levels. Use cautiously with a history of kidney stones. Avoid more than the amount usually found in foods if pregnant or breastfeeding.

Iodine: Iodine is commonly applied to the skin’s surface to clean wounds, sterilize the skin before surgical/invasive procedures, or sterilize the place for catheters before they are put in to collect urine. Betadine solution (topical disinfectant), for example, contains povidone-iodine. Other topical disinfectants include alcohol and antibiotics; iodine is sometimes used in combination with these. Commercially prepared iodine products are recommended in order to assure appropriate concentrations (strengths).

Probiotics: An increasing number of studies support the use of probiotics as a supplement to antibiotic therapy. Probiotic supplementation during treatment of antibiotics may reduce the side effects of antibiotics in the digestive tract. This includes reducing the growth of Clostridium difficile bacteria, which can lead to colitis, a common complication of antibiotics, especially in the elderly. Some probiotics may also help prevent the development of antibiotic resistance. In acutely ill children, synbiotics (nutritional supplements containing probiotics and prebiotics) have been linked to greater weight gain and fewer bacterial illnesses after antibiotics are ended. The evidence consistently supports supplementation of antibiotics.

Medications for Severe combined immunodeficiency (SCID)

Antibiotics: Antibiotics, such as erythromycin (ERYC©), azithromycin (Zithromax©), and clarithromycin (Biaxin© Filmtab, Biaxin© Granules, Biaxin© XL Filmtab, or Biaxin© XL Pac), are used to treat bacterial infections that are often associated with SCID.

Antifungals: Antifungals, such as trimethoprim and sulfamethoxazole (Bactrim© or Septra©), pentamidine (NebuPent©, Pentam©, Pentacarinat©), amphotericin B (Abelcet©), fluconazole (Diflucan©), ketoconazole (Nizoral©), nystatin (Mycostatin©), and atovaquone (Mepron©), are used to treat fungal infections that are commonly associated with SCID.

Antivirals: Antivirals, such as ganciclovir (Cytovene©), foscarnet (Foscavir©) and acyclovir (Zovirax©), are used to treat viral infections that are often associated with SCID.

SCID – Prognosis

Without treatment SCID usually results in severe infection and death in children by age of 2. When performed from an HLA-identical sibling, and in the first few months of life, HSCT can result in a greater than 90% long-term survival rate.