What is Severe Combined Immunodeficiency?
Combined immunodeficiency disorder refers to a health condition where the body struggles to fight off infections because of a deficiency in two types of immune system cells, T and B lymphocytes. People with this condition often start experiencing repeated infections very early on in life. They are prone to various types of infections, and sometimes, the usual immune-boosting therapies might not always be available to treat these recurrent issues.
The most critical version of these disorders is called Severe Combined Immunodeficiency Disease (SCID). This condition often starts showing signs by six months of age or even earlier, causing the child to suffer from bacterial, viral, fungal, and protozoal infections. These infections are serious and can result in early death, making SCID different from other combined immunodeficiency forms.
In SCID, both T and B cell functions are either impaired or completely missing. This condition can be either hereditary, random, or linked to the X chromosome, affecting newborn babies. Sadly, without treatment, most children with SCID usually do not live past their first year due to dominance of these opportunistic infections.
What Causes Severe Combined Immunodeficiency?
Severe Combined Immunodeficiency (SCID) is a group of very serious illnesses that affect the immune system. It has several types, causes, and examples:
1. One type of SCID, known as T-B-NK- SCID, can occur if there is a shortage of stem cells, leading to a disorder called reticular dysgenesis. It can also occur due to a problem with a gene related to a substance our body produces called adenosine deaminase (ADA). This faulty gene can cause poisonous substances to appear in cells that are important for our immune system (T, B, and NK cells).
2. T-B-NK+ SCID is caused by a defect in entities called RAG1/2 enzymes, needed by the body to cut DNA and make specific parts of the immune system. It can also happen due to an issue with another substance called Artemis, which is responsible for repairing DNA after it’s cut by RAG1/2.
3. T-B+NK- SCID can be a type that’s inherited from the mother (X-linked) and leads to a lack of IL receptors, which are needed for various substances that assist the immune system (cytokines) due to a shortage of something called the common gamma chain. A similar type known as Jak 3 kinase deficiency is caused by a lack of Jak 3 kinase, a substance that helps signals in the immune system.
4. IL-7 deficiency is a type of T-B+NK+ SCID, where there’s a lack of IL-7 alpha chains that usually helps T cells (essential cells for our immunity) to develop properly. A similar type of this disorder can also occur due to faulty signal transduction due to something called ZAP-70 deficiency.
5. T+B+NK+ MHC failure is a type consisting of two conditions: failure of MHC class I and MHC class II. The first one (MHC class I deficiency) happens when there’s an inability to express MHC class I due to a problem in a process called TAP-2 transcription. The second one (MHC class II deficiency) occurs due to a problem in the process of making MHC class II proteins.
Each of these types can cause different problems and symptoms and would need different treatment strategies.
Risk Factors and Frequency for Severe Combined Immunodeficiency
The Jeffrey Modell Foundation has been working since 2003 to increase public and medical community’s knowledge about primary immunodeficiencies, including severe combined immunodeficiency disease, or SCID. They established a program to screen newborns for SCID and T cell lymphopenia, which now reaches 96% of all newborns in the US.
The symptoms of SCID often appear early, with 89% of affected infants showing signs within the first six months of life. Common symptoms include:
- Recurrent pneumonia (observed in 66% of patients)
- Failure to thrive (observed in 60% of patients)
- Chronic diarrhea (observed in 35% of patients)
In the US, SCID is not very common, affecting only about 1 in 58,000 live births. However, families where parents are closely related (consanguineous relationships) have a greater risk of having children with SCID, especially when the disease is inherited in an autosomal-recessive manner.
Signs and Symptoms of Severe Combined Immunodeficiency
Severe combined immune deficiency is a condition that affects the body’s immunity, making individuals susceptible to infections. It often manifests in the first few weeks or months of life. Below are some common features of this condition:
- Early appearance (in the first few weeks or months of life)
- Exposure to primarily viral or fungal infections
- Frequent respiratory infections
- Oral thrush (candidiasis)
- Failure to thrive or grow properly
- Lack of white blood cells (lymphopenia) – often unnoticed
- Infections by rare microorganisms
- Opportunistic infections
- Recurrent infections
- Frequent use of antimicrobials without noticeable improvement
- Inflammation and infection of internal organs
- Blood disorders, including anemia and low platelet count
- Possibility of autoimmune conditions
People with severe combined immune deficiency may show several physical symptoms and signs, such as:
- Meningitis symptoms
- Blood infections (septicemia)
- Arthritis
- Bacteremia
- Fever
- Frequent cough
- Fatigue (Malaise)
- Intestinal malabsorption (Poor nutrient absorption)
- Bronchiectasis (Damage to airways)
- Reactions against transplanted cells or tissues
- Recurring tonsillitis
- Acute suffocation
- Skin infections caused by viruses and bacteria
Further, people with this condition may have physical defects or abnormalities, such as:
- Absence of tonsils
- Sore throat
- Pus infection in the eyes (purulent conjunctivitis)
- Granuloma (accumulation of immune cells forming a nodule)
- Skin problems
- Various cancers, including brain tumours
- Skin inflammation (eczema)
- Failure to thrive
- Chronic diarrhea
- Tuberculosis
- Short stature
- Excessive growth of lymph tissues (lymphoproliferative disorders)
- Absence of lymph nodes
- Bleeding
- Underdeveloped or absent thymus gland (thymic aplasia or hypoplasia)
- Recurrent skin abscesses
- Muscle spasms (tetany)
- Severe weight loss (cachexia)
- Thrush infections (candidiasis) in the mouth and elsewhere
- Angioedema (swelling beneath the skin)
- Malnutrition
There are other potential physical manifestations:
- Heart abnormalities
- Low body temperature (hypothermia)
- Weakness (asthenia)
- Loss of appetite (anorexia)
- Loss of weight
- Headache
- Convulsions
- Underactive parathyroid glands (hypoparathyroidism)
- Mouth ulcers (aphthous stomatitis)
- Urinary tract infection
- Abnormalities in fetus (hydrops fetalis, fetal demise)
- Denture abnormalities
And more symptoms could include:
- Itching (pruritus)
- Vasculitis (inflammation of blood vessels)
- Hearing problems, including deafness
- Severe skin inflammation (erythroderma)
- Muscle disease (myopathy)
- Retarded growth in the womb (intrauterine growth retardation)
- Dwarfism
- Excessive white blood cells in lungs (lymphocytic interstitial pneumonitis)
- Lack of pigment in the skin, hair, and eyes (albinism)
- Abnormally small head size (microcephaly)
- Glomerulonephritis (inflammation and damage to the kidney’s filters)
- Hemolytic-uremic syndrome (blood disorder resulting in kidney failure and low platelet count)
Additional manifestations in severe combined immune deficiency patients may include:
- Enlarged tongue (macroglossia)
- Pigmented birthmarks (Cafe-au-lait spots)
- Exocrine pancreatic insufficiency (Difficulty digesting food)
- Inflammation of body tissues (serositis)
- Bone loss and fractures (osteoporosis)
- Curvature of the spine (scoliosis)
- Poor wound healing
- Mental retardation
- Nail dystrophy (malformed nails)
- Delayed brain disease (late-onset primary encephalopathy)
- Thyroid inflammation (thyroiditis)
- Malformation of the urinary and genital systems
Further, there could be:
- Spider veins (venous telangiectasias) on the trunk and limbs
- Dwarfism of the bones (chondrodysplasia)
- Amyloidosis (build-up of abnormal proteins in organs)
- Delayed separation of the umbilical cord
- Gum infection (periodontitis)
Testing for Severe Combined Immunodeficiency
If you’re being examined for severe combined immunodeficiency (SCID), a range of tests might be carried out to assess your immune system’s functioning. These could include looking at different types of proteins that help your body fight off infections and diseases (known as immunoglobulins), how well your blood cells that help control your body’s immune response (B and T lymphocytes) are functioning, among other tests.
The tests may include looking at different subgroups of your lymphocytes, a type of white blood cell; checking how these cells respond to different stimuli; measuring the levels of different types of immunoglobulins in your serum (the clear part of your blood); and examining how well your body produces antibodies (proteins that your immune system creates to protect itself).
Moreover, the tests may include looking at your body’s response to different types of infections and diseases, as well as your body’s capacity to mimic the presence of foreign substances (a capability studied using isohemagglutinins). Additionally, your doctor may do tests to examine how well your body’s cells that help fight off bacteria (known as phagocytes) are working. Some components of the system that enhances your body’s immune response (the complement system) may also be quantified.
Microbial studies may also be carried out to check for the presence of bacteria and viruses in your blood, urine, or other body fluids. The doctor might also run tests to check if your immune system is mistakenly attacking your own body’s cells (a condition known as autoimmune disorder).
To examine your body’s blood clotting capability, different coagulation tests might be conducted. Additionally, other investigations might be performed depending on your condition, such as imaging tests (like x-ray, ultrasound, or CT scan), examining a tiny piece of your bone marrow under a microscope, checking the levels of various chemicals in your blood, or testing your DNA to identify any inherited disorders.
Treatment Options for Severe Combined Immunodeficiency
A bone marrow transplant might help in treating a few specific conditions such as RAG1/2 SCID, ADA-SCID, Artemis SCID, and Wiskott-Aldrich syndrome. The procedure can help replace the abnormal blood-forming cells found in the bone marrow with healthy cells.
Treatment with gammaglobulin might also be beneficial for some other conditions like ADA-SCID, RAG1/2 SCID, Jak 3 kinase deficiency, Artemis SCID, Bare lymphocyte syndrome, MHC class II deficiency, X-linked SCID, and CD3 SCID. Gammaglobulin is a type of protein in your blood that can aid in boosting your immune system.
Other options could be beneficial as well. Such as:
- Transfer factor: these are proteins that can boost your immune system.
- Antibiotics: used to treat bacterial infections.
- Antifungals: used to treat fungal infections.
- Antiparasitic drugs: used to treat infections caused by parasites.
- Antivirals: used to treat viral infections.
- Irradiated blood transfusions: a process that uses radiation to eliminate or reduce white blood cells in blood to be transfused.
- Vitamins: these are essential nutrients that contribute to a healthy life.
- Gene therapy: this is an experimental treatment that involves altering the genes inside your body’s cells to stop disease.
- Anti-inflammatory drugs: these reduce inflammation and can relieve pain.
- Use of cytokines: these are proteins that help your cells communicate during an immune response.
Overall, treatment can vary greatly depending on the specific condition and individual factors, so it’s important to discuss all options with your medical team.
What else can Severe Combined Immunodeficiency be?
When diagnosing severe combined immunodeficiency (SCID), doctors can consider other types of combined immunodeficiencies. These patients may share similar symptoms. For instance, those with absence of the thymus gland or T cell deficiency, like DiGeorge syndrome or CHARGE syndrome, may also experience opportunistic infections similar to SCID patients.
Here are some other health conditions that can resemble SCID and should be contemplated:
- Calcium channel deficiencies
- Wiskott-Aldrich syndrome
- NF-kappa-B essential modifier (NEMO) deficiency
- Zeta-chain-associated protein 70 deficiency
- HIV/AIDS
Moreover, malabsorption disorders causing extreme malnutrition can also mimic the symptoms of SCID. Hence, they should be taken into account during diagnosis.
What to expect with Severe Combined Immunodeficiency
Severe Combined Immunodeficiency (SCID), a type of immune system disorder, has the worst outlook compared to other similar conditions. This can only be improved if a bone marrow transplant or experimental gene therapy is successful.
Generally, for people with primary immunodeficiencies (a group of disorders where part of the body’s immune system is missing or functions improperly), long-term treatment with medicines that kill or stop the growth of microorganisms like bacteria (antimicrobials) is needed to improve their quality of life. Every person with these conditions may require a unique approach to treatment, such as genetic testing to identify different enzyme deficiencies.
Possible Complications When Diagnosed with Severe Combined Immunodeficiency
Some severe health conditions that can be life-threatening can include infections caused by different harmful microorganisms like bacteria, viruses, fungi, and parasites. These can lead to multiple organs in the body failing or diseases related to hormones (endocrinopathy). There’s also a chance of getting rare forms of cancer (opportunistic malignancy) and experiencing serious health emergencies like septic shock, congenital disabilities, and respiratory issues.
Also, other possible conditions are:
- Anaphylactic shock, which is a severe allergic reaction
- Conditions affecting blood clotting which can cause bleeding disorders
- Heart failure
- Issues with the kidney that can be acute (short-term) or chronic (long-term) renal failure
- Premature death
- Problems with metabolism leading to conditions like acidosis and alkalosis
- Complications in the nervous system like seizures and coma
