Primary Immunodeficiency Disorders

What is Primary Immune Deficiency Disease?

Primary cellular immunodeficiencies (PID) are a group of inherited disorders characterized by severe impairment of the immune systems in the body, which generally leads to early death from infectious complications. Mainly T lymphocytes, B lymphocytes and Natural Killer cells play a pivotal role for immune system, whereas neutrophils and other phagocytes play a role in primary defence.

To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood.

What Causes Primary Immune Deficiency Disease?

While not contagious, these diseases are caused by hereditary or genetic defects, and, although most disorders present at birth or in early childhood, the disorders can affect anyone, regardless of age or gender. However, certain varieties affect the male child only. Some affect a single part of the immune system; others may affect one or more components of the system.

What are the Symptoms?

While the diseases may differ depending on type and person to person, they all share one common feature: each results from a defect in one of the functions of the body’s normal immune system and results in severe and recurrent infections.

Because one of the most important functions of the normal immune system is to protect us against infections, patients with PID commonly have an increased susceptibility to infections.

The symptoms are usually in the form of

• Frequent and recurrent pneumonia
• Bronchitis
• Sinus infections
• Ear infections
• Meningitis
• Skin infections and blood infections

In addition to frequent infections, other problems that may occur include:

• Abnormailities in nails, skin and bones
• Inflammation and infection of internal organs
• Blood disorders, such as low platelet counts or anemia
• Digestive problems, such as cramping, loss of appetite, nausea and diarrhea
• Delayed growth and development
• Autoimmune disorders, such as lupus, rheumatoid arthritis or type 1 diabetes

How do we classify Primary Immune Deficiency Disease to decide on the outcome?

Unlike cancers, diagnostic criteria and conditioning for Primary Immune Deficiency (PID) diseases is different for different types of PIDs.

For example commonly found diseases are:-

• SEVERE COMBINED IMMUNE DEFICIENCY (SCID) is a commonest disease caused by a group of genetic disorders with a shared phenotype of deficient T- and B-lymphocyte function (with or without abnormal natural killer cell development). Except for those patients with SCID due to deficiency of adenosine deaminase (ADA), for which a replacement enzyme exists, the only curative therapy for SCID is Allogeneic BMT.
  
  However, early results with gene insertion into autologous hematopoietic stem cells for children with X-linked SCID and ADA deficiency suggest that eventually, this might become a more common form of curative treatment for many PIDs.
  
  At the time of diagnosis, patients with SCID generally have already developed, or are at an extremely elevated risk of developing, a life-threatening infection. This necessitates rapid initiation of BMT. Successful outcomes are more likely to be achieved when the patient is still very young, preferably less than 6 months of age with all type of graft.
• Diseases include syndromes with T-cell defects (for example, Wiskott–Aldrich Syndrome (WAS) and Hyper IGM1 Syndrome
• Inherited predispositions to development of Hemophagocytic Lymphohistiocytosis (HLH) (for example, Familial HLH, Chediak – Higashi Syndrome (CHS), Griscelli Syndrome and X-Linked Lymphoproliferative Disease) and Phagocytic Disorders (for example, severe congenital neutropenia (SCN), Leukocyte Adhesion Deficiency and Chronic Granulomatous Disease (CGD).
• COMMON VARIABLE IMMUNE DEFICIENCY (CVID): This is a disorder characterised by abnormality in B cells resulting in decreased or absent levels of immunoglobulins. The simple but expensive treatment for this condition is monthly replacement of immunoglobulins by intravenous infusions. Some of them might require a BMT eventually.

How do we Diagnose Primary Immune Deficiency Disease?

• Complete Blood Count: A careful examination of routine blood count often gives an indication by reduced lymphocyte or neutrophil counts. WAS is suggested by abnormalities in platelets and CHS is suggested by presence of large inclusion bodies inside the white cells.
• Flow Cytometry: This is the key test to determine the presence or absence or reduction in various immune cells. The current classification depends on the percentage of T, B and NK cells in the blood.
• Quantitative Immunoglobulins: a measure of various immunoglobulin levels. This is done to detect abnormalities in the B lymphocyte compartment.
• Cytogenetics: This is done to find out the abnormalities in the chromosomes. When certain genes are mutated, it leads to complete, partial or defective immune cells.
• Antenatal Screening: For mothers who have already had a child with a PID, prenatal testing can be done for subsequent pregnancies. Samples of amniotic fluid, blood or cells from the placenta are tested for PIDs in order to be prepared to start treating a child with PID soon after birth.

What are the Complications of Primary Immune Deficiency Disease?

• Recurrent infections
• Autoimmune disorders
• Damage to heart, lungs, nervous system or digestive tract
• Slowed growth
• Increased risk of cancer
• Death from serious infection

How do we treat Primary Immune Deficiency Disease?

Definitive cure is generally only achieved by ALLOGENEIC BMT, though recent advances in gene therapy hold significant promise that this may soon be a viable.

When is BMT needed for children with Primary Immune Deficiency Disease?

As soon as, it is diagnosed, several studies have demonstrated that infants transplanted at less than 3.5 months of age had a 95% Overall Survival (OS), compared to only 76% OS in older children.

This is likely due to the development of pulmonary infections prior to transplant, which have been associated with significantly poorer outcomes. In addition, transplants performed within the first month of life are associated with more rapid T-lymphocyte reconstitution, perhaps due to better function of thymus gland in younger children.

How is Conditioning for BMT done in Primary Immune Deficiency Disease?

Few cases don’t need conditioning. Otherwise Reduced Intensity Conditioning with low doses of chemotherapy or radiation is the preferred option.

Who can be a donor for BMT?

Although we prefer a matched family donor, a Half Matched (Haploidentical) family donor or a Matched unrelated donor (PBSC or BM) or cord blood are suitable alternatives. As BMT is required as an emergency procedure in this condition, Haploidentical Family Donor is often the preferred option if a matched family donor is not available.

What are the results of BMT in Primary Immune Deficiency Disease?

BMT is the only cure for patients who suffer from PID. Matched family donors have significantly improved 3-year OS (90%) and the results of alternate donor BMT are improving as well.