The Immune System, Primary Immunodeficiency & Resources

The immune system is an extensive internal network that consists of cells, tissues and organs whose job it is to protect and defend the body from harmful invasion by foreign bodies such as viruses, bacteria, toxins, etc.

This system, sometimes referred to as the lymphatic organs, is spread throughout the body and each component has its specific job. Some act to recognize the foreign body, some manufacture the fighters, some distribute them, some regulate them, some produce the clean up teams, and some keep a record of the invasion so that a similar attack can be responded to effectively.

The bone marrow plays a major role in all of this. Here all the cells of the immune system originate. Some of these cells will remain in the bone marrow and mature into the so called B lymphocytes (literally, lymph-cells). Some of these B cells will produce the antibodies to respond to the invading foreign body. These antibodies are very specific proteins that recognize and lock onto a particular protein and by doing so trigger a response in other cells to move in, surround, destroy and remove the invading body. Some of these B cells will keep a record of the invasion and response for use in future.

Some cells that form in the bone marrow move out to the thymus gland where they mature into T lymphocytes. Like the B cells they come in a variety of types for a variety of jobs. Some trigger the B cells into action, some regulate the speed of reaction, some destroy, some clean-up.

These cells, carried throughout the body by the blood, are the front and centre operators of the system that scans, filters and fights for the well-being of the body.

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What is Primary Immunodeficiency (PI)?

Primary immunodeficiency refers to an immune system which from birth is either broken or completely missing. It is not a condition acquired after birth from infection or accident. It is a genetic malfunction, unique to an individual, and can affect just one cell or many parts of the immune system.

Each individual has his or her own blueprint, a map made up of millions of bits of information called genes. The gene-map of each individual is a unique mix of genes from the mother and father. This map instructs the body how to build and how to maintain itself. Sometimes there are malfunctions in this map. When it fails to produce a functioning immune system the disease resulting is called a primary immune deficiency (PI). Sometimes there may be a history of such a malfunction in the family, but often there is not. It all depends upon how the genes of the parents have come together to make up the blueprint for a unique and distinct individual.

The World Health Organization recognizes more than 150 different forms of PI. These forms range widely in severity and symptoms. Early diagnosis is crucial because an untreated PI can lead to serious damage to organs, physical disabilities, and in the most severe cases, death.

Approximately 13,000 Canadians suffer from a PI. That may not seem so large a number, but that is greater than the total number of those who suffer from leukemia and lymphoma combined.

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What are some types of PI?

IgA deficiency is the most common form of PI. IgA is an immune-globulin found primarily in the saliva and other body fluids that guard the entrances into the body. People without sufficient IgA may suffer from allergies, colds, and respiratory infections. Usually the condition is not severe and many people do not have any symptoms at all. It seems those of European ancestry are the most affected group. Because this PI varies across racial and ethnic lines there are various estimates of how often it occurs, but the average seems to be 1 in every 600.

DiGeorge syndrome, also known as microdeletion 22q11 syndrome, is the absence of or a very small thymus gland. The thymus is the gland that matures T cells. The majority of people with DiGeorge syndrome develop fairly normal numbers of T and B lymphocytes over time. It is estimated this PI affects 1 in 4000.

Common Variable Immunodeficiency (CVID), also known as hypogammaglobulinemia, is a group of disorders characterized by impaired antibody responses. This PI is marked by lower blood levels of two immune-globulins, IgG and IgA, and in about half the cases, of a third immune-globulin, IgM. People with CVID do not make sufficient or effective antibodies to fight bacterial and viral infections. The most common symptoms initially are recurrent and difficult to clear infections of ear, nose, sinuses, bronchi and lungs. Serious and even life-threatening infections are an issue, as is organ damage from recurrent infection, especially in the lungs, and bone abscesses. Some may be unable to produce or maintain antibody responses to vaccinations. CVID affects males and females in equal number. Some display symptoms early in life, and some not until their twenties or later. “Variable” refers to the fact that CVID can present in many ways and there is a wide range in severity. It is estimated this PI affects 1 in 10,000.

X-Linked Agammaglobulinemia is a PI affecting males. It is a blockage of the ability to produce B cells. Infections of the gastrointestinal tract, lungs, skin, or upper respiratory tract are common symptoms of this PI. It is estimated this PI affects 1 in 50,000.

Severe Combined Immunodeficiency (SCID), also known as “bubble boy disease”, is a rare, but most serious group of immune disorders in which both B and T cells are lacking or non-functional. About 50% of infants with SCID have B-cells that just do not work. This makes fighting off any infection almost impossible. It is estimated this PI affects 1 in 1,000,000.

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How is PI diagnosed?

There are many variations in how PI presents due to the fact that the immune system can be broken in so many ways. There are warning signs of PI, such as recurrent infections (ear infections, pneumonia, bronchitis, sinusitis, skin infections).

For some the first infection will be serious and life-threatening, and a definite red flag that there may be a problem with the immune system. Some will suffer recurrent infections from infancy. However, some infants with PI will not show symptoms early on due to IgA received through breast milk from the mother or from antibodies that cross the placenta in the womb and remain in the infant’s body until 4-6 months of age when normal infants start to make their own antibodies. In some cases warning symptoms will not show up until much later in life, even as late as one’s forties or fifties.

Diagnosis begins with the understanding and recognition of the warning signs. Are there more infections than normal? Do infections recur after treatment with medications? Do infections not respond to usual medications? The infections involved differ for adults and children. Please see the charts below. All too often the significance of the warning signs is overlooked, sometimes because they may seem quite mild. Each infection may be treated as a stand-alone illness. Delay in diagnosis and treatment often carries serious health consequences such as the development of more serious infections, chronic illnesses, and even death.

10 Warning Signs
of Primary Immunodeficiency for Children up to age 18

If your child has two or more of these signs, ask your doctor about Primary Immunodeficiency. It could save your child's life.

1.	Four or more new ear infections within 1 year.
2.	Two or more serious sinus infections within 1 year.
3.	Two or more months on antibiotics with little effect.
4.	Two or more pneumonias within 1 year.
5.	Failure of an infant to gain weight or grow normally.
6.	Recurrent, deep skin or organ abscesses.
7.	Persistent thrush in mouth or fungal infection on skin.
8.	Need for intravenous antibiotics to clear infections.
9.	Two or more deep-seated infections including septicemia.
10.	A family history of Primary Immunodeficiency.

10 Warning Signs
of Primary Immunodeficiency for Adults

If you have two or more of these signs, speak to your doctor about a possible Primary Immunodeficiency.

1.	Two or more new ear infections within 1 year.
2.	Two or more new sinus infections within 1 year, in the absence of allergy.
3.	One pneumonia per year for more than 1 year.
4.	Chronic diarrhea with weight loss.
5.	Recurrent viral infections (colds, herpes, warts, condyloma).
6.	Recurrent need for intravenous antibiotics to clear infections.
7.	Recurrent, deep abscesses of the skin or internal organs.
8.	Persistent thrush or fungal infection on skin or elsewhere
9.	Infection with normally harmless tuberculosis-like bacteria.
10.	A family history of Primary Immunodeficiency.

When a physician suspects a PI, the individual ought to be referred to an immunologist.. Blood samples from the patient will be tested to evaluate the functioning of the immune system. The tests are very specific and accurate. The results of the tests, along with the history of infections and current health, will provide the basis for a sound diagnosis. The Canadian Immunodeficiency Society strongly suggests that diagnosis be made by an immunologist.

Because PI is genetic, it may be advisable for blood relatives of the patient to be tested for PI. In some cases, even a fetus can be tested for a specific disease.

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How is PI treated?

A patient with a PI will be treated for any current infection with specific antibiotics, anti-viral or antifungal medications. In some PIs, to prevent permanent organ damage from recurrent infections, low or moderate doses of antibiotics may be recommended.

Some patients will need more of a boost. In cases where the patient is not producing a supply or adequate supply of antibodies, these antibodies can be received by injection. This injection can be made into a vein (intravenous immunoglobulin, IVIG) or under the skin (subcutaneous immunoglobulin, SCIG).

IVIG usually is scheduled every three to four weeks, and SCIG scheduled on a daily to weekly basis. IVIG and SCIG provide the consistent level of needed antibodies. Once started, treatment is usually lifelong. The supply of these antibodies is coordinated by the Canadian Blood Services and Hema-Quebec. Plasma containing antibodies is separated from the blood, treated, condensed, screened, and prepared for the individual doses. One dose may be made up from the contributions of more than a thousand donors.

In the most severe cases, where the immune system is completely non-functional (SCID), and in other extreme cases, a bone marrow transplant may be required. Because a transplant requires a match, this process can take weeks or months. While awaiting the transplant the patient may be kept in reverse isolation and given preparatory treatment. In some cases chemotherapy is used to remove any remaining parts of the broken immune system. When an appropriate donor is found, the transplant is performed. The new marrow provides the patient a new and fully functioning immune system. In some cases there may be some side effects, and in some cases medication may be required to prevent the donor cells from attacking the recipient until the patient becomes tolerant.

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Immunizations

Individuals with a Primary Immunodeficiency should talk to their immunologists before receiving any vaccinations or injections. They could cause serious illness or death. Individuals with a Primary Immunodeficiency should not receive any live vaccinations including:

bacille-Calmette-Guerin (BCG)
chicken pox (varicella) vaccine
measles-mumps-rubella (MMR) vaccine
oral poliovirus vaccine
rotavirus vaccine
vaccine against tuberculosis (TB)
yellow fever vaccine

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Additional Resources

Resources for Children

Our Immune System written by Sara Le Bien, provided by the Immune Deficiency Foundation
This storybook educates children about primary immunodeficiency diseases through delightful, eye-catching illustrations. The characters explain how the immune system works and describe the treatments for pediatric patients. Children will understand their own bodies and be better prepared to deal with their own primary immunodeficiency.

Immune System Poster provided by the Jeffrey Modell Foundation
This poster contains the following sections: "Your Body's Defense"--A fun and informative illustration of how the immune system works; "What is Primary Immunodeficiency (PI)?"--An Important Health Message to Parents/Guardians, and Everyone; and an Activity Page with educational trivia and word games.

Canadian Resources

Canadian Immunodeficiency Society (CI Society) www.cisociety.com
Canadian Immunodeficiences Patient Organization (CIPO) www.cipo.ca

International Resources

Genetic Interest Group (Genetic Disorder Support) www.gig.org.uk
Immune Deficiences Foundation New Zealand www.idfnz.org.nz
Immune Deficiency Foundation USA www.primaryimmune.org
International Patient Organization for Primary Immunodeficiency www.ipopi.org
Jeffrey Modell Foundation/NPI Resource Centre, USA www.Info4pi.org
Michigan Immunodeficiency Foundation www.midf.org
Finnish Patient Organization for PIDs www.immuunipuutospotilaidenyhdistys.fi
Paul Ehrlich Institute www.pei.de
The Binding Site Group www.PIDtesting.com
The Centre for Immunodeficiency www.centreforimmunodeficiency.com