Primary Immunodeficiency - A Cause of Recurrent Infections

Primary immunodeficiency diseases are caused by intrinsic defects in the cells of the immune system and are often caused by inherited genetic defects. This is in contrast to secondary immunodeficiency diseases such as acquired immunodeficiency syndrome caused by infection with human immunodeficiency virus. The hallmark of primary immunodeficiency diseases is increased susceptibility to infection, but they can cause other problems as well. The diseases are grouped according to what part of the immune system is affected.

The World Health Organization recognizes approximately 70 primary immune deficiency diseases including:

  • X-linked Agammaglobulinemia (Bruton’s Disease)
  • Common Variable Immune deficiency (Hypogammaglobulinemia)
  • Selective IgA Deficiency
  • Severe Combined Immune Deficiency (boy-in-bubble disease)

Antibody Deficiencies

Antibodies are proteins made by white blood cells called B Lymphocytes and plasma cells. The function of antibodies is to recognize and mark bacteria, viruses, and other foreign invaders so that other parts of the immune system will respond to these invaders by killing them. One example of antibody deficiency is:

IgG Subclass Deficiency

Selective IgG subclass deficiency in patients with normal total IgG concentrations was described in 1968. Since then there have been numerous reports of an association of frequent infections, mainly of the sinuses and lung, with a deficiency of one or more IgG subclasses. Nearly every combination of subclass deficiency has been described, but some appear to be more relevant than others are. Deficiency of IgG2 with or without concurrent IgA deficiency seems to have the greatest association with recurrent infections. Response to H. Influenza bacteria is made through IgG2 subclass.

There is an association of IgG4 deficiency with recurrent sinusitis and pneumonia and these patients often progress to bronchiectasis.

Deficiency of IgG1 is associated with pyogenic (pus-forming) infections of the lung.

IgG3 deficiency is associated with respiratory infections and viral infections of the urinary tract.

Selective IgA Deficiency

Isolated IgA deficiency is the most common of the primary immunodeficiency diseases, with an incidence record as high as 1:333 blood bank donors.

Many patients with IgA deficiency is clinically normal, but there are higher incidences of infectious, allergic, collagen-vascular, and gastrointestinal disorders in patients with reduced IgA concentrations.

There is also an increased incidence of malignancy, particularly of the gastrointestinal tract, in IgA-deficient patients.

There are increased bacterial infections in the respiratory and genitourinary tracts.

Antibodies to food antigens, especially cow’s milk, are common and may be related to the high incidence of malabsorption.

Autoantibodies are also frequent and are often related to clinically relevant autoimmune disease.

Coeliac disease is more common in IgA deficiency.

Transient Hypogammaglobulinemia of Infancy (THI)

If compared with normal adults, all children are immunodeficient at birth and require several years for immunoglobulins and antibody responses to become "normal". A small number of children with recurrent infections have been identified who have depressed immunoglobulin concentrations that eventually normalize.

These patients can be distinguished from those with more serious immunodeficiency in that their ability to form specific antibody to immunization is intact despite the low immunoglobulin levels. Unfortunately, the only way to make a definitive diagnosis of these children is through prolonged follow-up.

The decision to treat these patients will be based on the incidence of infection and severity of the antibody deficiency, and not immunoglobulin concentrations alone.

  • X-linked Agammaglobulinemia an inherited deficiency that appears in the first 3 years of life. Infants with this deficiency develop recurrent pus-producing infections of the ears, lungs, sinuses, and bones and can get infection in the bloodstream and internal organs. They are also susceptible to viruses such as hepatitis and polio.

Combined Immunodeficiencies

T Lymphocytes are white blood cells that are critical to a healthy immune system. Some T Lymphocytes develop into killer cells that destroy infected cells while others become helper cells that communicate with other immune cells and instruct B cells to make antibodies. People who lack both killer T lymphocytes and antibodies to fight against foreign invaders develop severe illnesses. The most common deficiency is:

  • X-linked Severe Combined Immunodeficiency (SCID) — an inherited deficiency caused by a defective gene for a T lymphocyte molecule important for T cell growth. Patients are diagnosed within the first year of life with frequent and severe infections often caused by organisms that do not affect people with healthy immune systems.

Complement Deficiencies

The complement system consists of a group of proteins that attach to antibody-coated foreign invaders like bacteria and viruses. These proteins work together to disable and kill invading pathogens. People deficient in one or another of these proteins have diminished ability to kill invaders, resulting in increased infections. Such people may develop antibodies that react against the body’s own cells and tissues, resulting in autoimmune diseases with immune-related damage to the body. The most common deficiencies are:

  • C2 Deficiency — An inherited defect in the gene for complement protein called C2. This defect can cause an autoimmune disease such as systemic lupus erythematosus or can result in severe infections such as meningitis. The illnesses usually appear in childhood or in early adulthood.

Phagocytic Cell Deficiencies

Phagocytes include white blood cells called neutrophils and macrophages that engulf and kill antibody-coated foreign invaders. Phagocytes can be defective either in their ability to kill pathogens or in their ability to move to the site of infection. In either case, the defect results in increased infections. The most severe form of phagocytic cell deficiency is:

  • Chronic Granulomatous Disease (CGD) — inherited deficiencies of molecules needed by neutrophils to kill certain infectious organisms. These illnesses usually appear early in childhood but may appear as late as adolescence. People with chronic granulomatous disease develop frequent and severe infections of the skin, lungs, and bones and develop localized, swollen collections of inflamed tissues called granulomas.

Clinical Approaches to Diagnosis

History

As most primary immune deficiency is inherited, a history of death from infections in infancy may point to SCID whilst deaths from liver abscesses in childhood might suggest CGD.

A number of immunodeficiencies are associated with autoimmune diseases and, in particular mothers who carry the X-linked gene for CGD are more likely to suffer from SLE.

Investigations

The absolute Lymphocyte count may be an important indicator of primary immunodeficiency. In SCID it is almost invariably low. As the success from bone marrow transplant is much higher if the diagnosis is made in the first 2 months, its important to think of this disease early.

How can the Immune System be evaluated?

Simple tests that can be done in community labs provide valuable information on the immune system and can allow suspecting the presence of a congenital or acquired immune deficiency. They should be ordered after the infectious episode has settled, since infections, especially those due to viruses, can alter the results of immunological tests.

These simple tests include the following:

  • Complete and differential blood cell counts
    In adults, the absolute lymphocyte count should be between the normal ranges for the lab. Children younger than 8 years or so have higher lymphocytes and lower polymorphs than adults.
  • The intradermal tuberculin tests and IMC Multitest
    These tests investigate delayed type hypersensitivity. The Multitest evaluates responses to seven common antigens (tetanus toxin, diphtheria toxin, tuberculin, Candida albicans, Trichophyton, proteus, and streptococcus). The score should be > 5 in women and between 8 and 10 in men.
  • Protein serum Electrophoresis
    The tests provide a rough estimate of immunoglobulin levels. Its results should be expressed as grams per litre (g/L) rather than as percentages, and should be interpreted in the light of age-related variations.
  • Other tests
    A broad array of other tests is available, although most are done only in specialized or hospital-based labs. They include assays by weight of immunoglobulins A, G, and m; determination of titres of antibodies acquired via infections or immunization; and enumeration of T and B cell subsets.

What tests should be ordered in a child with recurrent respiratory tract infections?

Except when the clinical picture immediately suggests an immune deficiency, sophisticated immunological tests are inappropriate in this situation.

In most severe cases, a careful medical history and the simple tests below suffice:

  • A detailed ENT evaluation, in particular looking for hypertrophy of the tonsils and/or adenoids, and for infection of the maxillary and/or ethmoidal sinuses.
  • A chest X-Ray film
  • Complete and differential white cell count
  • And, in patients with hypochromic anaemia, assays for serum iron or plasma ferritin to look for iron deficiency (present in 25 to 30% of children with recurrent respiratory infections)

In some patients with extraordinarily frequent infectious episodes, a helpful test is an assay by weight of the various immunoglobulin classes to look for IgA deficiency or, in infants for transient hypogammaglobulinemia of infancy. Some localized hospital labs can perform assays of IgG subclasses.

Factors associated with recurrent respiratory tract infections should be looked for, such as cystic fibrosis (sweat test), gastroesophageal reflux (upper gastrointestinal tract radiography), or a bronchial foreign body.

IMMUNODEFICIENCY FAQ'S

Q: What is gene therapy and what disorders does it treat?

A: Gene therapy is a new technology aimed at replacing or repairing abnormal disease producing genes in the patients with genetic diseases such as the Primary immunodeficiency Diseases. In one form of gene therapy samples of cells of the immune system are taken from the patient’s blood or bone marrow, the normal gene is introduced into these cells and they are given back to the patient.

Gene therapy has already proven successful in 2 forms of Severe combined Immunodeficiency.

Q: Can antibody deficiency be treated?

A: YES, Until a few years ago, the only form of active treatment for antibody deficiency was antibody therapy, and the only form of prevention was isolation. For children, this meant staying out of school and out of contact with other children and adults.

Today, however, antibody replacement therapy is available. Because antibodies are also known as immunoglobulins, the terms immunoglobulin therapy and immune globulin intravenous (IGIV) therapy are also commonly used.

IGIV therapy replaces the antibodies that are missing. The infusion contains antibodies purified from the blood donated by volunteer donors. These antibodies remain in circulation for about one month, just as the bodies’ own antibodies.

Q: What is IVIG and what disorders does it treat?

A: IVIG is used for 3 purposes:

  • Patients who don't make antibodies or gammaglobulin
  • For patients with certain specific infections and
  • Patients with certain autoimmune and inflammatory diseases

Some patients may have no, or too few, antibodies and thus suffer from recurrent infections. Sometimes the antibody producing cells (B-cells) of individuals have an intrinsic inability to make antibodies; these are patients with primary immunodeficiency diseases, and many require life-long IVIG. Examples include X-linked Agammaglobulinemia and Combined Variable Immunodeficiency. Blood tests are available to tell if a patient has low antibody levels and needs IVIG.

A second use if IVIG is in the treatment of certain infections in which antibiotics or antiviral therapy is ineffective. Examples include severe parvovirus infection and chronic viral meningitis. These patients do not require life-long IVIG and it is stopped after the infection is controlled

A final use of IVIG is in certain inflammatory and immunologic diseases, often of unknown causes. Examples include childhood acute febrile disease termed Kawasaki disease, and a blood disease termed immune thrombocytopenia, where blood platelets are low and the patients develop bruising or bleeding.

Q: What are the symptoms of antibody deficiency?

A: Antibody deficiencies limit the ability of the immune system to recognize and remove infection causing bacteria and viruses. A patient with an antibody deficiency will therefore tend to have both more frequent infections, and will often have difficulty getting rid of an infection. These patients are also less capable of "developing immunity" and as a result, often suffer from chronic and recurring infections

Most commonly antibody deficiency patients are subjected to chronic bronchitis and infections of the sinuses, ears, and throat. Although these infections may not be life threatening, they can lead to serious damage such as loss of hearing from chronic ear infections and breathing troubles from chronic pneumonia. They also interfere with an active, healthy life-style, causing repeated absences from school.

Q: Is antibody deficiency the same as AIDS?

A: NO. Acquired immune deficiency syndrome (AIDS) is a widespread disruption of the immune system caused by a special viral infection, known as human immunodeficiency virus (HIV). Primary antibody deficiencies (and most secondary antibody deficiencies) are not contagious, and do not present any risk to other people. In fact healthy people carrying infections pose a threat to people with antibody deficiencies because they are so vulnerable to infections

Q: Is it possible to outgrow a Primary Immune Deficiency?

A: Primary Immunodeficiencies are a diverse group of disorders that predisposes people to develop recurrent infections.

Some T-cell disorders like DiGeorge Syndrome may increase their T-cell numbers as they progress in age. This will often be associated with improving T-cell function.

The most common immune deficiency that resolves with age is transient hypogammaglobulinemia. These patients develop symptoms at approximately 6 month of age. This is about the time when the maternal antibodies are diminishing in the infant’s circulation. At this time, the infant may not be able to completely maintain his/her immunoglobulins on his or her own. Infections may occur during this time. Serum immunoglobulins in the infant may ultimately reach normal levels at 4 to 6 years of age. Other immunodeficiencies, such as IgA deficiency, may also resolve with age.

Useful link – JCAAI : Immunodeficiency
http://www.jcaai.org/page/102612/index.v3page

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