Primary Immunodeficiency: An Overview

Primary immunodeficiency disorders are so called because there is no secondary factor, such as an infection or chemotherapy, to account for the immunodeficiency. Patients with primary immunodeficiency experience recurrent infections which may be persistent, severe or unusual, depending on which part of the immune system is affected.

The first primary immunodeficiency disorder was recognised by Dr Ogdon Bruton in 1952. Since then many other primary immunodeficiencies have been identified. However, despite a growing awareness of these conditions within the medical profession, many people remain undiagnosed.

This booklet explains the background to primary immunodeficiency, outlines the major conditions and describes the role which nurses, midwives and health visitors can play in their diagnosis and treatment.

Note: If you are involved in administering intravenous immunoglobulin therapy to patients with primary antibody deficiency, you are advised also to read the guidelines The Administration of Intravenous Immunoglobulin, written by the Immunology Nursing Special Interest Group of the Royal College of Nursing.

The PiA gratefully acknowledges the assistance of Peter Vickers and the following members of its Nursing Advisory Panel in the preparation of this booklet: Sister Veronica Brennan, Sister Sheila Cochrane, Sister Jane Gaspar, Sister Teresa Green and Sister Wendy Larmouth.

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The Immune System

The immune system is extremely complicated, with many branches interacting to give the body the protection (or immunity) that it needs. When functioning adequately, the immune system:

Each part of the immune system co-operates with the others, and optimal functioning of the entire system depends upon the proper functioning of each of the components. Immunodeficiency diseases result when any portion of the immune system is missing, damaged or malfunctioning.

The cells of the immune system (adapted from the IDF Patient and Family Handbook, Immune Deficiency Foundation)
When discussing primary immunodeficiency, we are most concerned with:

T-Lymphocytes (Cellular Immunity)
These cells originate in the bone marrow and mature in the thymus. They are classified according to their function or role:

T-lymphocytes produce proteins called cytokines, such as interleukin and gamma-interferon. The cytokines act as messages between cells of the immune system (and other cells) and are essential for the destruction of invading organisms such as viruses, fungi and some bacteria.

B Lymphocytes (Humoral Immunity)
These cells originate and mature in the bone marrow. They produce antibodies - also known as immunoglobulins (Ig) - and are very important in the body's defence against bacteria.

There are five classes of immunoglobulin, IgG, IgA, IgM, IgE and IgD. If there is a defect in the production or maturation of B lymphocytes (particularly if IgG, IgA or IgM are affected) the patient will suffer bacterial infections. He/she may also suffer from viral and fungal infections, but these are less prominent as they are usually taken care of by the T lymphocytes.

Phagocytes
Phagocytes participate in the immune system by ingesting and killing micro-organisms. This task is made easier if the micro-organism is coated with antibody or complement. Monocytes develop into macrophages when they migrate to tissues.

The Complement System
The complement system acts as a mediator of inflammation and serves as a connection between the cellular and humoral components of the immune system. It consists of a series of proteins in the blood (numbered C1 to C9) that act in a sequential cascading manner. These proteins are triggered by antibody (the classical pathway) or other components of the complement system (the alternative pathway). Their function is to:

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Primary Immunodeficiency Diseases

This section outlines the principal primary immunodeficiency diseases.

Antibody Deficiencies (B Cell Defects)
Defects in the maturation or function of the B cells can give rise to a number of antibody deficiencies.

Selective IgA deficiency is the most common B cell disorder. It has been estimated that one in 700 of the population in the UK may be IgA deficient. IgA deficiency does not necessarily cause serious problems, and undoubtedly many people have the disorder without realising it. However, some individuals with selective IgA deficiency do suffer from infections more frequently than the general population, and may take longer to shake off such infections. Autoimmune diseases are also more prevalent in these people.

IgG deficiencies are much more serious because IgG is at the centre of humoral defences comprising 80% of antibodies produced by our bodies. IgG is a relatively small molecule which can get out of the blood into the tissues, especially inflamed tissue. It is also carried across the placenta and ensures that there is protection from infections following birth until a baby's immune system starts to function effectively.

Common variable immunodeficiency (CVI) is a spectrum of immune disorders that can occur spontaneously at any age, in both males and females. These patients usually have very low serum levels of immunoglobulin classes, with normal or slightly reduced numbers of B cells. T cells are also not fully functional in a proportion of patients.

Patients with CVI are susceptible to frequent bacterial infections, particularly of the chest, ears and sinuses. Infection of the gut, particularly with Giardia lamblia is also a prominent problem. There is a high incidence of gut cancer and lymphoma. In common with XLA (see below) unusual enteroviral infection can be a problem, leading to meningo-encephalitis and a dermatomyositis-like disorder.

X-linked agammaglobulinaemia (XLA), also known as Bruton's agammaglobulinaemia, is an inherited type of antibody deficiency. It usually presents during the first two years of life. There are low levels of all classes of immunoglobulin and either no or very low numbers of circulating B lymphocytes. XLA affects only males but females can be carriers of the condition. Bacterial infections are frequent and can be severe. The gene has been identified and pre-natal counselling can now be offered.

Hyper IgM syndrome is another X-linked condition, but can be more serious than XLA and problems with opportunistic infections such as pneumocystis carinii occur. Furthermore, there is a worrying incidence of liver cancer. Patients with this condition have low levels of IgA and IgG. However, they have normal or - most often - raised levels of IgM. Bone-marrow transplant is now being offered to the more seriously affected children.

IgG subclass deficiency occurs when one or more of the four IgG subclasses is missing. IgG2 deficiency is the commonest and can result in problems with recurrent bacterial infection particularly of the respiratory tract. Serum IgG levels may be normal, so subclasses and specific antibodies need to be measured and test immunisations given if this diagnosis is not to be missed.

Specific antibody deficiency occurs when one or more specific antibodies are absent or deficient, sometimes resulting in recurrent and/or frequent infections. This deficiency is usually detected by test immunisation.

Transient antibody deficiency of infancy occurs when an infant takes rather longer than usual to develop a mature immune system. This condition usually corrects itself by the time the child is two to three years old. In the meantime, supportive measures should be taken to prevent potentially overwhelming infections: extra vigilance, antibiotic therapy and, in some cases, short-term replacement immunoglobulin therapy.

Combined B Cell and T Cell Defects
These are serious disorders in which both arms of the specific immune response are affected.

Severe combined immunodeficiency (SCID) is a term that refers to a group of inherited and potentially fatal conditions. The affected infant is unable to respond to infection, either because the T lymphocytes fail to function or because they are absent altogether. B lymphocyte function is also impaired. Infections are usually fatal within the first year of life unless a successful bone marrow transplant is carried out. Early diagnosis is vital in order for the child to be nursed with supportive and anti-microbial therapy in protective isolation in a specialised centre, until a matching bone marrow donor is found. The genes for several of these disorders have been identified, enabling better diagnosis and genetic advice.

Wiskott-Aldrich syndrome can cause eczema, bruising, bleeding and severe bacterial infections. The gene responsible for this disease has now been identified. Treatment involves immunoglobulin replacement therapy and sometimes splenectomy. In selected patients bone marrow transplantation can be curative (see below).

Congenital thymic aplasia, or DiGeorge syndrome, is a failure of the thymus to develop in the early stages of fetal life. It is also associated with defects of the heart and parathyroid glands. It is one of a spectrum of congenital problems, all of which have an underlying deletion of chromosome 22 (22q11pter). Collectively they are termed "CATCH 22" as a reminder of the organs involved: cardiac, abnormal face, thymus, cleft palate and hypocalcaemia (due to the missing parathyroids).

Chronic mucocutaneous candidiasis is a condition in which the patient suffers severe persistent candida infections. It can usually be managed by drug therapy, although in extreme cases a bone marrow transplant may be necessary.

Defects of Phagocytosis
Chronic granulomatous disease (CGD) is a disorder of phagocytes that can cause abscesses, both in external tissues and internal organs (particularly in the lungs and bones). Antibiotic therapy is the main treatment, although recently gamma-interferon has been shown to have a place in treating this condition. Gene therapy may be possible in the future.

Neutropenia is caused by a reduction in the numbers of neutrophils, the "scavenging" cells that kill most micro-organisms that enter the body. The bone marrow may not produce enough neutrophils, or the neutrophils may be destroyed rapidly.

Symptoms of neutropenia include skin and lung infections, mouth ulcers and sore throat are particularly common. Cyclical neutropenia is characterised by a regular pattern of weeks of relative good health followed by several days of illness.

Complement Defects
People who lack C1, C4 or C2 cannot activate C3 through the classical pathway and therefore are more susceptible to infections with certain bacteria which have to be opsonised before they can be killed, such as pneumococcus, haemophilus and meningococcus.

Deficiencies of alternative pathway components also occur. Properdin deficiency is an X-linked disorder and therefore only occurs in males. Deficiencies of properdin and Factor D are most often associated with infections with the meningococcus.

Hereditary angioedema (HAE) and acquired C1-inhibitor deficiency are uncommon complement deficiencies which are caused by the deficiency of a plasma protein known as C1-inhibitor. They can lead to attacks of abdominal pain and/or severe swelling in the tissues. This swelling can be quite gross and may affect any part of the body. Acute attacks are treated by general supportive measures and also by infusion with the missing protein. The frequency and severity of the long-term attacks of angioedema can be reduced by androgenic steroids and by tranexamic acid. It is also possible to use inhibitor concentrate in maintenance therapy.

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The Nursing Assessment of Primary Immunodeficiency

Immunodeficiency should be suspected in every patient, whatever age, with recurrent, persistent, severe or unusual infections. Therefore, an observant, well-informed nurse in any field can play a vital role in the early detection of primary immunodeficiency.

Paediatric nurses, health visitors and school nurses are often the first healthcare professionals to hear parents describe a family history of a pattern of frequent infections, or to see infants and toddlers in hospital with recurring episodes of any of the following: pneumonia, meningitis, chronic skin infections, gastrointestinal infections, persistent diarrhoea, or failure to thrive.

Midwives are sometimes forewarned about a baby who is about to be born to a family which has already had a child with SCID. They and the doctors are able to test the baby immediately and take extra precautions to prevent infection, although the baby will have a certain amount of passive immunity passed on from its mother for the first 3-4 months of life.

A midwife may also be asked to look after a pregnant woman who has antibody deficiency, and whose infant may be at risk for the first few months of life if she has not received sufficient replacement antibodies during pregnancy.

Practice nurses and district nurses should be aware of patients who repeatedly require antibiotics. You should consider an underlying antibody deficiency, which will need a referral from the general practitioner to an immunologist for further investigation.

When a primary immunodeficiency is suspected, various blood tests will be performed by the immunologist to measure and determine the different immune responses. The first-line investigations will usually be:

More specialised tests will be performed as necessary.

The nurse, in her role as health educator, needs to prepare the patient for these tests by explaining what they are for and why they are necessary.

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The Treatment of Primary Immunodeficiency

Once the patient has been referred to an immunologist and a primary immunodeficiency has been identified, the treatment will depend on the nature of the disease. Nurses - if possible, specialist immunology nurses - can educate patients and their families about general preventive health measures, the importance of detecting any signs of infection early and the need for prompt treatment.

Antibiotics
If antibiotics are necessary to combat an infection, it is usual for an immune deficient patient to have an increased dose for a longer period of time (7 to 10 days) than people with a normal immune system.

Some patients with antibody deficiency, particularly IgG Subclass Deficiency, are prescribed prophylactic antibiotics. This involves taking a single daily dose of a broad spectrum antibiotic to prevent the development of infections. There are theoretical concerns about the development of antibiotic resistance by bacteria, but in practice this is not usually a problem. In a few cases, if symptoms break through, it may be necessary to "rotate" different antibiotics or to prescribe an increased dose.

Physiotherapy
Particularly if bronchiectasis (lung damage) is present as a result of repeated infections, a patient can be assisted by a physiotherapist to perform regular physiotherapy, including breathing exercises and postural drainage. Chest physiotherapy, tailored to patient's individual problems, helps most people with antibody deficiency. A booklet on chest exercises is available from the PiA.

Immunisations
Health visitors, practice nurses, paediatric nurses and school nurse should be aware that children who have, or who are suspected of having, a primary immunodeficiency must not receive any immunisation with a live virus. This may result in severe illness or even death, due to overwhelming sepsis. If a parent or sibling has an immunodeficiency care must be taken to prevent the immunised virus spreading from the child receiving the immunisation. This is particularly important for live polio vaccine. Advice about immunisations can be obtained from your nearest specialist immunology centre.

Replacement Immunoglobulin Therapy
Most antibody deficient patients require long-term or lifelong treatment with replacement immunoglobulin, administered by one of three routes:

Administering intravenous immunoglobulin
For patients receiving intravenous infusions of immunoglobulin:

The product name, batch numbers, procedure used and the start and end times of the infusion should always be recorded in the patient's notes.

As immunoglobulin products are manufactured from donated human blood, there is a theoretical risk of virus transmission. In all patients receiving replacement immunoglobulin therapy, blood samples should be obtained at regular intervals to assess liver function. In addition, patients should be observed throughout infusion in case of adverse reactions.

Serious adverse reactions are very rare and are nearly always related to a too rapid rate of infusion or to the presence of undetected, untreated bacterial infection.

The following table categorises the adverse reactions to replacement immunoglobulin therapy that can occur, and the action to be taken:

More detailed Guidelines for the Administration of Intravenous Immunoglobulin for nurses are available from the RCN Immunology Nursing Special Interest Group.

Home therapy
Self-infusion of immunoglobulin at home provides greater convenience and independence. Home therapy programmes are now available at certain specialist immunology centres, where suitable patients and their partners/parents are taught all aspects of self-infusion with intravenous/subcutaneous immunoglobulin. Once trained, a patient should be monitored carefully at home by a specialist immunology nurse.

The care and management of patients on replacement immunoglobulin therapy

During the assessment and care of a patient on replacement immunoglobulin therapy, the nurse should ensure that:

With children, a local anaesthetic cream (e.g. EMLA) may be used prior to infusion.

In the overall management of a patient on intravenous or subcutaneous immunoglobulin therapy, the nurse should aim to:

All patients with primary immunodeficiency should be followed up on a regular basis by an immunologist and, if possible, a specialist immunology nurse.

For further information, advice and support please refer to the Specialist Immunology nurse at your nearest specialist immunology centre (see the list at the end of this booklet).

Bone Marrow Transplantation
In some more serious immunodeficiencies, bone marrow transplantation (BMT) offers a hope of lifelong cure. The first successful transplants were performed in children with severe combined immunodeficiency and Wiskott-Aldrich syndrome using matched, related donors.

A better understanding of immunodeficiency diseases and advanced techniques for tissue typing and transplantation mean that BMT can now be offered for a wider range of serious and rare immunological conditions using unrelated as well as related donors. Diseases for which BMT may now be considered are:

Less usual indications include:

Future developments that are being explored are peripheral blood stem cell and cord blood stem cell transplants.

Gene Therapy
(Information kindly provided by Dr H B Gaspar, Institute of Child Health, London)

The fundamental basis of gene therapy involves the transfer of genetic material into the cells or tissues of an organism. For a number of reasons, the primary immunodeficiencies have become attractive initial targets for this new technology and have been instrumental in the development of new techniques. One of the major reasons for this is that the primary immunodeficiencies are single gene disorders, for which many of the genes have been characterised and investigated. Also, the genes involved in many of the immunodeficiencies are detrimental to only a very specific population of cells, such as neutrophils or lymphocytes. Thus a correct copy of the defective gene needs only to be introduced into the cells of the bone marrow in order potentially to effect a cure. Furthermore, since the bone marrow is readily accessible and can be manipulated outside the body, introduction of the gene becomes more feasible.

Gene therapy for primary immunodeficiency can be likened to an autologous bone marrow transplant in which the bone marrow is "corrected" by the insertion of a functional copy of the gene. The gene is inserted into the bone marrow cells by means of vectors, which are normally modified viruses that carry the functional gene. The corrected marrow is then returned to the patient peripherally. It is then hoped that the corrected bone marrow cells will grow and multiply, giving rise to properly functioning lymphocytes or neutrophils.

The initial clinical trials of gene therapy for primary immunodeficiencies have met with only limited success. A number of children have been treated, and although the gene has been introduced into bone marrow cells, too few cells have been successfully corrected and a complete cure of patients has not yet been achieved. However, these first trials have served to illustrate some of the hurdles that need to be overcome before successful gene therapy becomes a clinical reality.

Primary immunodeficiencies for which gene therapy may be possible include:

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Specialist Immunology Centres In THE UK

HTC denotes a Home Therapy Training Centre.

(List correct as of May 1997)

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Further reading

Ammann, A. J. and Hong, R. (1989). "Disorders of T Cell System." In Steihm, E.R. Ed., Immunological Disorders in Infants and Children, 3rd edition. Philadelphia: W. B. Saunders.

Asherson, G. L., and Webster, A. D. B. (1980). Diagnosis and Treatment of Immunodeficiency Diseases. Oxford: Blackwell Scientific Publications.

Blore, J., and Haeney, M. R. (1989). "Primary Antibody Deficiency and Diagnostic Delay." British Medical Journal Vol. 298: 516-517.

Chapel, H. M., and Brennan, V. M. (1989). Home Therapy Guidelines. Department of Immunology, Oxford Radcliffe NHS Trust.

Chapel, H. M., et al. (1994). "Consensus Document on the Diagnosis and Management of Primary Antibody Deficiency." British Medical Journal Vol. 308: 581-585. Full document London: Primary Immunodeficiency Association.

Chapel, H. M., and Haeney, M. R. (1994). Essentials of Clinical Immunology 3rd edition. Oxford: Blackwell Scientific Publications.

Cochrane, S. (1994). "A Mark of Approval." Professional Nurse November 1994: 106-110.

Gardulf, A., et al. (1995). "Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs." The Lancet Vol. 345: 365-369.

Haeney, M. R. (1990). "Clinical Aspects of Antibody Deficiency." Hospital Update, 16: 122-34.

Haeney, M. R. (1994). "Intravenous immunoglobulin in Primary Immundeficiency." Clinical and Experimental Immunology Vol. 97 Suppl. 1, July 1994: 11-15.

Misbah, S., Chapel, H.M., et al. (1993). "Adverse effects of Intravenous Immunoglobulin." Drug Safety 9 (4) 254-262

Saxon, A., and Steihm, E.R. (1989) "Disorders of B Lymphocyte System." In Steihm, E.R. Ed., Immunological Disorders in Infants and Children, 3rd edition, Philadelphia: W. B. Saunders.

WHO (1995). "Report on Primary Immunodeficiency Diseases." Supplement to Clin. Exp. Immunol.

NURSES: 07.97

Published with the help of an educational grant from Baxter Healthcare Ltd.