Primary immunodeficiency diseases are a heterogeneous group of disorders, which affect the cells, tissues, and proteins of the immune system. Since their initial description in 1953, it has become clear that they are more prevalent than originally appreciated. It has also become apparent that they can present in older children, adolescents, and adults, and that they can be associated with relatively mild clinical disease.

Although the initial description of patients with primary immunodeficiency diseases focused on their increased susceptibility to infection, these patients may also present with a variety of other clinical manifestations. In some patients with primary immune deficiency disorders, non- infectious manifestations, such as autoimmune disease and/or gastrointestinal disease, may dominate their clinical course.

The early detection of patients with primary immunodeficiency diseases is critical as effective therapy is available for virtually all of the different disorders. Treatment is most beneficial if instituted before there has been irreversible damage to target organs (e.g. the lung) by infection or autoimmune disease. Similarly, early recognition of primary immunodeficiency may lead to a precise genetic diagnosis, which may be important to the family in planning their future reproductive options.

Many of the primary immunodeficiency diseases are genetically determined. The mutations responsible for many of these disorders have been identified. Some of these are inherited as autosomal recessive traits, some as X-linked recessive traits, and at least two are inherited as an autosomal dominant trait. Others are not inherited as single gene defects. Two of the most common primary immunodeficiency diseases, Common Variable Immunodeficiency (CVID) and Selective IgA deficiency, usually occur sporadically and do not appear to be due to single gene defects in most cases.

 

Classification

The immune system can be conceptually divided into several functional compartments. A disorder, which predominantly affects each compartment, is shown in brackets.

• The B-lymphocyte system (eg. Bruton’s agammaglobulinemia)
• The T-lymphocyte system (eg. DiGeorge syndrome)
• Combined disorders (eg Severe Combined Immune Deficiency)
• The Phagocytic system (eg. Chronic granulomatous disease)
• The Complement system (eg. Individual complement components)

Each of these functional compartments plays a critical role in host defence against infection and inflammation. It is most helpful to classify primary immunodeficiency diseases according to which functional compartment of the immune system is impaired. Thus, there are disorders that affect the B-lymphocyte system, disorders that affect the T-lymphocyte system, disorders that affect both the B- lymphocyte and T-lymphocyte systems, disorders that affect the phagocytic system, and disorders that affect the complement system. As discussed below, the pattern of infections may reflect the type of host immune defect.

 

Clinical Manifestations

Infections:
Increased susceptibility to infection is the hallmark of primary immunodeficiency diseases. Typically, the infections involve multiple organs or multiple sites within the same organ. Recurrent sinopulmonary infections, such as otitis media, sinusitis, bronchitis, and pneumonia, are the most common presenting manifestations of primary immunodeficiency diseases. In some patients the first infection may be so severe or unusual that it raises the possibility of an underlying immunodeficiency. A patient who presents with Pneumocystis carinii pneumonia is likely to be immunodeficient even if it is his/her first infection.

The type of infectious agent and the location of the infection may give valuable information about the underlying immunologic defect. For example, individuals who have B-cell deficiencies have an increased susceptibility to infection with encapsulated pyogenic bacteria, such as the pneumococcus and H.influenzae, and to enteroviruses. Patients who are deficient in T-cells may have infections with a variety of micro-organisms but appear especially susceptible to fungi, viruses and Pneumocystis. Patients with complement deficiencies may present with blood- borne infections, such as bacteremia and meningitis, caused by encapsulated bacteria. And, finally, patients with phagocytic disorders characteristically have infections of the skin and reticuloendothelial system.

Predisposition to recurrent infections may occur in several disorders (table 1). It is important these conditions are considered in the differential diagnosis of a child or adult presenting with recurrent infections.

Autoimmune and rheumatic disease:
Patients with primary immunodeficiency diseases may also present with a variety of autoimmune or rheumatic disorders. In some patients the manifestations of the autoimmune disease may be limited to a single tissue or organ, such as occurs in autoimmune haemolytic anaemia or autoimmune thrombocytopenia.

Gastrointestinal:
Chronic diarrhoea, malabsorption and even malnutrition may be important manifestations of primary immunodeficiency diseases, especially in infants and young children. In some instances, the cause is clearly infectious. However, a variety of autoimmune or chronic inflammatory diseases, which have no clear infectious etiology, may also occur in patients with primary immunodeficiency diseases.

Haematological disease:
Anemia, thrombocytopenia, or leukopenia may be seen in patients with primary immunodeficiency diseases. In some instances, the hematologic abnormalities are the consequence of the same underlying abnormality that is responsible for the immunodeficiency. For example, the Wiskott-Aldrich Syndrome is characterized by variable defects in B-lymphocyte and T-lymphocyte function as a consequence of mutations of the WASP protein. These patients also have intrinsic abnormalities of their platelets, which result in small platelets and thrombocytopenia.

 

Laboratory Diagnosis of Immunodeficiency

Inexpensive screening tests can be undertaken in primary care. In general, a full blood count and an immunoglobulin level should be undertaken if a primary immune deficiency is suspected. More detailed laboratory testing is used to delineate the precise immunologic defect and should be undertaken in a tertiary referral centre. DNA diagnostic tests are available for many of these disorders.

Evaluation of B lymphocyte function:
The initial screening test for B-lymphocyte function is the measurement of serum immunoglobulins. Immunoglobulin levels change with age (figure 1). It is therefore important that levels are compared with age-appropriate normal ranges. The ranges may very depending on the laboratory performing the tests. Serum IgG, IgA and IgM levels will identify patients with panhypogammaglobulinemia as well as patients who have a deficiency of an individual class of immunoglobulin, such as selective IgA deficiency. Specific antibody responses to protein antigens (eg Diphtheria, tetanus toxoids and Hepatitis B) and carbohydrate antigens (pneumococcal antibodies) can also be measured. Immunisation with live viral vaccines should be avoided whenever an immunodeficiency is suspected because of the risk of vaccine induced disease.

Evaluation of T lymphocyte function:
Testing for defects in T-lymphocyte function is relatively difficult because of the lack of inexpensive and reliable screening tests. Although not a primary immune deficiency, an HIV test should be considered in the appropriate clinical context. Delayed type hypersensitivity (DTH) skin tests using a panel of ubiquitous antigens can be used as a screening test in older children and adults. Other tests including T-lymphocyte numbers and T-cell function including in vitro assessment of lymphocyte proliferation in response to non-specific mitogens and specific antigens (e.g. candida) can also be undertaken in specialist centres.

Evaluation of phagocytic function:
The evaluation of phagocytic cells generally entails assessment of both their number and their function. Disorders such as congenital agranulocytosis or cyclical neutropenia can be detected by the full blood count and differential. Assessment of phagocytic cell function requires a number of more specialised assays. The most common of these assesses the ability of phagocytic cells to respond with an oxidative burst by measuring the reduction of nitroblue tetrazolium (NBT test).

Evaluation of complement function:
Screening tests for complement deficiency include immunochemical measurement of C3 and C4 as well assessment of the classical and alternate pathways. Most of the genetically determined deficiencies of the classical activating pathway (C1, C4 and C2), of C3, and of the terminal components (C5, 6, 7,8, and 9) can be detected by immunochemical assays. These tests should be undertaken in tertiary referral centres.

 

Indications For Referral

Patients with an identified primary immune deficiency disorder should be referred to a clinical immunology service. In general, suspicion of a primary immune deficiency should be aroused in patients suffering from recurrent or atypical infections. Others who have an abnormal screening test should also be referred for further evaluation. A list of tertiary hospital immunology services is listed in table 4.

 

Acknowledgement
This article was modified from information published by the Immune Deficiency Foundation of America.

 

Table 1. Host defects predisposing to recurrent infections

Local anatomical defects eg obstruction to a bronchus Generalised anatomical defects eg burns Systemic disorders eg diabetes and recurrent thrush Allergies eg recurrent sinusitis Malignancy (multiple mechanisms including anatomical obstruction, chemotherapy or nutrition) Cystic fibrosis Malnutrition (primary or secondary to another disorder) Congenital immune deficiencies Acquired immune deficiencies (eg AIDS, immunosuppression induced by medications) Immotile cilia syndrome

 

Table 2. Age related immunoglobulin levels in g/L (data derived from multiple sources)

Age	IgG	IgA	IgM
0-14 days	6.0-16.0	0.01-.1	0.1-0.6
2-6 weeks	2.0-6.0	0.01-0.5	0.2-0.8
7 weeks-6months	2.0-7.0	0.01-0.8	0.2-1.0
7-24 months	3.0-10.5	0.1-1.2	0.3-1.5
2-5 years	4.5-11.5	0.3-1.6	0.5-1.9
6-10 years	6.0-13.0	0.4-2.2	0.5-2.1
11-16 years	6.0-15.0	0.7-2.3	0.5-2.2
Adult	7.0-16.0	0.8-4.0	0.4-2.5
>70 years	6.0-15.0	0.8-4.0	0.4-2.4

 

 

Case History
The following case illustrates that not all patient suffering from recurrent infections have an immune deficiency disorder.

Patient M is a four-year-old boy who has been troubled by recurrent infections since two years of age. He initially suffered recurrent otitis media. Tympanostomy tubes were inserted with a resultant decrease in ear infections. Since that time he has been suffering up to 10 episodes of acute sinusitis and rhinitis each year. Further history indicated recurrent sneezing associated with clear rhinorrhoea.

Physical findings included marked swelling of the nasal mucosa. Initial investigations showed a normal blood count as well as immunoglobulin levels. He was also able to respond appropriately to immunisations with protein and carbohydrate antigens. Allergy testing revealed strongly positive tests to house dust mites on skin testing.

The family was advised to undertake house dust mite avoidance measures by purchasing pillow mattress and duvet covers from the allergy Awareness Association as well as purchasing a dehumidifier. He was commenced on a combination of Claratyne as well as Butacort aqueous nasal spray twice daily.

Over a period of four weeks his rhinorrhoea and sneezing improved markedly. Over the last winter he suffered only one nasal infection, which was promptly treated with oral antibiotics. In the long term he will be a candidate for allergen specific immunotherapy.

 

Table 3. Indications for referral to a tertiary immunology service

Infections Multiple infections eg more than 8-10 per a year Infections in multiple anatomical sites Infections in multiple anatomical sites Failure to respond to antibiotics Atypical organisms eg Pneumocystis More than 1 deep seated infection eg meningitis, osteomyelitis Unusual site eg encephalitis Unusual host response eg cold abscess, failure of ESR to increase with bronchiectasis, pneumonitis etc Part of the differential diagnosis for failure to thrive Abnormal screening tests for immune deficiency Family history of a primary immune deficiency disorder Patients needing genetic counselling

 

 

Table 4. Clinical Immunology Contacts in New Zealand

Institution	Contact	Address	Phone	e-mail
Auckland Public Hospital	Dr Rohan Ameratunga	Park Rd, Grafton, Auckland	09 3797440 ext 6113
Auckland Public Hospital	Dr Marianne Empson	Park Rd, Grafton, Auckland	09 3797440 ext 5429
Starship Children’s Hospital	Dr Jan Sinclair	Level 6, Starship, Private Bag 92024, Auckland	09 307 8900	JanS@adhb.govt.nz
Wellington Public Hospital	Dr Penny Fitzharris
Christchurch Public Hospital	Dr John O’Donnell

 

Figure 1. Normal immunoglobulin levels vary with age.

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Last updated 30 Apr 2006