Immunodeficiency may occur at any age and be congenital (primary) or acquired, secondary to some other disease, or occur transiently in infancy.
Primary immunodeficiencies can be classified into three groups:
- predominant antibody defects,
- predominant defects of cell-mediated immunity,
- deficiencies associated with other defects.
As a normal antibody response involves cell co-operation it is not surprising that antibody defects occur in all three groups. The major deficiencies together with immunoglobulin patterns are shown in the Table. In addition to those listed immunodeficiency may also occur sporadically and with thymoma or transcobalamin II deficiency. Normal IgG concentrations do not exclude deficiency of IgG subclasses. Deficiencies of all subclasses have been reported but it is only when the predominant IgG1 subclass is deficient that a low total IgG can be expected. Similarily immunoglobulin concentrations can be within their reference ranges in the presence of deficiencies of specific antibodies (functional deficiencies).
Primary immune deficiencies affecting immunoglobulin concentrations
Disease Immunoglobulin pattern Clinical manifestations:
- Selective IgA absent IgA, serum and saliva mucosal surface infection, atopy
- 30% symptom free
- Selective IgM absent or low IgM septicaemia
- Severe combined maternal IgG present opportunistic infections
- (SCID) IgA and IgM absent
- X-linked maternal IgG present recurrent,pyogenic, infections
- (Bruton’s) IgA and surface Igs absent.
- IgM variable
- IDS with thrombocytopaenia low IgM,absent iso haemagglutinins ENT infections
- Deficient Ab responses
- Ataxia telangiectasia Variable, IgA absent 60% cerebellar ataxia
- IgG2 subclass Normal IgG recurrent pyogenic
- Pneumococcal and Hib
- IgA and IgM Normal IgG gut disease
- IgG and IgA raised IgM recurrent infection
- Common variable variable variable
- IDS Immune Deficiency Syndrome
- Hib Haemophilus influenzae type B
Selective IgA deficiency occurs at a rate of approximately 1:500 of the population and in some 40% of patients is associated with IgG2 subclass deficiency. In such patients there is an increased frequency of infections and good response to IgG replacement therapy. The other antibody deficiences are extremely rare showing incidences of 1/100,000 or less.
The administration of blood or blood products to patients with IgA deficiency may induce the formation of anti-IgA antibodies. In such cases repeat transfusion may precipitate an anaphylactoid response. Patients with absent IgA should be screened for anti-IgA antibodies. Individuals who test positive, and need blood transfusion, should always be given IgA deficient donor units obtainable from the Blood Authority.
Transient immunodeficiency in infancy is not rare (4% of live births). Infants present with frequent or severe infections and have low concentrations of IgG while IgA and IgM concentrations are usually normal for their age. This hypogammaglobulinaemia of infancy may be seen in families where there is a history of primary immunodeficiency and may represent the heterozygote state. In other instances it is secondary, eg to intrauterine infection, or due to prematurity. The infant born before 34 weeks gestation is particularly at risk as maternal IgG is largely transferred across the placenta in the last trimester of pregnancy. In most cases of transient hypogammaglobulinaemia of infancy normal concentrations of serum immunoglobulins are achieved after the slow start.
Secondary immunodeficiency can be found in relation to a variety of disease states which may be characterised by differences in immunoglobulin pattern. Secondary immunodeficiency is more common than the primary forms.
Clinical conditions giving rise to secondary hypogammaglobulinaemia:
Clinical Conditions Immunoglobulin Pattern
- Marrow disorders Hypoplasia Predominantly low IgG, less effect on IgA and IgM
- Bone metastases
- Short Survival of IgG Nephrotic syndrome
- Protein-losing enteropathy
- Myotonic dystophy
- Toxic factors Prolonged uraemia IgM more affected
- than IgA and IgG
- Gluten-sensitive enteropathy
- Severe infection
- Malignancy B-cell neoplasia
The investigation of a patient with a putative immune defect includes the assessment of the patient’s ability to produce fully functional antibody in response to infection or challenge. Antibodies against a panel of protein and polysaccharide antigens can be used to assess a patient’s ability to make protective antibodies against vaccines to common pathogens. This is the most sensitive method of detecting abnormalities in antibody production. A patient may have normal levels of serum immunoglobulins, and IgG subclasses, but still be unable to respond to the polysaccharide capsules of pathogens such as the Pneumococcus or Haemophilus influenzae type b.
Antibody responses may be either thymus dependent (TD) where effective antibody responses need T-cell help, or thymus independent (TI) where no such cooperation is required. This latter phenomenon is illustrated by the ability of polysaccharide antigens to induce antibody responses in T-cell deficient animals, when protein antigens (TD) fail to elicit a response.
TI antigens can be further subclassified into TI-1 and TI-2 on the basis of the pattern of ontogeny of antibody response and the ability of Btk gene deficient mice to respond to TI-1 antigens (lipopolysaccharides) but not to TI-2 antigens (polysaccharides). Although this classification is based primarily on animal experimental work, the observations do have clinical relevance. The ability to respond to protein antigens such as Tetanus or Diphtheria toxins, as well as viral proteins, is essentially mature at birth. Immunisation with such antigens results in the induction of immunological memory responses and antibody levels can be enhanced by repeated immunisation. Protein-polysaccharide conjugate antigens, such as the Haemophilus b conjugate vaccine, behave like TD antigens.
Children under 2 years do not respond to TI-2 antigens, the appearance of qualitatively and quantitatively adult-type responses may be delayed until the age of 7 or 8 years. This delayed ontogeny of anti-polysaccharide antibody responses explains the susceptibility of children to develope invasive disease caused by encapsulated bacterial pathogens. Antibody responses to TI-1 antigens mature within the first few months of life and are not a component of the routine investigative protocols. The appearance of isohaemagglutinins in the serum acts as a surrogate marker for TI antibody responses.
Protein antigens induce antibody of IgG1 and IgG3 isotypes. Young children produce chiefly IgG1 antibody to the capsular polysaccharide of Streptococcus pneumoniae, but with increasing age the antibody isotype switches to IgG2, the predominant isotype of the adult immune response to this antigen. Protein-polysaccharide conjugates induce IgG1 responses against the relevant bacterial polysaccharide irrespective of age.
Strategy for the assessment of specific antibody responses
Ideally specific antibody responses should be measured against a panel of protein and carbohydrate antigens. Suitable protein antigens include Tetanus and Diphtheria toxoids (TD response) and the most useful polysaccharide antigens (TI-2 response) are the pneumococcal polysaccharide, Haemophilus influenzae type b polyribose phosphate and the meningococcal polysaccharides. The immunisation status of the patient and their age are essential information for the interpretation of the results. If antibody levels are low, the patient should be immunised with the relevant vaccine and antibody levels re-evaluated after 3 to 4 weeks. Evaluation of anti-pneumococcal responses should be confined to children above two years. Failure to mount an effective response after immunisation with one ore more vaccines indicates impaired antibody production, and a functional immune defect.
Immunisation of patients with putative immune defects should always be with inactivated vaccines. The use of live vaccines in these clinical situations is contraindicated and will have serious consequences.
Investigation of specific antibody responses are useful in the assessment of the following groups of patients:
- Patients, especially children, with recurrent bacterial sepsis, particularily those with recurrent upper or lower respiratory tract infections
- Patients with invasive disease caused by encapsulated organisms like Streptococcus pneumoniae
- To assess immune reconstitution following bone-marrow transplantation
- Patients who are asplenic or have functional hyposplenism
- For the assessment of protective antibody levels against tetanus and diphtheria as an indication of the need for re-immunisation
- To assess the significance of reduced IgG or IgG subclass levels in patients undergoing investigation for putative immune defect
- To differentiate congenital, from transient infantile, hypogammaglobulinaemia. The latter usually responds to primary immunisation
Sample requirement: 5 mL serum
Information requested: In addition to the patient’s name, date of birth, sex, hospital number, and racial origin, the request form should show:
- A summary of the clinical details (including family history, age at onset and length of illness).
- Full vaccination history (including whether patient has received the following and if so, the results) – BCG and Mantoux, Oral poliovaccine, Tetanus toxoid.
- Isohaemagglutinin titres if available, or blood group.
- Clinical diagnosis, provisional or differential.
- Reports on peripheral blood film and absolute counts of lymphocytes and neutrophils; with bone marrow or tissue biopsy if available.
- Chest x-ray report.
- Haemoglobin concentration.
If investigation of both cellular and humoral immunity is required, the PRU must be contacted prior to the collection of blood samples. Without previous discussion, only immunoglobulin concentrations will be measured.
Reference range: for the relevant age related reference ranges see PRU Handbook of Clinical Immunochemistry