Most patients with an immune deficiency present with
recurrent infections. While there is no accepted definition
of ‘too many’ infections, features that may indicate
immune deficiency are shown in Box. Frequent,
severe infections or infections caused by unusual organisms
or at unusual sites are the most useful indicator.
Baseline investigations include full blood count with
white cell differential, acute phase reactants (CRP, see
below), renal and liver function tests, urine dipstick,
serum immunoglobulins with protein electrophoresis,
and total IgE level. Additional microbiological, virological
and radiological tests may be appropriate. At this
stage, it may be clear which category of immune deficiency
should be considered, and specific investigation
can be undertaken, as described below.
If an immune deficiency is suspected but has not yet
been formally characterised, patients should not receive
live vaccines because of the risk of vaccine-induced
disease. Discussion with specialists will help determine
whether additional preventative measures, such as prophylactic
antibiotics, are indicated.
Primary phagocyte deficiencies
Neutrophil function and dysfunction (green boxes).
Primary phagocyte deficiencies (see Fig.)
usually present with recurrent bacterial and fungal
infections which may affect unusual sites. Aggressive
management of existing infections, including intravenous
antibiotics and surgical drainage of abscesses,
and long-term prophylaxis with antibacterial and antifungal
agents, is required. Specific treatment depends
upon the nature of the defect; haematopoietic stem cell
transplantation may be considered .
Leucocyte adhesion deficiencies
These are rare disorders of phagocyte migration, when
failure to express adhesion molecules on the surface of
leucocytes results in their inability to exit the blood
stream. They are characterised by recurrent bacterial
infections with high blood neutrophil counts but sites
of infection lack pus or other evidence of neutrophil
Chronic granulomatous disease
This is caused by mutations in the genes encoding
the NADPH oxidase enzymes, which results in failure
of oxidative killing. The defect leads to susceptibility
to catalase-positive organisms, such as Staphylococcus
aureus, Burkholderia cenocepacia and Aspergillus. Intracellular
killing of mycobacteria is also impaired. Infections
most commonly involve the lungs, lymph nodes, soft
tissues, bone, skin and urinary tract, and are characterised
histologically by granuloma formation.
Defects in cytokines and cytokine receptors
Defects of cytokines such as IFN-γ, IL-12 or their
receptors also result in failure of intracellular
killing, with particular susceptibility to mycobacterial
Complement pathway deficiencies
The complement pathway. The activation of C3 is central to complement activation.
Genetic deficiencies of almost all the complement
pathway proteins (see Fig.) have been described.
Many present with recurrent infection with encapsulated
bacteria, particularly Neisseria species, reflecting
the importance of the membrane attack complex in
defence against these bacteria. In addition, genetic deficiencies
of the classical complement pathway (C1, C2
and C4) are associated with a high prevalence of autoimmune
disease, particularly systemic lupus erythematosus
In contrast to other complement deficiencies,
mannose-binding lectin deficiency is very common
(5% of the northern European population). Complete
deficiency may predispose to bacterial infections in
the presence of an additional cause of immune compromise,
such as premature birth or chemotherapy,
but is otherwise well tolerated. Deficiency of the
complement regulatory protein Cl inhibitor is not associated
with recurrent infections but causes recurrent
Investigations and management
Complement C3 and C4 are the only complement components
that are routinely measured. Screening for complement
deficiencies is performed using more specialised
functional tests of complement-mediated haemolysis,
known as CH50 and AP50 (classical haemolytic pathway
50 and alternative pathway 50). If abnormal, these
haemolytic tests should be followed by measurement of
individual complement components.
There is no definitive treatment for complement deficiencies.
Patients should be vaccinated with meningococcal,
pneumococcal and H. influenzae B vaccines in
order to boost their adaptive immune responses. Lifelong
prophylactic penicillin to prevent meningococcal
infection is recommended. At-risk family members
should also be screened.
Primary deficiencies of the adaptive immune system
Primary T-lymphocyte deficiencies
These are characterised by recurrent viral, protozoal and
fungal infections (see Box). In addition, many T-cell
deficiencies are associated with defective antibody
production because of the importance of T cells in
regulating B cells. These disorders generally present
in childhood and are illustrated in Figure 4.6.
This results from failure of development of the 3rd/4th
pharyngeal pouch, usually caused by a deletion of
22q11. It is associated with multiple abnormalities,
including congenital heart disease, hypocalcaemia,
tracheo-oesophageal fistulae, cleft lip and palate, and
absent thymic development. The immune deficiency is
characterised by very low numbers of circulating T cells,
despite normal development in the bone marrow.
Bare lymphocyte syndromes
These are caused by absent expression of HLA molecules
within the thymus. If HLA class I molecules are
affected, CD8+ lymphocytes fail to develop, while absent
expression of HLA class II molecules affects CD4+ lymphocyte
maturation. In addition to recurrent infections,
failure to express HLA class I is associated with systemic
vasculitis caused by uncontrolled activation of NK cells.
Autoimmune lymphoproliferative syndrome
This is caused by failure of normal lymphocyte apoptosis
, leading to non-malignant accumulation of
autoreactive cells. This results in lymphadenopathy,
splenomegaly and a variety of autoimmune diseases.
Investigations and management
The principal tests for T-lymphocyte deficiencies are a
total blood lymphocyte count and quantitation of lymphocyte
subpopulations by flow cytometry. Serum
immunoglobulins should also be measured. Secondline,
functional tests of T-cell activation and proliferation
may be indicated. Patients in whom T-lymphocyte deficiencies
are suspected should be tested for human
immunodeficiency (HIV) infection .
Anti-Pneumocystis and antifungal prophylaxis, and
aggressive management of infections, are required.
Immunoglobulin replacement may be indicated if antibody
production is impaired. Haematopoietic stem cell
transplantation (HSCT) may be appropriate.
Combined B- and T-lymphocyte
Severe combined immune deficiency (SCID) is caused
by defects in lymphoid precursors and results in combined
failure of B- and T-cell maturation. The absence of
an effective adaptive immune response causes recurrent
bacterial, fungal and viral infections soon after birth.
HSCT is the only current treatment, although
gene therapy is under investigation.
Primary antibody deficiencies
B lymphocytes and primary antibody deficiencies (green boxes).
Primary antibody deficiencies (Fig. ) are characterised
by recurrent bacterial infections, particularly of the respiratory
and gastrointestinal tract. The most common
causative organisms are encapsulated bacteria, such as
Strep. pneumoniae and H. influenzae. These disorders may
present in infancy, when the protective benefit of transferred
maternal immunoglobulin has waned. However,
three forms of primary antibody deficiency can also
present in adulthood:
• Selective IgA deficiency is the most common primary
immune deficiency, affecting 1 : 600 northern
Europeans. In most patients, low (< 0.05 g/L) or
undetectable IgA is an incidental finding with no
clinical sequelae. However, 30% of individuals
experience recurrent mild respiratory and
gastrointestinal infections. In some patients, there is
a compensatory increase in serum IgG levels.
Specific treatment is generally not required.
• Common variable immune deficiency (CVID) is a
heterogeneous primary immune deficiency of
unknown cause. It is characterised by low serum
IgG levels and failure to make antibody responses
to exogenous pathogens. Paradoxically, antibodymediated
autoimmune diseases, such as
autoimmune haemolytic anaemia, are common.
CVID is also associated with an increased risk of
malignancy, particularly lymphoproliferative
• Specific antibody deficiency or functional IgG antibody
deficiency is a poorly characterised condition
which causes defective antibody responses to
polysaccharide antigens. Some patients are deficient
in antibody subclasses IgG2 and IgG4, and this
condition was previously called IgG subclass
There is overlap between specific antibody deficiency,
IgA deficiency and CVID, and some patients may
progress to a more global antibody deficiency over time.
Investigations include serum immunoglobulins (Box ), with protein and urine electrophoresis to exclude
secondary causes of hypogammaglobulinaemia, and B
and T lymphocyte counts in blood by flow cytometry.
Specific antibody responses to known pathogens can be
assessed by measuring IgG antibodies against tetanus,
H. influenzae and Strep. pneumoniae (most patients will
have been exposed to these antigens through infection
or immunisation). If specific antibody levels are low,
immunisation with the appropriate killed vaccine
should be followed by repeat antibody measurement
6–8 weeks later; failure to mount a response indicates a
defect in antibody production. These functional tests
have superseded IgG subclass quantitation.
With the exception of individuals with selective IgA
deficiency, patients with antibody deficiencies require
aggressive treatment of infections, and prophylactic
antibiotics may be indicated. The mainstay of treatment
is life-long immunoglobulin replacement therapy. This
is derived from pooled plasma and contains
IgG antibodies to a wide variety of common organisms.
Immunoglobulin replacement may be administered
either intravenously or subcutaneously, often by the
patient, with the aim of maintaining trough IgG levels
within the normal range. Immunisation is generally
not effective because of the defect in IgG antibody production.
As with all primary immune deficiencies, live
vaccines should be avoided .
Secondary immune deficiencies
Secondary immune deficiencies are much more common
than primary immune deficiencies (Box). Common
causes include infections, such as HIV and measles, and
cytotoxic and immunosuppressive drugs, particularly
those used in the management of transplantation,
autoimmunity and cancer. Physiological immune deficiency
occurs at the extremes of life; the decline of the
immune response in the elderly is known as immune