DEFENCE AGAINST INFECTION

therapy is the standard treatment, aiming to maintain a trough

IgG level of about 8 g/litre.
X-linked hyper-IgM syndrome (CD40 ligand deficiency) recurrent bacterial upper and lower respiratory tract infections are
common in this rare condition. Patients are predisposed to Pneumocystis jiroveci (formerly known as P. carinii) pneumonia (which
affects 20%40%) and other opportunistic infections. Pulmonary
infection with cytomegalovirus, Cryptococcus, Histoplasma
a and
mycobacteria including BCG may occur.
Cryptosporidium is a common cause of chronic watery diarrhoea
and contributes to the high incidence of sclerosing cholangitis and
liver failure. Recurrent oral ulcers and proctitis are common and
usually associated with unexplained neutropenia. The long-term
prognosis is poor; 25-year survival is less than 30%.

The immunocompromised
patient: primary
immunodeficiencies
Vincent J Tormey
A David B Webster
Primary immunodeficiency diseases result from genetic defects in
the development and maturation of cells of the immune system.
They lead to an increased susceptibility to infections, which are
usually characteristic of the specific immune defect. They are classified into combined cellular and antibody deficiencies, predominant antibody deficiencies, phagocytic deficiencies, complement
deficiencies and miscellaneous disorders (Figure 1). Early diagnosis
and treatment are essential for the prevention of devastating consequences, because many of the conditions are treatable.
It is important to have a high index of suspicion for primary
immunodeficiency, particularly in children. Figure 2 lists features
that should alert clinicians to the presence of underlying immunodeficiency. Laboratory investigations should start with a broad
screen (Figure 3), but then focus on the likely underlying immunodeficiency. It is essential to use age-related normal ranges. In
infants, a total lymphocyte count of less than 2.5 x 109/litre should
be considered diagnostic of severe combined immunodeficiency
(SCID) until proven otherwise. This is a medical emergency and
urgent referral to a specialist SCID centre is essential.

Classification of primary immunodeficiencies

Severe combined immunodeficiency
TB+NK+ (IL7R deficiency, CD45 defects)
TB+NK (X-linked c defect, JAK-3 defect)
TBNK+ (RAG defects1)
TBNK (reticular agenesis, adenosine deaminase
deficiency)
1

Omenns syndrome is a variant of severe combined immunodeficiency in

which mutations allow partial RAG function

Combined immunodeficiencies
X-linked hyper-IgM syndrome type 1
WiskottAldrich syndrome
DiGeorge anomaly (predominantly T cell)
Ataxiatelangiectasia
Nijmegen breakage syndrome
Predominantly antibody deficiencies
X-linked agammaglobulinaemia
Common variable immunodeficiency (polygenic)
IgG subclass deficiency (polygenic)
IgA deficiency (polygenic)
Autosomal recessive hyper-IgM syndrome type 2
Specific antibody deficiency
Transient hypogammaglobulinaemia of infancy
Other well-recognized immunodeficiencies
X-linked lymphoproliferative syndrome
Chronic mucocutaneous candidiasis
Hyper-IgE syndrome
Complement deficiencies
Phagocytic deficiencies
Chronic granulomatous disease
Glucose-6-phosphate dehydrogenase deficiency
Leucocyte adhesion defect
Cyclic neutropenia
Severe congenital neutropenia
Th1 cytokine defects
Interferon- receptor R1 deficiency
Interleukin- receptor R2 deficiency
Interleukin-12 1 deficiency
Interleukin-12 P40 deficiency
STAT1 deficiency

Clinical features
Antibody defects are the most common primary immunodeficiencies; the prevalence in Caucasians ranges from 1/600 (IgA deficiency) to 1/200,000 (X-linked agammaglobulinaemia). Patients
present with sinopulmonary infections with bronchopneumonia,
lobar pneumonia, bronchiectasis, otitis media, mastoiditis and
chronic sinusitis. Common pathogens include non-encapsulated
Haemophilus influenzae, Streptococcus pneumoniaee and Moraxella
catarrhalis. Gastrointestinal infections are also common, most
often with Giardia lamblia
a or Campylobacter jejuni. Infection with
Ureaplasma urealyticum and Mycoplasma
a spp. can occur in the
respiratory tract, joints and urogenital tract, the latter sometimes
causing urethral strictures, epididymitis and prostatitis.
Enteroviral infections are less common. Severe sequelae include
chronic meningoencephalitis and dermatomyositis/fasciitis. Mycobacterial infections are rare in common variable immunodeficiency,
possibly because of the protective effect of increased interferon-
and interleukin-12 production.
There is no close correlation between degree of hypogammaglobulinaemia and susceptibility to infection. IgG replacement
Vincent J Tormey
y is Consultant Immunologist at University College
Hospital, Galway, Ireland.
A David B Websterr is Consultant Immunologist at the Royal Free Hospital
Trust, London, UK.
MEDICINE 33:3

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DEFENCE AGAINST INFECTION

When to investigate for immunodeficiency

Principles of management

Family history of immunodeficiency/death from infection

Infants and young children with failure to thrive, opportunistic
infections, persisting infections with low-virulence organisms,
severe diarrhoea, unusual/extensive skin rashes,
hepatosplenomegaly
Recurring/persisting sinopulmonary infection
Recurring skin infections, abscesses or periodontitis
Recurrent Neisseria infection
Infection with unusual (opportunistic) organisms

SCID has an incidence of about 1/100,000 births. It usually

presents in the first 6 months of life, with failure to thrive, chronic
diarrhoea, oral and cutaneous candidiasis and persistent infections
despite conventional treatment. Marked deterioration is usually
triggered by a broad range of pathogenic and opportunistic bacterial, fungal or viral infections, particularly. P. jiroveci, herpesviruses and enteric viruses. Infants usually die before 1 year of age
unless treated with bone marrow transplantation. Early diagnosis
and referral to a SCID transplant centre is essential.
Phagocytic defects individuals with chronic granulomatous
disease have various genetic defects in the respiratory burst pathway (NADPH oxidase system) in phagocytes, leading to failure to
kill pathogenic bacteria (particularly catalase-positive organisms)
and fungi. They suffer severe recurrent infections, most commonly
pneumonia, lymphadenitis, cutaneous and hepatic abscesses,
osteomyelitis and septicaemia. The most common organisms are
Staphylococcus aureus, Aspergillus spp., and enteric Gram-negative
bacteria including Serratia marcescens and Burkholderia cepacia.
In addition, many patients have diffuse granulomata in the gastrointestinal and urinary tracts; the mechanism is unclear. Some very
rare defects in leucocyte adhesion molecules ( integrins) lead to
rapidly spreading skin necrosis following trivial local infection.

Complement deficiencies the prevalence ranges from 1/10,000

(C2 deficiency) to 1/million; clinical expression is variable. Onset
of symptoms may be at any age. C3-deficient patients have increased susceptibility to bacterial infection in which opsonization is
important in host defence (e.g. Strep. pneumoniae, Strep. pyogenes,
H. influenzae). Those with C1, C2 or C4 deficiency have a similar
but less marked susceptibility because they can activate C3 via
the alternative pathway; however, they are susceptible to immune
complex diseases, particularly systemic lupus erythematosus.
Deficiencies in the terminal C59 components result in failure
of formation of the membrane attack complex and increased
susceptibility to Neisseria meningitidis because of the impaired
bactericidal activity of complement. Deficiencies in factor H, factor
I and properdin are also associated with increased susceptibility to
N. meningitidis. Patients with complement component deficiencies should be vaccinated with pneumococcal, meningococcal
and H. influenzaee type b vaccines, and may require antibiotic
prophylaxis.
Interferon-/interleukin-12

defects are very rare. They specifically increase susceptibility to mycobacterial infections, including
persistant BCG infection. Occasionally, Salmonella
a and viral infections have been described. The severity of the clinical phenotype
depends on the genotype.

Screening investigations
Full blood count, including differential WBC, platelet count
and size
Quantitative serum immunoglobulins (IgG, IgA, IgM, IgE;
IgG subclasses occasionally helpful)
Antibody titre to vaccinations (e.g. tetanus toxoid, pneumococcal polysaccharide) (in adults interpretation is difficult in
the under-5s)
Lymphocyte subsets by flow cytometry (total T cell CD2 or
CD3, T cell subsets CD4 and CD8, B cell CD19, NK cell CD16
and CD56)
MHC class II, adenosine deaminase, purine nucleoside
phosphorylase (simple screening for some severe combined
immunodeficiencies)
Neutrophil function (respiratory burst) (nitro-blue tetrozolium
test or dihydrorodamine flow cytometry-based test)
Total haemolytic complement both classical and alternative
pathways (CH50, AP50)

Management
The principles of management are listed in Figure 4.

FURTHER READING
Bonilla F A, Geha R S. Primary immunodeficiency diseases. J Allerg Clin
Immunol 2003; 111: (Suppl): S57181.
Chapel H, Geha R, Rosen F. IUIS PID (primary immunodeficiencies)
Classification Committee. Primary immunodeficiency diseases: an
update. Clin Exp Immunol 2003; 132: 915.
Ochs H D, C I E Smith, Puck J M, eds. Primary immunodeficiency diseases.
A molecular and genetic approach. Oxford: Oxford University Press,
1999.

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MEDICINE 33:3

Early diagnosis and referral to immunodeficiency centre

Protective isolation in severe combined immunodeficiency
Co-trimoxazole prophylaxis in T cell deficiencies
Blood transfusions should be irradiated and cytomegalovirusnegative in T cell deficiency, to avoid graft-vs-host disease
and infection
Consider early bone marrow transplantation in severe
combined immunodeficiency, and possibly in X-linked
hyper-IgM syndrome and WiskottAldrich syndrome
Avoid live attenuated vaccines in all severe antibody and
cellular immune deficiencies
Intravenous immunoglobulin in hypogammaglobulinaemia
Antifungal prophylaxis in chronic granulomatous disease and
chronic mucocutaneous candidiasis
Aggressive treatment of infections with antibiotics

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2005 The Medicine Publishing Company Ltd