Primary Immunodeficiency

Overview

Immunodeficiency describes disorders in which part of the immune system is absent or not functioning normally. Primary immunodeficiency (PID) describes immunodeficiency secondary to disorders with the immune cells themselves in the absence of a secondary cause (e.g. a different disease, drug treatment, toxins etc.).

Many PIDs are inherited single-gene disorders that present in infancy/childhood except for common variable immunodeficiency which is usually seen in adults.

Epidemiology

• Most PIDs are rare, however, symptomatic PID may affect up to 1 in 500 people.
• IgA deficiency is relatively common in around 1 in 500 people, particularly Caucasian people

Classification

PID can be broadly categorised into:

• Neutrophil disorders
• B-cell and antibody disorders:
• T-cell disorders:
• Combined B- and T-cell disorders

Presentation

General features

Some general features that may suggest immunodeficiency can be remembered using the SPUR acronym:

• Severe infections (e.g. pneumonia and abscess formation)
• Persistent infections
• Unusual infections
• Recurrent infections

Other features that may raise suspicion of PID include:

• A family history of immunodeficiency
• Unexplained infant deaths
• Consanguinity
• Early-onset eczematous skin rashes
• Early-onset autoimmunity
• Failure to thrive, especially chronic diarrhoea/infection
• Adverse reactions to immunisations
• Complications of viral infections

Investigations

Overview

Initial tests include:

• Full blood count (FBC) and differential:
  • May show derangements depending on the type of PID present
  • A lymphocyte count <1 in a <1 year old is severe combined immunodeficiency (SCID) until proven otherwise
• Serum immunoglobulins (IgG, IgM, IgA):
  • May show derangements depending on the type of PID present
• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP):
  • Non-specific markers of inflammation, may be elevated
• Cultures from relevant infection sites:
  • May identify infectious pathogens

Patients with suspected PID should be referred to an immunologist, who may perform specialist tests:

• Flow cytometry/immunophenotyping:
  • Uses a flow cytometer to identify cells using specific molecules (e.g. CD4) and measuring how many there are
• Vaccine antibody responses:
  • Involves giving vaccines and measuring antibody responses
• Lymphocyte functional tests (e.g. proliferation assays):
  • Stimulant molecules (e.g. mitogens) are used to trigger lymphocytes and their actions are recorded (e.g. cell division or cytokine release)
• Genetic testing:
  • May identify an underlying genetic disorder

Neutrophil Disorders

Chronic granulomatous disease

Chronic granulomatous disease (CGD) is a genetic disorder characterised by an impaired ability of phagocytes (neutrophils, monocytes, and macrophages) to produce reactive oxidative species to destroy pathogens after they are phagocytosed. This is due to defects in parts of the NADPH oxidase enzyme.

Key features include:

• Recurrent serious bacterial and fungal infections, particularly Staphylococcus aureus and Aspergillus species

Key investigations include:

• Nitroblue tetrazolium test (NBT):
  • Neutrophils can normally convert NBT into formazan, which is a dark blue pigment which can be seen with microscopy
  • In CGD, patients cannot reduce NBT
• Dihydrorhodamine (DHR) 123 test:
  • This involves using flow cytometry to detect the ability of neutrophils to convert DHR 123 into another molecule.

Chediak-Higashi syndrome

In Chediak-Higashi syndrome (CHS), phagocytes cannot form phagolysosomes properly, leading to reduced phagocytosis.

Key features include:

• Recurrent bacterial infection
• Partial albinism
• Peripheral neuropathy

Key investigations include:

• Bone marrow analysis:
  • Giant inclusion bodies in leukocyte precursors

Leukocyte adhesion deficiency

In leukocyte adhesion deficiency (LAD), neutrophils cannot adhere to receptors in vascular endothelia, meaning they cannot extravasate and enter tissues. There are three main types of LAD.

Key features include:

• Recurrent bacterial infections
• Delayed umbilical cord sloughing
• Reduced/absent numbers of neutrophils at infection sites

Key investigations include:

• Full blood count (FBC) and differential:
  • May show neutrophilia as they cannot leave blood vessels
• Flow cytometry:
  • Identifies abnormal proteins on cells (e.g. CD18 in LAD1) 

B-cell and Antibody Disorders:

Transient hypogammaglobulinaemia of infancy

A neonate’s immunoglobulins come from the mother during pregnancy and wane until around 6 months of age when the infant starts to produce their own IgG. In transient hypogammaglobulinaemia of infancy (THI), this effect is extended and the synthesis of IgG is delayed, resulting in hypogammaglobulinaemia persisting beyond 6 months of age.

Key features include:

• Recurrent upper and lower respiratory tract infections
• Atopy
• Asymptomatic

Key investigations include:

• Serum immunoglobulins (IgG, IgM, IgA):
  • IgA reduced
  • IgM and IgA may be normal/reduced

Common variable immunodeficiency (CVID)

Common variable immunodeficiency (CVID) describes recurrent infection and hypogammaglobulinaemia due to many different causes. The ‘variable’ part describes the varied presentations of CVID, ranging from recurrent infections to autoimmunity and lymphoma

Key features and investigations include:

• Low antibodies (IgG, IgM, IgA)
• Presentation can vary from recurrent infections to autoimmunity and lymphoma

Bruton’s (x-linked) agammaglobulinaemia

Bruton’s (x-linked) agammaglobulinaemia (XLA) occurs due to defects in Bruton’s tyrosine kinase (BTK) which is essential in B-cell maturation. This leads to impaired B-cell maturation resulting in their absence and reduced immunoglobulins of all classes (agammaglobulinaemia).

Key features include:

• Neonates may be asymptomatic until around 6 months when maternal IgG decreases
• Recurrent bacterial infections

Key investigations include:

• Immunoglobulins (IgG, IgM, IgA):
  • Absent
• Immunophenotyping:
  • Absent B-cells

Selective IgA deficiency

Selective IgA deficiency (SIgAD) describes reduced amounts of immunoglobulin A and is the most common primary immunodeficiency. It is most often due to B-cell maturation defects.

Key features include:

• Recurrent upper respiratory tract and sinus infections
• Associated with coeliac disease and may cause a falsely negative coeliac screen
• Anaphylaxis may occur in blood transfusions due to self-anti-IgA antibodies reacting with IgA from donor blood

Key investigations include:

• Immunoglobulins (IgG, IgM, IgA):
  • Low IgA

Hyper IgM syndrome

Hyper IgM syndrome is a primary immunodeficiency due to mutations and defective signalling in CD40, which is important for B-cells to switch from the production of one antibody type to another. 

Key features include:

• Pneumocystis jirovecii pneumonia (PCP)
• Hepatitis
• Chronic diarrhoea

Key investigations include:

• Immunoglobulins (IgG, IgM, IgA):
  • IgM is elevated

T-cell Disorders

DiGeorge syndrome

DiGeorge syndrome occurs due to a 22q11.2 microdeletion leading to congenital heart disease, developmental delay and learning disabilities, cleft palate, hypocalcaemia, and thymic aplasia/hypoplasia, which results in impaired T-cell function.

Key features include:

• Congenital heart disease (e.g. tetralogy of Fallot)
• Developmental delay
• Learning difficulties
• Cleft palate
• Recurrent infection

Key investigations include:

• Serum calcium and PTH:
  • Both may be low
• T-cell count:
  • May be low
• Genetic testing:
  • Identifies 22q11.2 deletion

Combined B- and T-cell Disorders

Severe combined immunodeficiency (SCID)

Severe combined immunodeficiency (SCID) describes a group of genetic disorders leading to disturbed T- and B-cell development. The most common cause is X-linked SCID which leads to mutations in interleukin 2 (IL2) receptors resulting in a near or complete failure of lymphocytes to develop and function.

A lymphocyte count <1 in a <1 year old is severe combined immunodeficiency (SCID) until proven otherwise

Key features include:

• May be healthy at birth due to maternal IgG
• Recurrent/severe infection
• Chronic diarrhoea
• Failure to thrive

Key investigations include:

• Full blood count (FBC) and differential:
  • Low lymphocytes
  • Low absolute lymphocyte count
• Chest X-ray:
  • May show an absent thymic shadow
• Immunoglobulins (IgG, IgM, IgA):
  • All are absent/low
  • IgG may be normal due to maternal IgG persisting for up to 6 months
• Flow cytometry:
  • Absolute/significant reduction in T-cell numbers
• T-cell proliferation studies:
  • Mitogens lead to no response

Ataxic telangiectasia

Ataxia-telangiectasia (AT) is an autosomal recessive disorder due to a defect in the ATM gene which is involved in recognising and repairing damaged DNA. It is characterised by ataxia and telangiectasia.

Key features include:

• Cerebellar ataxia
• Telangiectasia
• Pes cavus
• Immunodeficiency:
  • Recurrent infections
  • IgA deficiency
  • Poor vaccine responses
• Increased risk of malignancy:
  • Particularly lymphoma or leukaemia

Key investigations include:

Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder leading to defects in the Wiskott-Aldrich protein (WASp) leading to eczema, thrombocytopenia, and immunodeficiency.

Key features include:

• Eczema
• Thrombocytopenia
• Bloody diarrhoea
• Recurrent infection

Key investigations include:

• Full blood count (FBC):
  • Shows thrombocytopenia
• Immunoglobulins (IgG, IgM, IgA):
  • IgM may be low
• WASp analysis:
  • Low
• Genetic testing:
  • Identifies genetic defect