Description

Primary antibody deficiency syndromes include congenital and acquired antibody deficiencies but not those secondary to other diseases (eg myeloma, chronic lymphocytic leukaemia or protein-losing enteropathies). There is often a significant delay in reaching a diagnosis of primary antibody deficiency, leading to an increase in morbidity and mortality.^[1]

Types of primary antibody deficiency^[1]

• Common variable immune deficiency: low serum IgG and IgA concentrations, including IgG subclasses, with or without low serum IgM levels.^[2]
• Bruton's X-linked hypogammaglobulinaemia: usually presents before the age of 2 years and most often from 6-12 months.
• Transient hypogammaglobulinaemia of infancy: delayed onset of immunoglobulin synthesis in infants with presentation in the second half of the first year and recovery when aged 2-3 years. High incidence of recurrent upper respiratory infections but usually not severe infections, and doesn't require immunoglobulin therapy.
• IgG subclass deficiencies: may be an indication for immunoglobulin replacement therapy in patients with recurrent infections who also do not produce specific IgG antibodies after test immunisations.^[3]
• Specific antibody deficiency: occurs in patients with a classic history of humoral immune deficiency who fail to respond to test immunisations, despite having normal serum concentrations of total IgG, IgA, IgM and IgG subclasses.
• Hyper IgM syndrome: immunoglobulin deficiency but with increased IgM.
• Selective IgA deficiency: occurs in 1 in 700 of the population. Many affected people may be symptom-free, particularly if the deficiency is discovered by chance. Patients with the deficiency who have recurrent infections may also have an underlying deficiency in a subclass of IgG or specific antibody.
• Combined B-cell and T-cell deficiency, eg severe combined immune deficiency.

Presentation^[2][3]

Primary immune deficiency is associated with recurrent and severe infections such as sinusitis, otitis media, conjunctivitis, pneumonia, meningitis, septic arthritis and a chronic asymmetrical polyarthritis. The possibility of a primary antibody deficiency is suggested by:

• Unexplained failure to thrive.
• Excess of infections. Adults often present with recurrent sinusitis.
• Recurrent infections requiring frequent prescription of antibiotics.
• Particularly severe, unusual or persistent infections, even if serum immunoglobulin concentrations are normal.
• Chronic infections such as tonsillitis, otitis media, or recurrent boils.
• Need for instigation of second-line tests for chronic infection, eg sweat tests.
• Abnormal lymphoid tissue, such as nodular lymphoid hyperplasia in the gut or congenital absence of tonsils.
• Unexplained signs such as hepatosplenomegaly or arthropathy.

Differential diagnosis^[1]

• Secondary immunodeficiencies, including HIV infection.
• Other conditions which cause severe recurrent or chronic respiratory infections such as cystic fibrosis, bronchiectasis.
• Other causes of recurrent or persistent diarrhoea, eg Crohn's disease.
• Other causes of recurrent or persistent infections, eg diabetes mellitus.
• Other causes of failure to thrive.

Investigations^[3]

• Serum immunoglobulin concentrations, including IgG subclasses.
• When serum immunoglobulin concentrations are greatly depressed, confirmatory tests are not always necessary.
• Functional antibody responses to immunisations, common bacteria and red cell antigens may be required.
• Plasma B lymphocyte sub-populations concerned with antibody production.
• CT scanning may be required to detect changes of chronic lung disease, such as fibrosis.^[4]

Management^[2][5]

• Prompt antibiotic treatment. Consider constant prophylaxis.
• Patients with reduced levels of serum IgG with low levels of IgA and/or IgM and a clinical history of bacterial infections will require regular intravenous (IV) immunoglobulin, although in patients with partial immunoglobulin deficiency and mild-to-moderate symptoms, antibiotic treatment may be sufficient. The dosage of IV immunoglobulin should initially be 0.4-0.6 g/kg/month with titration to maintain trough IgG (the lowest level before the next dose) in the normal range.
• Subcutaneous immunoglobulin is an alternative to IV administration and may be preferred in patients who wish to be treated at home, have poor veins or have adverse reactions to IV products.^[6]
• Higher doses may be needed in patients with known lung damage.^[7]
• Side-effects (which include headache, nausea, chills and fever) can be reduced by lowering the rate of infusion.^[8]
• Haemopoietic stem cell transplant may be considered for patients with severe combined immune deficiency.^[4]
• Tympanostomy tubes and endoscopic sinus surgery may be required for patients with recurrent otitis media or sinusitis.^[3]

Complications

Complications of primary antibody deficiency include acute infections, which may be due to unusual organisms such as mycoplasmas and long-term complications:^[9]

• Chest: bronchiectasis, fungal infections, polyclonal lymphoid aggregates, granulomas, lymphoma.
• Sinuses: recurrent sinusitis.
• Bowel: infections (giardia, cryptosporidia), malabsorption, autoimmune enteropathy, sclerosing cholangitis, atrophic gastritis, food sensitive enteropathy, colitis, gastric carcinoma.
• Liver: hepatitis, associated autoimmune diseases (chronic active hepatitis, primary biliary cirrhosis, sclerosing cholangitis), non-infective granulomas.
• Joints: septic arthropathy, chronic sterile arthropathy and/or arthralgia.
• Blood: autoimmune haemolytic anaemia, immune thrombocytopenic purpura, iron-deficiency anaemia, anaemia of chronic illness, aplastic anaemia.
• CNS: acute enteroviral meningoencephalitis, chronic cerebral granulomas.
• Spleen: unexplained splenomegaly in 30% of patients.
• Eyes: keratoconjunctivitis, uveitis.

Prognosis

• This depends on the nature and severity of the primary antibody deficiency.
• In general terms, the earlier the condition is recognised, the better the prognosis.^[10]