Hypogammaglobulinaemia

A state of deficiency of plasma gamma globulins and impairment of antibody formation. The commonest cause worldwide is malnutrition.¹ Hypogammaglobulinaemia may be primary or secondary:

• In the primary form, there is a reduced rate of synthesis of gamma globulins, whereas the secondary form results from an increased rate of break down or loss of gamma globulins.
• Examples of the primary immunodeficiencies associated with immunoglobulin disorders include:
  • Bruton's X-linked hypogammaglobulinaemia: usually presents at age 7-10 months
  • Common variable immune deficiency: Low serum IgG and IgA, with normal or low serum IgM
  • Transient hypogammaglobulinaemia of infancy: delayed onset of immunoglobulin synthesis in infants with presentation in 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.
  • Combined B cell and T cell deficiency, e.g. severe combined immune deficiency (SCID)
  • Selective IgA deficiency presents with upper and lower respiratory tract infections
  • Hyper IgM syndrome: immunoglobulin deficiency but with increased IgM
  • Specific antibody deficiency: classic history of humoral immune deficiency who fail to respond to test immunisations, despite having normal serum immunoglobulin concentrations.
• Secondary hypogammaglobulinaemia may occur in a wide range of conditions, e.g:
  • Myotonic dystrophy
  • Nephrotic syndrome, protein-losing enteropathy
  • Thyrotoxicosis
  • Uraemia
  • Viral infections
  • Immunosuppression treatment
  • Severe malnutrition
  • Multiple myeloma
  • Chronic lymphocytic leukaemia, lymphomas
  • Premature infants

Hypogammaglobulinaemia, especially more benign forms, may be easily overlooked. The Primary Immunodeficiency Association lists the following as warning signs of a primary immunodeficiency (see link to site at end of this article):

• Eight or more ear infections within 1 year
• Two or more serious sinus infections within 1 year
• Two or more months on antibiotics with little or no affect
• Two or more pneumonias within 1 year
• Failure of an infant to gain weight or grow normally
• Recurrent, deep skin or organ abscesses
• Persistent thrush in mouth or elsewhere on skin, after age 1
• Need for intravenous antibiotics to clear infections
• Two or more deep seated infections
• A family history of primary immune deficiency

• Most causes are very rare
• The less severe conditions such as IgA deficiency and transient hypogammaglobulinaemia of infancy may be asymptomatic or mild and therefore not diagnosed.
• IgA deficiency is the most common antibody deficiency syndrome (1 in 700), followed by common variable immunodeficiency (1 in 50,000).

Hypogammaglobulinaemia 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, e.g. 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
• Arthralgia, monoarticular or oligoarticular arthritis of the large joints with sterile effusions and septic arthritis may occur.
• There is an increased incidence of autoimmune and connective tissue disorders, e.g. rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, haemolytic anemia and autoimmune endocrine disorders.

• Other conditions which cause severe recurrent or chronic respiratory infections, e.g. cystic fibrosis
• Other causes of immunodeficiency, e.g. HIV infection, malignancy

• Peripheral lymphocytes: peripheral B cell levels are variable but often normal.
• Serum immunoglobulin concentrations, including IgG subclasses. Serum protein electrophoresis.
• 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.
• Chest x-ray and CT scan of chest: for lung abnormalities, e.g. interstitial infiltrates, bronchiectasis, emphysema or bullae and scarring.¹
• May require comprehensive investigation for underlying cause in cases of suspected hypogammaglobulinaemia.

• Start antibiotics early in acute infections.
• Intravenous immunoglobulin replacement therapy is the mainstay of treatment for all primary immunodeficiency syndromes except IgA deficiency. In selective IgA deficiency, oral immunoglobulin may improve chronic diarrhoea.
• One study found no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.²
• Live vaccines should not be given to patients with severe B-cell disorders but are not absolutely contraindicated in patients with IgA deficiency.
• Bone marrow transplantation is the treatment of choice for patients with SCID. There are also reports of success with gene therapy for patients with SCID.¹

• Despite immunoglobulin replacement, break-through infections may occur and may be due to unusual organisms such as mycoplasma.
• In many conditions, there is an increased risk of autoimmune disorders and cancer.
• Recurrent infections may lead to significant end-organ damage, especially in the respiratory tract.

• Early diagnosis and appropriate immunoglobulin replacement therapy are essential.
• Late diagnosis results in recurrent and often severe infections, malabsorption, anaemia, and bronchiectasis.
• The prognosis will depend on the nature and severity of the underlying disorder.