Hypogammaglobulinaemia

What is hypogammaglobulinaemia?

Hypogammaglobulinaemias are heterogeneous diseases of either primary origin (genetic disorders and/or chromosome anomalies) or secondary origin (induced by extrinsic factors - infectious agents, mediators such as corticosteroids and immunosuppressants, chemotherapy, metabolic diseases such as nephrotic syndrome, nutritional disorders, and environmental conditions such as ionising radiation).¹

• The primary antibody deficiency syndromes are a rare group of disorders presenting at any age.² In the primary form, there is a reduced rate of synthesis of gamma globulins, whereas the secondary form results from an increased rate of breakdown or loss of gamma globulins.

• Examples of the primary immunodeficiencies associated with immunoglobulin disorders include:
  

  • Selective immunoglobulin A (IgA) deficiency: presents with upper and lower respiratory tract infections.

  • Common variable immune deficiency: low serum IgG and IgA, with normal or low serum IgM.

  • Transient hypogammaglobulinaemia of infancy: relatively common primary immunodeficiency disease that affects infants and young children. 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.

  • Bruton's X-linked hypogammaglobulinaemia: usually presents at age 7-10 months.

  • Combined B-cell and T-cell deficiency - eg, severe combined immune deficiency (SCID).

  • Wiskott-Aldrich syndrome: low IgG and IgM levels with elevated IgA and IgE.

  • Hyper-IgM syndrome: immunoglobulin deficiency but with increased IgM.

  • Specific antibody deficiency: classic history of humoral immune deficiency, with the patient failing to respond to test immunisations, despite having normal serum immunoglobulin concentrations.

• Secondary hypogammaglobulinaemia may occur in a wide range of conditions - for example:

  • Nephrotic syndrome.

  • Protein-losing enteropathy.

  • Thyrotoxicosis.

  • Chronic kidney disease.

  • Viral infections.

  • Immunosuppression treatment.

  • Severe malnutrition.

  • Multiple myeloma.

  • Chronic lymphocytic leukaemia, lymphomas.

  • Premature infants.

How common is Hypogammaglobulinaemia? (Epidemiology)

• The prevalence of primary immunodeficiency disease in children and adolescents (ie all those under 18 years old) is estimated to be about 1 in 2,000.³

• Most causes are very rare. However, primary immunodeficiencies that result in hypogammaglobulinaemia or predominantly antibody deficiency disorders, make up the largest proportion of patients with primary immunodeficiency.⁴

• The most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia, which accounts for approximately 85% of cases.⁵

• 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, followed by common variable immunodeficiency.

• The increasing use of immunotherapy (eg, rituximab) and immune-suppressive therapy (eg, steroids, sulfasalazine and mycophenolate mofetil) has increased the occurrence of iatrogenic hypogammaglobulinaemia.⁶

Symptoms of hypogammaglobulinaemia

Hypogammaglobulinaemia, especially more benign forms, may be easily overlooked. Primary antibody deficiency syndromes most commonly present with recurrent infections due to encapsulated bacteria. However, the most common primary antibody deficiency (common variable immunodeficiency) may present with systemic and organ-specific autoimmunity.⁷

Hypogammaglobulinaemia is associated with recurrent, persistent and severe infections such as sinusitis, otitis media, conjunctivitis, pneumonia, meningitis, septic arthritis, failure to thrive and a chronic asymmetrical polyarthritis. Assessment should include a family history of any health problems suggesting possible immunodeficiency.

The Primary Immunodeficiency Association lists the following as warning signs of a primary immunodeficiency:⁸

• Children:

  • Four or more new ear infections within one year.

  • Two or more new sinus infections within one year.

  • Two or more months on antibiotics with little effect.

  • Two or more pneumonias within one year.

  • Failure of an infant to gain weight or grow normally.

  • Recurrent, deep skin or organ abscesses.

  • Persistent thrush or fungal infection on skin or elsewhere.

  • Need for intravenous antibiotics to clear infections.

  • Two or more deep-seated infections including septicaemia.

  • A family history of primary immunodeficiency.

• Adults:

  • Two or more new ear infections within one year.

  • Two or more new sinus infections within one year, in the absence of allergy.

  • One pneumonia per year, for more than one year.

  • Chronic diarrhoea with weight loss.

  • Recurrent viral infections

  • Recurrent need for intravenous antibiotics to clear infections.

  • Recurrent, deep abscesses of the skin or internal organs.

  • Persistent thrush or fungal infection on skin or elsewhere.

  • Infection with normally harmless tuberculosis-like bacteria.

  • A family history of primary immunodeficiency.

Other features of hypogammaglobulinaemia include:

• Unexplained signs such as hepatosplenomegaly or arthropathy.

• Arthralgia, monoarticular or oligoarticular arthritis of the large joints with sterile effusions and septic arthritis may occur.

• Anaphylaxis or other severe reactions following transfusion of blood products may indicate an underlying IgA deficiency.

• There is an increased incidence of autoimmune and connective tissue disorders - eg, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, haemolytic anaemia and autoimmune endocrine disorders.

Differential diagnosis

• Other conditions which cause severe recurrent or chronic respiratory infections - eg, cystic fibrosis, bronchiectasis.

• Other causes of primary immunodeficiency and secondary immunodeficiency - eg, complement deficiencies, HIV infection, malignancy.

Diagnosing hypogammaglobulinaemia

• FBC and blood film: peripheral lymphocytes: peripheral B-cell levels are variable but often normal.

• Plasma B lymphocyte sub-populations concerned with antibody production.

• Renal function tests and assessment of proteinuria if present.

• 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.

• Isohaemagglutinins: IgM antibodies to A and/or B blood group antigens are very low in X-linked agammaglobulinaemia.

• Assessment of cellular immunity - eg, mumps skin test antigen or candida antigen.

• CXR and high-resolution CT scan of chest: for lung abnormalities - eg, interstitial infiltrates, bronchiectasis, emphysema or bullae and scarring.

• May require comprehensive investigation for any suspected underlying cause - eg, nuclear scan using technetium ^{Tc 99m} dextran to diagnose protein-losing enteropathy.

Umbilical cord blood can be used in the prenatal diagnosis of some of the inherited causes of hypogammaglobulinaemia.

Managing hypogammaglobulinaemia⁹

The main principles of management include treatment of infections, immunoglobulin replacement and the treatment of any underlying cause.

• Start antibiotics early in acute infections.

• Intravenous immunoglobulin replacement therapy is the mainstay of treatment for all primary immunodeficiency syndromes except IgA deficiency.¹⁰

• Self-administered subcutaneous immunoglobulin therapy has been shown to be well tolerated and an effective alternative to intravenous immunoglobulin therapy.¹¹

• Systemic glucocorticoids can be used for cytopenias; rituximab as a steroid-sparing adjunctive agent have also shown benefits.

• Haematopoietic stem cell transplant can also be done when weighing for cost and IVIG availability. In cases with no response to treatment.

• If other treatments are ineffective, splenectomy may be considered.

• Tumour necrosis factor inhibitors have been used to treat granulomatous diseases in patients with common variable immunodeficiency.

• Live vaccines should not be given to patients with severe B-cell disorders but are not absolutely contra-indicated in patients with IgA deficiency.

• Substantial progress has been made in the period of a decade in treating several primary immunodeficiency disorders (including SCID) with gene therapy.¹²

Complications of hypogammaglobulinaemia

• Despite immunoglobulin replacement, breakthrough 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 (eg, hearing loss due to chronic otitis media), bronchiectasis, cor pulmonale.

Prognosis

• Early diagnosis and appropriate immunoglobulin replacement therapy are essential.

• Immunoglobulin replacement therapy has dramatically changed the clinical course of primary hypogammaglobulinaemias, significantly reducing the incidence of infectious events.⁶

• 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.