Approach

A clinical history of recurrent, chronic, or atypical infections (and failure to thrive in children) should prompt the measurement of serum immunoglobulins and other tests for immunodeficiency. The presence of hypogammaglobulinaemia should be confirmed on repeat testing. Any underlying secondary causes should be excluded before referral to a consultant immunologist for investigation of primary immunodeficiency (PID).[2] The referral centre will establish whether there is a known genetic cause, and if there is impaired antibody function in addition to the low immunoglobulin levels. The extent of organ involvement and chronic damage should also be assessed.

In some cases, the presence of hypogammaglobulinaemia may be an incidental finding on a screening blood test. Under such circumstances, a similar approach (of confirming the result, assessing infection history, and excluding secondary causes) should be used, with subsequent referral to an immunologist.

Severe combined immunodeficiency (SCID) is a medical emergency, and patients should be urgently referred to specialist centres for confirmed diagnosis and treatment as soon as it is suspected (i.e., if patients have low absolute lymphocyte counts and low immunoglobulins).

Clinical history

A clinical history of recurrent, severe, chronic, or atypical infections is the usual presenting feature. Other important presenting symptoms may include failure to thrive in children, chronic diarrhoea, and complications after receiving live vaccines. It is also important to establish whether there is chronic damage related to recurrent infection: shortness of breath, chronic cough, and sputum production may indicate the presence of bronchiectasis; sinus pain, nasal discharge, and postnasal drip may indicate the presence of chronic sinusitis; and diarrhoea and steatorrhoea may indicate the presence of malabsorption.

Common variable immunodeficiency disorder (the most frequent form of primary antibody deficiency) usually manifests in adolescence or early adulthood, although may not be evident until patients are middle-aged or older.[13]

There are no strict definitions of recurrent infection, but the following would suggest consideration of underlying immunodeficiency: ≥8 new ear infections in 1 year; ≥2 serious sinus infections in 1 year; ≥2 deep-seated infections; persistent thrush after 1 year of age; recurrent deep skin or organ abscesses; or ≥2 pneumonias within 1 year. Past medical history may also reveal secondary causes of hypogammaglobulinaemia, such as nephrotic syndrome, malabsorption/gastroenteropathy (e.g., intestinal lymphangiectasia), myeloma, leukaemia, lymphoma, or malnutrition.[2]

  • Granulomatous disease, enteropathy (coeliac-like/inflammatory), and autoimmune cytopenia may suggest common variable immunodeficiency (CVID).

  • Severe or recurrent infections in infancy (especially Pneumocystis jirovecii, respiratory syncytial virus, Candida, and bacteria), rashes, failure to thrive, diarrhoea, and infections from live vaccines (e.g., bacille Calmette-Guérin) suggest SCID.

  • Diarrhoea, failure to thrive, and recurrent infections when maternal immunoglobulins fall (i.e., in infancy or early childhood) suggest X-linked agammaglobulinaemia (XLA/Bruton's disease). Maternal immunoglobulins (IgGs) are transferred to the fetus in the third trimester and gradually decline during the first 6 months of life.

  • Transient hypogammaglobulinaemia of infancy may present with infections at about 6 months of age when maternal immunoglobulin levels fall. However, it is often an incidental finding in a child who may not have an increased risk of infection. The predisposition to infection (if present) usually resolves by 18 to 24 months of age (although immunoglobulin abnormalities may persist to 3 years of age).[26]

  • Patients with selective IgA deficiency may be asymptomatic or may have recurrent infections if other immune defects, such as specific antibody deficiency, are present. The defect is associated with increased risk of coeliac disease and risk of transfusion reactions from anti-IgA antibodies.

  • Patients with hyper-IgM syndrome experience recurrent bacterial infections and are prone to developing autoimmune diseases. Hyper-IgM syndrome can be X-linked or autosomal recessive.

  • Thymoma and hypogammaglobulinaemia may present with local effects of thymoma; recurrent infection (bacterial, viral, fungal, and Pneumocystis infections described); and/or autoimmunity (e.g., myasthenia gravis).

  • Patients with IgG subclass deficiency may be asymptomatic or have recurrent infections.

  • Patients with specific antibody deficiency have low response to specific immunisations and often have recurrent bacterial infections.

Medication history may reveal use of medications associated with low immunoglobulin levels (e.g., rituximab, carbamazepine, phenytoin, disease-modifying antirheumatic drugs, cytotoxic drugs, antimalarials, or immunosuppressive drugs).[2] There may also be a history of radiotherapy.

There may also be a positive family history of PID or autoimmunity (e.g., immune thrombocytopenic purpura, autoimmune haemolytic anaemia). A history of consanguinity should be sought.

Social history may reveal indicators of the severity and frequency of recurrent infections: for example, illness requiring time off school or work. INFO4PI.org: 10 warning signs of primary immunodeficiency Opens in new window

Physical examination

It is important to measure height and weight to identify whether a child is growing appropriately or failing to thrive.

Patients should be examined for:

  • pallor (anaemia is common)

  • tonsillar tissue (tonsils are small/absent with Bruton's disease)

  • fungal nail changes

  • eczema (may be seen in Wiskott-Aldrich syndrome, hyper-IgE syndrome, some forms of SCID)

  • lymphadenopathy

  • hepatosplenomegaly

  • abdominal distension (may be seen in malnourished patients)

  • goitre (may be seen with autoimmunity)

  • vitiligo (may be seen with autoimmunity)

  • alopecia (may be seen with autoimmunity)

  • dysmorphic features (may be seen in some rare syndromes such as DiGeorge syndrome)

  • neurological involvement (may occur in ataxia-telangiectasia)

  • evidence of bronchiectasis (crackles, high-pitched inspiratory squeaks, rhonchi on lung auscultation)

  • evidence of middle ear disease and/or tympanic perforation (recurrent ear infections may cause chronic damage).

Initial laboratory investigations

Serum immunoglobulins (IgG, IgM, IgA) should be measured and repeated to confirm abnormalities.

Full blood count is important to identify lymphopenia, anaemia, and thrombocytopenia (all can occur with hypogammaglobulinaemia) and to exclude neutropenia. Lymphopenia in infants with infections, diarrhoea, and/or failure to thrive is an important finding, as it suggests SCID. Lymphocytosis may be seen in chronic lymphocytic leukaemia or lymphoma.

Renal function, liver function (including serum albumin), and inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) should also be checked.

In adults, serum protein electrophoresis and serum free light chains should be performed to evaluate paraprotein, and urine protein electrophoresis for Bence Jones protein. It is important to analyse urine for protein excretion.

Microscopy, culture, and sensitivity should also be performed on all specimens (e.g., sputum, urine, nasal swabs) as appropriate.

If hypogammaglobulinaemia is suggested and no secondary causes are identified, the patient should be referred to a specialist PID centre for further investigations and management by a consultant immunologist.

Making a diagnosis of primary hypogammaglobulinaemia

Subsequent investigations are performed by the referral centre. Patients with hypogammaglobulinaemia require further tests, including pulmonary function tests and radiology (chest x-ray, computed tomography [CT] sinuses, CT chest). Genetic testing may also be performed to identify the molecular defect in many cases of primary hypogammaglobulinaemia. Some genetic defects are associated with particular clinical phenotypes, which require specific management. Clues to choice of test may be obvious from clinical history, pattern of immunoglobulin levels, or results of other investigations.

If immunoglobulins are normal and there is a high index of suspicion for humoral immunodeficiency, specific antimicrobial antibodies (for Streptococcus pneumoniae, Haemophilus influenzae, tetanus) may be measured. If these vaccine titres are low or non-protective, a vaccine challenge or 'booster immunisation' may be administered, with repeat vaccine titres 4 to 6 weeks after the immunisation to assess for appropriate response. Further tests may include flow cytometry assessment of lymphocyte subsets, IgG subclasses, complement function; checking for the presence of a spleen by ultrasound; and lymph node biopsy.

CVID

  • There is no single diagnostic test; CVID is a diagnosis of exclusion.

  • Laboratory testing shows hypogammaglobulinaemia (low IgG plus either low IgA or IgM, or both) and low specific antimicrobial antibody responses despite immunisation.

SCID

  • Laboratory testing shows low absolute lymphocyte counts (low/absent T cells; B cells and natural killer cells may be low [an abnormality associated with adenosine deaminase deficiency] or normal depending on the underlying form of SCID) and low immunoglobulins.

  • Diagnosis of adenosine deaminase (ADA) deficiency is usually established by demonstrating absent or very low (<1% of normal) ADA activity in red blood cells.[27] Deficiency of ADA results in an accumulation of deoxyadenosine, which is toxic to immature lymphocytes and leads to SCID.

  • Molecular genetic tests (single-gene testing or use of a multi-gene panel) can identify pathological ADA variants.

XLA (Bruton's disease)

  • Laboratory testing shows extremely low/absent B cells and low/absent immunoglobulins.

  • Flow cytometry shows absent Bruton tyrosine kinase (BTK) protein expression.

  • Molecular testing shows mutation of the BTK gene.

Transient hypogammaglobulinaemia of infancy

  • Laboratory testing shows low IgG (IgA is usually also reduced) and normal B-cell numbers.

  • Immunoglobulin abnormalities may persist to 3 years of age (although, if present, the predisposition to infection usually resolves by 18-24 months of age).[26]

Selective IgA deficiency

  • Laboratory testing shows undetectable IgA, and normal IgG and IgM.

  • Findings are often incidental, as the condition is usually asymptomatic.

Hyper-IgM syndrome

  • Laboratory testing shows raised or normal IgM levels, and reduced levels of IgA and IgG.

  • Genetic testing is available.

Thymoma and hypogammaglobulinaemia

  • Laboratory testing shows reduced or absent B cells.

  • May be an incidental radiological finding.

IgG subclass deficiency

  • Laboratory testing shows ≥1 of the following: reduced IgG1, reduced IgG2, reduced IgG3, or reduced IgG4 (total IgG may be normal). IgA is normal or low; IgM is normal; B- and T-cell numbers are often normal.

  • Measuring specific antimicrobial antibodies gives more detailed information about the immune response.

Specific antibody deficiency

  • Laboratory testing shows low specific antibodies (e.g., to Haemophilus or S pneumoniae) with normal total immunoglobulins.

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