Presentation: Infant or child with severe, recurrent, persistent and/or unusual infections

An eight-month-old boy is referred to paediatrics from primary care following a hospital admission for pneumonia. He has also had four ear infections in the last four months. He has chronic diarrhoea that has been attributed to the continuous use of antibiotics. He is on the 75th centile for height and 2nd centile for weight.

Genomic testing should be considered if patients are suspected to have a primary immunodeficiency. Indications include patients with any of the eight International Union of Immunological Societies categories of primary immunodeficiency, which are outlined below.

• Combined immunodeficiency, with or without associated features and atypical T cell numbers or function. This may include atypical naïve T cells, TRECs, repertoire, proliferations (such as PHA), reversed Cd4/8 ratio or increased gamma delta T cells).
• Predominantly antibody deficiencies with low or absent vaccine responses.
• Well-defined syndromes with immunodeficiency, such as Wiskott-Aldrich syndrome or DiGeorge syndrome.
• Diseases of immune dysregulation, including haemophagocytic lymphohistiocytosis (HLH).
• Congenital defects of phagocyte number, function or both. This should be evidenced by low phagocytic numbers and/or atypical DHR/NBT/phagocytosis/L-selectin shedding, CD11a,b,c or CD18, or atypical migration or adhesion.
• Defects in intrinsic and innate immunity.
• Autoinflammatory conditions.
• Complement deficiencies with atypical complement function.

Testing under these criteria would also include young children with inflammatory bowel disease, defined as bloody diarrhoea, severe failure to thrive and severe intestinal inflammation with histology consistent with chronic inflammatory intestinal pathology, of onset under six years of age (see ‘Infant with features of very early-onset inflammatory bowel disease‘).

R15 testing for suspected immunodeficiency should typically be requested by immunology or clinical genetics teams.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which contains information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient and/or family.
• For immunodeficiency conditions, there are a number of available panels, including:
  • R15 Primary immunodeficiency diseases (whole genome sequencing (WGS)): This will investigate chromosomal and single gene causes of immunodeficiency, immunodysregulation and/or autoinflammation. The test involves a WGS panel of many genes known to cause immunodeficiency, immunodysregulation, auto inflammation and HLH. This panel should also be used if monogenic early-onset inflammatory bowel disease is suspected.
• Note that other panels may also be appropriate, including:
  • R16 Severe combined immunodeficiency with adenosine deaminase deficiency, which should be used in individuals with ADA deficiency;
  • R234 Severe combined immunodeficiency with PNP deficiency, which should be used in individuals with PNP deficiency;
  • R235 Severe combined immunodeficiency with gamma chain deficiency, which should be used in individuals with low or absent gamma chain or low or absent STAT5 pTyr to IL-2,7 and 15;
  • R17 Lymphoproliferative syndrome with low or absent SAP expression, which should be used in individuals with absent SAP expression;
  • R232 Lymphoproliferative syndrome with low or absent perforin expression, which should be used in individuals with absent perforin expression;
  • R18 Lymphoproliferative syndrome with low or absent XIAP expression, which should be used in individuals with absent XIAP expression;
  • R19 Autoimmune lymphoproliferative syndrome with defective apoptosis, which should be used in individuals with defective Fas-mediated apoptosis, elevated alpha double negative T cells, elevated sFAS or elevated vitamin B12;
  • R233 Agammaglobulinaemia with low or absent BTK expression, which should be used in individuals with absent BTK expression;
  • R20 Wiskott-Aldrich syndrome (WAS), which should be used in individuals with a likely diagnosis of WAS; and
  • R204 Amyloidosis with no identifiable cause, which should be used in cases with confirmed amyloidosis.
• Semi-rapid testing with a two-week turnaround time may be possible if:
  • an acutely unwell child is felt to have a primary immunodeficiency;
  • the eligibility criteria for R15 are met; and
  • immediate management decisions rely on the genetic diagnosis.
• Please indicate on the request form the reasons for requesting more urgent analysis. Note that for cases in which the primary clinical indication is not primary immunodeficiency, or immunodeficiency is part of a more complex presentation, R14 Acutely unwell children with likely monogenic disorder is more appropriate.
• For tests that are undertaken using WGS, including R15, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three record of discussion forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• European Society for Immunodeficiencies: Diagnostic criteria PID
• Jeffrey Modell Foundation: 10 warning signs of primary immunodeficiency

References:

• Bousfiha A, Moundir A, Tangye SG and others. ‘The 2022 update of IUIS phenotypical classification for human inborn errors of immunity‘. Journal of Clinical Immunology 2022: volume 42, issue 7, pages 1,508–1,520. DOI: 10.1007/s10875-022-01352-z

For patients

• Immunodeficiency UK
• Jeffrey Modell Foundation