Primary immunodeficiencies

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  • See also

    Febrile child
    Community acquired pneumonia
    Pleural effusion and empyema
    Meningitis and encephalitis

    Key points

    1. Primary immunodeficiencies (PIDs) present with a variety of symptoms depending on which part of the immune system is affected
    2. Careful stepwise investigation in consultation with specialists allows for accurate diagnosis and prompt management
    3. Most young children with recurrent minor infections do not have a PID


    Primary immunodeficiencies:

    • Are a diverse group of genetically determined defects that can occur across all parts of the immune system
    • Lead to an increased risk of bacterial, fungal and/or viral infections
    • In severe PIDs, early diagnosis can prevent complications from infections and allows for curative treatment


    Early identification relies on a high index of suspicion.

    PIDs should be considered in all children with:

    • severe infection
    • infection with unusual or opportunistic organisms
    • recurrent infection - more than expected for age (eg healthy toddlers may have 5-10 minor infections per year, often more if attending childcare)
    • recurrent infection at the same site may also be due to an anatomical abnormality (eg meningitis and anatomical defects in the blood-brain-barrier)

    PIDs can be categorised into six main types:

    Type of PID


    Clinical features

    Antibody deficiency

    • X-linked agammaglobulinemia (XLA)
    • Common variable immunodeficiency (CVID) 
    • Specific antibody deficiency
    • Poor growth
    • Chronic diarrhoea and/or malabsorption
    • Recurrent/severe sinusitis or otitis media
    • Meningitis
    • Sepsis


    Combined immunodeficiency

    • Severe combined immunodeficiency (SCID) 
    • 22q11 deletion (DiGeorge syndrome)
    • X-linked Hyper-IgM
    • Wiskott-Aldrich syndrome
    • Poor growth
    • Absence of thymus
    • Chronic diarrhoea
    • Recurrent/severe sinusitis or otitis media
    • Severe eczema or nappy rash
    • Severe oral candidiasis
    • Severe or chronic viral infections eg EBV
    • DiGeorge syndrome: Congenital heart disease and/or characteristic facial features
    • Ectodermal dysplasia: absence of nails, thin hair, reduced sweating

    Phagocytic cell deficiency

    • Chronic granulomatous disease (CGD)
    • Leukocyte adhesion defect (LAD)
    • Chediak Higashi syndrome
    • Cyclic neutropenia
    • Recurrent skin or deep organ abscesses
    • Gingivitis
    • Osteomyelitis
    • Severe or recurrent pneumonia

    Complement deficiency

    • Hereditary angioedema
    • Specific complement deficiency
    • Meningitis or sepsis due to encapsulated bacteria (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type B)
    • Recurrent angioedema

    Immune dysregulation

    • Autoimmune lymphoproliferative syndrome (ALPS)
    • Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX)
    • Autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED)
    • Familial hemophagocytic lymphohistiocytosis (FHL) syndromes
    • Endocrine disorders
    • Chronic diarrhoea
    • Lymphadenopathy

    Autoinflammatory disorders

    • Familial Mediterranean Fever (FMF)
    • Chronic Recurrent Multifocal Osteomyelitis (CRMO)
    • Inflammatory bowel disease
    • Other autoinflammatory disorders
    • Recurrent fevers
    • Inflammatory arthritis or peritonitis
    • Rash
    • Splenomegaly


    There are a broad range of symptoms and signs of PIDs, including:

    • Poor growth (especially slow to gain weight)
    • Persistent lymphopenia (especially lymphocyte count <1 x 109/L in children <1 yo)
    • Chronic diarrhoea
    • Four or more middle ear infections within one year
    • Two or more serious sinus infections within one year
    • Recurrent deep skin or organ abscesses
    • Persistent thrush in the mouth, skin or elsewhere after 1 yo
    • Inadequate response to antibiotics (two or more months of antibiotics with little effect)
    • Repeat hospital admission for intravenous antibiotics
    • Invasive pneumococcal or meningococcal disease
    • Recurrent, severe or prolonged infections with common pathogens, eg adenovirus
    • Family history of immunodeficiency, previous sibling death (unexplained or due to infection), parental consanguinity


    • Persistent lymphadenopathy
    • Oral candidiasis
    • Gingivitis
    • Severe or chronic otitis media or sinusitis
    • Skin abscesses
    • Digital clubbing
    • Severe eczema or eczema-like rashes
    • Splenomegaly
    • Poor muscle bulk, fat stores or signs of nutritional deficiency



    First-line investigations include:

    • FBE and differential (compare with previous results)
    • Blood film (to assess for presence of Howell Jolly bodies)

    After specialist consultation, consider:

    • Total serum immunoglobulins G/A/M (IgG subclass should not be routinely measured)
    • Lymphocyte subsets – CD3/CD4/CD8/CD19/CD16/56
      • If SCID is suspected assessment of naïve T cells (CD45RA/RO) is required as CD4/CD8 numbers may be in the normal range 
    • HIV antibody
    • An abdominal ultrasound to confirm presence of a spleen and complement studies (eg CH50) in children with invasive meningococcal or pneumococcal disease

    Children aged >2 years presenting with invasive pneumococcal disease (sepsis, meningitis, complicated pneumonia or septic arthritis) with no clear predisposing condition, and all children with recurrent IPD should be investigated for immunodeficiency

    Any child with normal first-line investigations but high suspicion of PID should be referred to a paediatric immunologist for evaluation and consideration of second-line testing

    Children with suspected PID should not be administered live vaccines (this includes varicella, MMR, rotavirus and BCG vaccine)

    Consider consultation with local paediatric team when

    • Any child with severe infection or poor response to therapy
    • Any child with known or suspected primary immunodeficiency with fever
    • Unclear whether investigation and follow-up for suspected PID is required
    • Any child suspected of having SCID should be immediately discussed with a paediatric immunologist

    Consider transfer when

    Child requiring care above the level of comfort of the local hospital

    For emergency advice and paediatric or neonatal ICU transfers, see Retrieval Services

    Consider discharge when

    Child is well, has clear management plan in place and family are aware when to return for review

    Parent information

    ASCIA immunodeficiencies  
    Immune deficiencies Foundation Australia

    Additional notes

    The Australasian Society of Clinical Immunology and Allergy (ASCIA) provides free primary immunodeficiency e-training for health professionals-

    Last updated March 2021

  • Reference List

    1. Australasian Society of Clinical Immunology and Allergy (ASCIA) Immunodeficiency Strategy for Australia and New Zealand. (viewed February 4 2021)
    2. Richards S, Gennery AR, Davies EG, Wong M, Shaw PJ, Peake J et al. Australasian Society of Clinical Immunology and Allergy (ASCIA) Transplantation and Immunodeficiency (TAPIDs) group. Diagnosis and management of severe combined immunodeficiency in Australia and New Zealand. J Paediatr Child Health. 2020 Oct;56(10):1508-1513.
    3. Buckley RH. Immune Deficiency Foundation Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases, 3rd Edition. 2015. Immune Deficiency Foundation.
    4. Tangye SG, Al-Herz W, Bousfiha A et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies expert committee. J Clin Immunol 2020; 40:24–64.
    5. Butters C, Phuong LK, Cole T, Gwee A. Prevalence of immunodeficiency in children with invasive pneumococcal disease in the pneumococcal vaccine era: A systematic review. JAMA Pediatr. 2019
    6. Kirkpatrick P, Riminton S. Primary immunodeficiency diseases in Australia and New Zealand. J Clin Immunol. 2007 Sep;27(5):517-24.
    7. Subbarayan A, Colarusso G, Hughes SM, Gennery AR, Slatter M, Cant AJ, Arkwright PD. Clinical features that identify children with primary immunodeficiency diseases. Pediatrics. 2011 May;127(5):810-6.
    8. Reda SM, El-Ghoneimy DH, Afifi HM. Clinical predictors of primary immunodeficiency diseases in children. Allergy Asthma Immunol Res. 2013;5(2):88-95.