Primary immunodeficiency

Differential Diagnosis

• Humoural (65%): B cell defects
  • X-linked agammaglobulinemia
  • Common variable immune deficiency (CVID)
  • Transient hypogammaglobulinemia of infancy
  • Hyper-IgM syndrome
  • IgA deficiency
• Cell-mediated (5%): T-cell deficiencies
  • DiGeorge syndrome
  • Chronic mucocutaneous candidiasis
• Combined (15%): B- and T-cell deficiencies, often much more severe
  • Severe combined immunodeficiency disease (SCID)
  • Wiskott-Aldrich syndrome
  • Ataxia-telangiectasia
  • X-linked lymphoproliferative disease
  • CD40 ligand deficiency
  • Hyper-IgE syndrome
• Phagocytic (10%): neutrophil deficiencies
  • Phagocyte deficiencies
  • Chronic granulomatous disease (CGD)
  • Leukocyte adhesion deficiency
• Complement (5%)
  • C2 deficiency
  • Properdin deficiency
• Immune dysregulation
  • Hemophagocytic lymphohistiocytosis
  • Autoimmune lymphoproliferative disorder (ALPS)
  • Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
  • Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED)

Red Flags for Immunodeficiency

Children

• ≥4 new ear infections in 1 year
• ≥2 serious sinus infections in 1 year
• ≥2 months on antibiotics with little effect
• ≥2 pneumonias in 1 year
• Failure to gain weight or grow normally
• Recurrent deep skin or organ abscesses
• Persistent thrush in mouth or fungal skin infection
• Need for IV antibiotics to treat infections
• ≥2 deep-seated infections including bacteremia
• A family history of primary immunodeficiency

Adults

• ≥2 new ear infections in 1 year
• ≥2 new sinus infections in 1 year (in the absence of allergy)
• ≥2 new pneumonias in 2 years
• Chronic diarrhea with weight loss
• Recurrent viral infections, such as colds, herpes, warts, or condylomata
• Recurrent need for IV antibiotics to treat infections
• Recurrent, deep abscesses of skin or internal organs
• Persistent thrush or fungal infections
• Infection with non-tuberculous mycobacteria
• A family history of primary immunodeficiency

Investigations

• CBC and peripheral blood film, for lymphopenia, abnormal or unusual lymphocytes or phagocytes, and any other notable abnormalities
  • Lymphopenia may suggest T-cell immunodeficiency
• For suspected defect in humoural immunity
  • Serum immunoglobulin levels (IgG, IgM, IgA, and IgE)
  • Specific antibody titres
  • Pre- and post-vaccination IgG titres
  • Flow cytometry to count B cells
• For suspected defect in cellular immunity
  • TREC newborn screen
  • Flow cytometry to count CD4 and CD8 T-cells and NK cells
    • Flow cytometry is almost always abnormal in SCID
  • Cutaneous delayed hypersensitivity
  • Spontaneous NK cytotoxicity
• For suspected deficiencies in phagocytes
  • CBC and differential
  • Neutrophil staining for morphology on a peripheral blood film
  • Dihydrorhodamine 1,2,3 response (DHR) for neutrophil function
  • Flow cytometry for adhesion molecules
• For suspected complement deficiencies
  • CH50 assay (for total complement activity)
  • AH50 assay (for alternative pathway activity)
  • Lectin pathway function
  • Level and/or function of specific complement factors

Further Reading

• Primary immunodeficiency. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61. doi: 10.1186/s13223-018-0290-5
• Attending to Warning Signs of Primary Immunodeficiency Diseases Across the Range of Clinical Practice. J Clin Immunol. 2014;34(1):10-22. doi: 10.1007/s10875-013-9954-6
• Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696-726. doi: 10.1007/s10875-015-0201-1