Primary immunodeficiency

Clinical Manifestations

Immune Defect	Typical Infections	Typical Organisms
Humoural and complement	recurrent sinopulmonary infections, chronic GI infections, bacteremia, and meningitis	encapsulated bacteria, Giardia, Cryptosporidium, and Campylobacter
Phagocytic	recurrent invasive skin and soft tissue infections, especially abscesses	Staphylococcus aureus, Gram-negative bacilli, Aspergillus, and Nocardia
Cell-mediated	severe or prolonged infections with common viruses, opportunistic intracellular infections, and fungi	CMV, EBV, other human herpesviruses, mycobacteria, Candida, Cryptococcus, and Pneumocystis

Differential Diagnosis

Children

Disease	Defect	Age at Diagnosis	Notes
Humoural (65%)
X-linked agammaglobulinemia
Common variable immunodeficiency (CVID)
Transient hypogammaglobulinemia of infancy
Hyper-IgM syndrome
IgA deficiency
Cell-Mediated (5%)
DiGeorge syndrome	thymus aplasia
Chronic mucocutaneous candidiasis
Combined (15%)
Severe combined immunodeficiency disease (SCID)	near-absolute T cell deficiency
Wiskott-Aldrich syndrome			eczema, thrombocytopenia
Ataxia-telangiectasia
X-linked lymphoproliferative disease
CD40 ligand deficiency
Hyper-IgE syndrome (Job syndrome)	STAT3 mutation		eczema, pneumatoceles, mucocutaneous candidiasis, recurrent cutaneous and respiratory infections, and elevated IgE
Phagocytic (10%)
Phagocyte deficiencies
Chronic granulomatous disease (CGD)	NADPH oxidase		GI and GU granulomas, infections with Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus
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)

Adults

Disease	Arm of Immune System
Adult-Onset Common
Common variable immunodeficiency	Humoural
IgA deficiency	Humoural
IgG subclass deficiency	Humoural
Complement deficiencies	Complement
Delayed Presentation Possible
Adenosine deaminase deficiency	Combined
Wiskott-Aldrich syndrome	Combined
X-linked agammaglobulinemia	Humoural
Chronic granulomatous disease	Phagocytic
Childhood Onset with Survival to Adulthood
Common variable immunodeficiency	Humoural
IgA deficiency	Humoural
IgG subclass deficiency	Humoural
Complement deficiencies	Complement
X-linked agammaglobulinemia	Humoural
X-linked hyper-IgM syndrome	Humoural
Chronic granulomatous disease	Phagocytic
Severe combined immunodeficiency	Combined
Wiskott-Aldrich syndrome	Combined
Ataxia-telangiectasia	Combined
Leukocyte adhesion deficiency	Phagocytic

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