Primary immunodeficiency

Clinical Manifestations

Immune Defect	Typical Infections	Typical Organisms
cell-mediated (T cells)	persistent viral infections, opportunistic infections, disseminated infections	Pneumocystis jirovecii, Cryptococcus, Herpesviridae
humoural (B cells)	respiratory infections with encapsulated organisms, chronic diarrhea, aseptic meningitis	Haemophilus influenzae, Streptococcus pneumoniae, Giardia lamblia, Campylobacter, enteroviruses
phagocytic	recurrent abscesses, gingivitis, aphthous ulcers	Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Aspergillus, Nocardia
monocytic	disseminated infections and multifocal osteomyelitis	non-tuberculous mycobacteria, Salmonella, Histoplasma capsulatum, Coccidioides immitis
TLR	recurrent meningitis, bacteremia, absence of fever	Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus, HSV
complement	recurrent bacteremia and meningitis	Neisseria
T cells and phagocytes	eczema, kyphoscoliosis, pathologic fratures, pulmonary and cutaneous infections, mucocutaneous candidiasis	Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, Candida albicans

Differential Diagnosis

Children

Disease	Defect	Age at Diagnosis	Notes
Humoural (65%)
X-linked agammaglobulinemia	BTK mutation		X-linked, very low antibody levels
Common variable immunodeficiency (CVID)	multiple	20-40 years	low IgG with poor antibody response
Transient hypogammaglobulinemia of infancy
Hyper-IgM syndrome	multiple		X-linked or autosomal recessive, high IgM with poor T-cell function
IgA deficiency	decreased IgA		low IgA, often associated with other immunodeficiencies
Cell-Mediated (5%)
DiGeorge syndrome	thymus aplasia
Chronic mucocutaneous candidiasis
Combined (15%)
Severe combined immunodeficiency disease (SCID)	near-absolute T cell deficiency		lymphopenia with hypogammaglobulinemia
Wiskott-Aldrich syndrome	WASP mutation		X-linked, eczema, thrombocytopenia, low IgM with high IgA
Ataxia-telangiectasia	ATM mutation		autosomal recessive, with low IgA, CD3, and CD4, and malignancies
X-linked lymphoproliferative disease	SAP mutation		X-linked, low EBNA antibodies
CD40 ligand deficiency
Hyper-IgE syndrome (Job syndrome)	STAT3 mutation		eczema, pneumatoceles, mucocutaneous candidiasis, recurrent cutaneous and respiratory infections, and elevated IgE
Phagocytic (10%)
Chronic granulomatous disease (CGD)	NADPH oxidase		GI and GU granulomas, infections with Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus
Leukocyte adhesion deficiency	multiple types		autosomal recessive
TLR3 deficiency			recurrent HSV encephalitis
Complement (5%)
C2 deficiency and other classical complement deficiencies	classical complement pathway		low CH50, autoimmune disease in C1-C4, bacteremia and meningitis
Properdin deficiency	alternative complement pathway		more severe than classical complement deficiencies
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	Notes
Adult-Onset Common
IgA deficiency	Humoural
Common variable immunodeficiency	Humoural
IgG subclass deficiency	Humoural
Complement deficiencies	Complement
Good syndrome	Combined humoural and cell-mediated	Very rare. Associated with thymoma and autoimmune diseases
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