by Dr. Sylvia van den Berg and Dr. Cathy van Rooyen
PATHCHAT Edition No. 4
Please contact your local Ampath pathologist for more information.
Endorsed by the Infectious Diseases Peer Group
Overview of Primary Immunodeficiencies (PIDs)
Primary immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders that lead to an increased susceptibility to recurrent and severe infections.
Signs That Suggest a Primary Immunodeficiency
(First three features are most predictive):
- Family history of immunodeficiency or unexplained early death (<30 years)
- Failure to thrive
- Need for IV antibiotics and/or hospitalization to clear infections
- Six or more new infections in one year
- Two or more sinus infections or pneumonia in one year
- Four or more new ear infections in one year
- Two or more episodes of sepsis or meningitis in a lifetime
- Two or more months of antibiotics with little or no effect
- Recurrent or resistant Candida infections
- Recurrent tissue or organ abscesses
- Infections with opportunistic pathogens
- Structural damage due to infections
- Complications from live vaccines
- Chronic diarrhea
- Non-healing wounds
- Extensive skin lesions
- Persistent lymphopenia
- Unexplained fever or autoimmunity
Additional Features in Infants
- Delayed umbilical separation (>30 days)
- Congenital heart defects
- Hypocalcemia
- Absent thymic shadow on chest X-ray
Common Pathogens That Indicate a Primary Immunodeficiency
Certain recurrent infections with sentinel organisms should raise suspicion for PID, including:
- Recurrent sinopulmonary infections with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae type B, Moraxella catarrhalis).
- Pneumocystis jirovecii pneumonia
- Pseudomonas aeruginosa infections
- Enteroviral meningoencephalitis
- Cryptosporidium enteric infections
- Recurrent infections with Staphylococcus aureus, Coagulase-negative Staphylococci, Serratia marcescens, Chromobacterium violaceum, or Aspergillus spp.
- Recurrent herpes viral infections
- Infections with live vaccines (BCG, oral polio, measles, rotavirus, varicella)
- Prolonged or recurrent Candida infections
- Recurrent invasive Neisserial infections
- Systemic or deep infections with nontuberculous mycobacteria
Major Subtypes of Primary Immunodeficiencies & Clinical Findings
1. Humoral (B-Cell) Immunodeficiencies
Common conditions:
- X-linked or autosomal recessive agammaglobulinemia
- Common Variable Immunodeficiency (CVID)
- IgG subclass deficiency
- Selective IgA deficiency
- Transient hypogammaglobulinemia of infancy
Common infections & pathogens:
- Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae)
- Fungal and parasitic infections (Giardia lamblia, Cryptosporidium species)
- Enteroviral infections
- Sinus infections, otitis media, bronchiectasis, conjunctivitis, infectious diarrhea
2. Combined (B- and T-Cell) Immunodeficiencies
Common conditions:
- Severe Combined Immunodeficiency (SCID)
- Omenn Syndrome
- CD40 ligand deficiency
- DiGeorge Syndrome (Complete form)
- MHC class I and II deficiencies
Common infections & pathogens:
- Mycobacterium species
- Viruses (Cytomegalovirus, Epstein-Barr virus, Varicella virus, Enterovirus)
- Fungal infections (Candida, Pneumocystis jirovecii)
- Severe recurrent bacterial, viral, and opportunistic infections
3. Phagocytic Disorders
Common conditions:
- Chronic Granulomatous Disease (CGD)
- Leukocyte Adhesion Deficiencies (LAD)
Common infections & pathogens:
- Skin, oral, and anorectal infections
- Abscesses and poor wound healing
- Infections with S. aureus, Pseudomonas, Serratia, Nocardia, Klebsiella, Salmonella, Candida, Aspergillus
4. Complement Deficiencies
Common conditions:
- C1-C9 deficiencies
- Mannan-binding lectin (MBL) deficiency
Common infections & pathogens:
- Encapsulated bacteria (S. pneumoniae, H. influenzae, Neisseria meningitidis)
- Recurrent meningococcal or gonococcal infections
- Tuberculosis, Legionnaire’s disease
Diagnostic Approach to Primary Immunodeficiencies
1. Initial Screening Tests
- Full Blood Count (FBC) with differential
- CRP and ESR
- HIV, CMV, EBV, TB, PCP, and disseminated BCGosis testing
- Chest X-ray (to assess thymic shadow and lung disease)
- Screening for cystic fibrosis or allergies
2. Specific Immunodeficiency Tests
Humoral Immunodeficiency Testing:
- Serum Immunoglobulins (IgG, IgA, IgM, IgE)
- IgG subclasses
- Specific antibody titers (to S. pneumoniae, H. influenzae, tetanus, diphtheria)
- B-cell immunophenotyping & function testing
T-Cell Immunodeficiency Testing:
- HIV ELISA or PCR in babies
- T-cell Receptor Excision Circle (TREC) PCR (neonatal screening for SCID)
- Lymphocyte immunophenotyping (CD3, CD4, CD8, NK cells)
- Lymphocyte proliferation tests (to mitogens and recall antigens)
- Genetic testing for SCID and related disorders
Neutrophil Function Testing:
- Neutrophil oxidative burst, phagocytosis, and chemotaxis
- Leukocyte adhesion markers (CD11, CD18)
- Neutrophil antibodies (for autoimmune neutropenia)
Complement Function Testing:
- CH100 (classical pathway) and AH100 (alternative pathway)
- Complement C3 and C4 levels
- Mannan-binding lectin (MBL) levels
Conclusion
Diagnosing primary immunodeficiencies is complex, and early detection is critical for improving patient outcomes. Specialist consultation is advised for difficult cases, and a high index of suspicion should always be maintained.
Key Takeaway: Early diagnosis and aggressive management of infections can reduce morbidity and mortality.
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