What are the types of infant immunodeficiency?

Types of Infant Immunodeficiency

Primary immunodeficiencies in infants are categorized into several major types based on the affected immune components, with the most common being antibody deficiencies, combined immunodeficiencies, phagocytic defects, complement disorders, and immune dysregulation syndromes. 1

Major Categories of Primary Immunodeficiency in Infants

1. Combined Immunodeficiencies (CIDs)

• Severe Combined Immunodeficiency (SCID)

  • Presents with failure to thrive, diarrhea, severe/disseminated infections, opportunistic infections, rash
  • Abnormal newborn screening with low TREC counts
  • Requires urgent intervention as it is life-threatening
  • Various genetic subtypes with different T/B/NK cell patterns (e.g., T-B-NK+ in RAG1/RAG2 deficiency, T-B+NK- in X-linked SCID)

• CD40L Deficiency

  • Recurrent serious pyogenic infections
  • Opportunistic infections (especially Pneumocystis pneumonia)

2. Immunodeficiency Syndromes

• Wiskott-Aldrich Syndrome (WAS)

  • Thrombocytopenia with bleeding and bruising
  • Eczema
  • Recurrent infections with encapsulated organisms
  • Autoimmunity

• Ataxia-Telangiectasia (AT)

  • Chronic sinopulmonary disease
  • Cerebellar ataxia
  • Oculocutaneous telangiectasia
  • Increased risk of malignancy

• DiGeorge Syndrome (DGS)

  • Hypocalcemic seizures due to hypoparathyroidism
  • Cardiac disease
  • Abnormal facial features
  • Infections
  • Abnormal newborn screening

3. Antibody Deficiencies

• Recurrent sinopulmonary infections with encapsulated bacteria
• Recurrent viral respiratory tract and gastrointestinal infections
• Includes conditions like:
  • X-linked agammaglobulinemia
  • Common Variable Immunodeficiency (CVID)
  • Selective IgA Deficiency (SIGAD)
  • IgG Subclass Deficiency (IGGSD)
  • Specific Antibody Deficiency (SAD)
  • Transient Hypogammaglobulinemia of Infancy (THI)

4. Immune Dysregulation Disorders

• Characterized by autoimmunity, lymphoproliferation, hemophagocytic lymphohistiocytosis (HLH)
• Examples include:
  • Familial Hemophagocytic Lymphohistiocytosis (FHL)
  • Autoimmune Lymphoproliferative Syndrome (ALPS)
  • Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

5. Phagocytic Cell Defects

• Chronic Granulomatous Disease (CGD)

  • Deep-seated infections
  • Abscess with granuloma formation

• Leukocyte Adhesion Deficiency (LAD)

  • Recurrent serious bacterial infections
  • Delayed separation of the umbilical cord
  • Poor wound healing
  • Lack of pus formation

• Hyper IgE Syndrome (HIES) type 1

  • Chronic dermatitis
  • Recurrent serious lung infections with pneumatoceles
  • Skin infections
  • Bone fragility
  • Failure to shed primary teeth

• Mendelian Susceptibility to Mycobacterial Disease (MSMD)

  • Severe mycobacterial and Salmonella species infections

6. Innate Immune Defects

• NEMO Deficiency

  • Severe bacterial infections
  • Opportunistic infections
  • Anhidrotic ectodermal dysplasia

• IRAK-4 Defect

  • Severe gram-positive bacterial infections in early childhood

• Chronic Mucocutaneous Candidiasis (CMCC)

  • Chronic skin and mucous membrane fungal infections

• Herpes Simplex Encephalitis (HSE)

  • Specific susceptibility to herpes simplex virus infection of the brain

7. Autoinflammatory Disorders

• Episodic fever often associated with dermatitis, gastrointestinal symptoms, and arthropathy

8. Complement Deficiency

• Recurrent bacterial infections (especially with encapsulated strains and Neisseria species)
• Autoimmunity

9. Immunodeficiency Associated with Autoantibodies

• Anti-GM-CSF autoantibodies: Cryptococcal meningitis and pulmonary alveolar proteinosis
• Anti-IFN-γ autoantibodies: Disseminated infections with mycobacteria, Salmonella, and various fungi

Diagnostic Approach

Early diagnosis is critical for optimal outcomes. The diagnostic approach should include:

1. Initial screening tests:

   • Complete blood count with differential
   • Serum immunoglobulin levels (IgG, IgA, IgM)
   • Lymphocyte subset analysis by flow cytometry

2. Advanced testing based on clinical presentation:

   • T-cell function tests (lymphocyte proliferation)
   • Specific antibody titers to vaccines
   • NK cell function assays
   • Complement pathway evaluation
   • Genetic testing for suspected specific defects

Management Considerations

Management must be tailored to the specific immunodeficiency but generally includes:

• Strict isolation to prevent infections
• Avoidance of live vaccines in affected infants and household contacts
• Prophylactic antimicrobials
• Immunoglobulin replacement therapy when appropriate
• Hematopoietic stem cell transplantation for severe defects, especially SCID

Important Pitfalls to Avoid

1. Delaying diagnosis and definitive treatment - Early intervention dramatically improves outcomes, especially for SCID
2. Administering live vaccines - Can cause disseminated infection in immunodeficient infants
3. Overlooking maternal T-cell engraftment - Can mask T-cell deficiencies in infants
4. Misinterpreting immunoglobulin levels - Transplacental maternal IgG can mask antibody deficiencies in early infancy

Primary immunodeficiencies occur in approximately 1:2,000 live births, with antibody deficiencies accounting for about half of all cases. The principal clinical manifestation is increased susceptibility to infection, with the pattern of infections varying based on the specific immune defect. 1