Leukocyte Adhesion Deficiency

Diagnosis

Indications for Testing

• Child with delayed separation of the umbilical cord or recurrent infections in whom more common immunodeficiencies have been ruled out
• Tissue infections with absence of pus and/or high peripheral neutrophil counts

Laboratory Testing

• Initial screening
  • General immunodeficiency screening
    • CBC with differential
    • Comprehensive metabolic profile
    • Quantitative serum immunoglobulins (IgA, IgG, IgM)
    • Lymphocyte subset analyses – depending on clinical presentation
  • Rule out other diseases associated with immunodeficiency
    • HIV-1,2 testing
    • Plasma cell disorders – monoclonal protein detection, quantitation, and characterization with serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), IgA, IgG, IgM
    • Cystic fibrosis – sweat chloride testing using an accredited cystic fibrosis center
  • Rule out diseases associated with protein losses (eg, protein-losing enteropathy, nephropathy)
• More specific screening – based on initial screening results
  • Clinical presentation may require multiple immune system investigations
  • Definitive diagnosis, prognostication, genetic counseling, and treatment may require genetic testing
  • Complement testing
• Flow cytometric analysis
  • Assess presence of beta 2 (β2) integrins CD11 and CD18
    • Decreased/absent expression of CD11/CD18 – consistent with leukocyte adhesion deficiency-1 (LAD1)
      • 2-10% expression – moderate deficiency; reasonable survival rate into adulthood
      • >10% expression – mild deficiency; may not be recognized until late teen years
      • <2% – severe deficiency; majority die in infancy unless bone marrow transplant is performed
    • Normal expression of CD11/CD18 – consistent with LAD2 or LAD3
  • Assess presence of CD15s – indicated if LAD2 is suspected
    • Absent expression of CD15s – consistent with LAD2
  • Other testing
    • Neutrophil rolling, neutrophil adherence, neutrophil motility – performed only in specialized laboratories
    • Bombay blood group phenotype testing – present in LAD2
    • Platelet aggregation – abnormal in LAD3
    • Molecular sequence analysis – defines exact molecular defect

Differential Diagnosis

• Sepsis
• Neutropenic disorders
• Agranulocytosis
• IRAK-4 deficiency
• Job syndrome
• Chronic granulomatous disease
• Myeloperoxidase deficiency
• Congenital disorders of glycosylation
• Leukemoid reaction in infants
• Other congenital coagulation disorders (particularly in LAD3 due to bleeding tendency)

Background

Epidemiology

• Incidence/prevalence – rare
  • LAD1 – most common type
• Age – usually identified in infancy or early childhood

Inheritance

Pathophysiology

• LAD involves defects in integrin and selectin expression
  • Blood neutrophils – the first line of defense against bacterial and fungal infection
  • Blood leukocytes migrate into the site of inflammation
    • Requires expression of P and E selectins on the endothelial cells with their ligands on leukocytes, which requires the family of integrins be present
      • CD18 – essential component of the β2 integrins (CD11a/CD18, CD11b/CD18, and CD11c/CD18)
  • Lack of integrin and selectin expression leads to defective adhesion of neutrophils that in turn leads to increased susceptibility to bacterial and fungal infections
  • Other LAD-like syndromes with defects in adhesion/chemotaxis have been identified (eg, RAC-2, which regulates actin cytoskeleton; leukocyte hyperadhesion syndrome)

Clinical Presentation