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 (refer to the Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm and Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm)
  • 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 CD15 – indicated if LAD2 is suspected
    • Absent expression of CD15 – 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