Indications for Testing

• Child with recurrent infections and in whom more common immunodeficiencies have been ruled out
• Tissue infections with absence of inflammatory cells and high peripheral neutrophil counts

Laboratory Testing

• CBC – reveals leukocytosis with neutrophilia (even in the absence of infection but exaggerated during infection)
• Flow cytometric analysis
  • CD11b and CD18 expression on leukocytes
    • Normal expression – LAD I or LAD III
    • Decreased expression – consistent with LAD I
      • 1-10% expression – 33% survive to age 40 years
      • >10% expression – mild deficiency; may not be recognized until late teen years
    • No expression – 75% die in infancy unless transplanted
  • Analysis using CD15a monoclonal to determine SLe antibody expression if LAD I suspected
    • Confirm diagnosis with gene sequencing of GDP-fucose transporter
  • CD15
    • Absent or decreased expression – consistent with LAD II
• Other testing – neutrophil rolling, neutrophil adherence, platelet aggregation

Differential Diagnosis

• Sepsis
• Neutropenic disorders
• Agranulocytosis
• IRAK-4 deficiency
• Job syndrome
• Chronic granulomatous disease
• Myeloperoxidase deficiency
• Congenital disorders of glycosylation

Leukocyte adhesion disorders (LAD) are a primary immune deficiency affecting phagocytic blood cells.

Epidemiology

• Incidence – <1/1,000,000
  • LAD I – most common syndrome
• Age – usually identified in infancy or early childhood

Inheritance 

• Autosomal recessive
• Heterogeneous mutations in the CD18 leukocyte integrin gene
  • At least 3 defects identified
    • LAD I – β integrin expression defect; mutation of ITGB2 gene
    • LAD II – selectin defect; mutation of SLC35C1 gene
    • LAD III – combined defect in integrin activation resulting in abnormal functionality of platelets and leukocytes; mutation of RASGRP2 gene

Pathophysiology

• Blood neutrophils are the first line of defense against bacterial and fungal infection
• Initial neutrophil adherence is weak but becomes strong with the aid of β integrin interactions
• LAD involves defects in integrin and selectin expression, leading to defective adhesion of neutrophils that in turn leads to increased susceptibility to bacterial and fungal infections

Clinical Presentation

• LAD I – characterized by delayed separation of the umbilical cord, recurrent soft tissue infections, chronic periodontitis, marked leukocytosis and lack of neutrophils in tissue infections
• LAD II – same features as LAD I plus short stature, CNS abnormalities (seizures), and developmental delay; no delay in separation of umbilical cord
• LAD III – same features as LAD I with severe bleeding tendency

Treatment

• Early intervention for periodontal disease
• Preventive antibiotics for infection
• Allogeneic bone marrow transplant for severe disease

Tests generally appear in the order most useful for common clinical situations

General

• Bunting M, Harris ES, McIntyre TM, Prescott SM, Zimmerman GA. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr Opin Hematol. 2002; 9 (1) :30-35.PubMed
• Cox DP, Weathers DR. Leukocyte adhesion deficiency type 1: an important consideration in the clinical differential diagnosis of prepubertal periodontitis. A case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 105 (1) :86-90.PubMed
• Etzioni A. Defects in the leukocyte adhesion cascade. Clin Rev Allergy Immunol. 2010; 38 (1) :54-60.PubMed
• Etzioni A. Leukocyte adhesion deficiencies: molecular basis, clinical findings, and therapeutic options. Adv Exp Med Biol. 2007; 601 :51-60.PubMed
• Gazit Y, Mory A, Etzioni A, Frydman M, Scheuerman O, Gershoni-Baruch R, Garty BZ. Leukocyte adhesion deficiency type II: long-term follow-up and review of the literature. J Clin Immunol. 2010; 30 (2) :308-313.PubMed
• Immune Deficiency Foundation. [Accessed: 17 Apr 2009] 
• Notarangelo LD, Badolato R. Leukocyte trafficking in primary immunodeficiencies. J Leukoc Biol. 2009; 85 (3) :335-343.PubMed
• Webber EC, Church J, Rand TH, Shah AJ. Leukocyte adhesion deficiency in a female patient without delayed umbilical cord separation. J Paediatr Child Health. 2007; 43 (5) :406-408.PubMed

Bruton Agammaglobulinemia
Chronic Granulomatous Disease
Complement Deficiency
Immunodeficiency, Innate System
Immunoglobulin Disorders
Neutrophil Disorders
Severe Combined Immunodeficiencies
T-Cell Deficiency Disorders, Inherited