Laboratory Studies

Extreme neutrophilia (>15,000/mcL) is a constant feature of leukocyte adhesion deficiency (LAD) type 1, type 2, type 3, and Rac2 deficiency because of inability of neutrophil margination.

The WBC count is 15-161 X 10³/µL (15,000-161,000/mcL) with 50-90% neutrophils.
Neutrophilia is present in the absence of infections and increases with infections.
In E-selectin deficiency, mild neutropenia is present but increases with infections.

The diagnosis of LAD type 1 is confirmed by an absence of CD11a,b,c/CD18 on neutrophils, macrophages, and lymphocytes on flow cytometry.

In addition, neutrophil function is impaired, with abnormal adherence, chemotaxis phagocytosis, and deficient respiratory burst.
Numbers of T and B cells and their function are normal.
However, natural killer (NK)-cell and T-cell cytotoxicity is depressed.
Responses on mixed lymphocyte culture (MLC) may be markedly decreased.
CD15s expression is normal in LAD type 1.

In LAD type 2, CD15s (sLeX) expression is absent on neutrophils. CD11/CD18 expression is normal.

Neutrophil rolling is decreased but adhesion is normal.
Numbers and function of T and B cells are decreased.
Erythrocyte H antigens are absent, leading to expression of the Bombay (hh) phenotype. As a result, anti-H antibodies are present.

In examination of infections in children with LAD type 1, signs of inflammation, eg, erythema, pus formation, are decreased to absent.

Necrotic cutaneous, mucous membrane, and periodontal infections are the hallmark of LAD type 1.
In deep-seated infections, such as in the lungs and abdomen, the same process occurs.
Inflammatory infiltrations are decreased.
Therefore, findings on chest or abdominal radiography findings may lead to underestimates of the infectious process.
Imaging studies more sensitive than radiography, such as chest CT, may define the infectious process better than radiography.
Appropriate cultures are obtained from suspected infectious sites. Although inflammatory cells are decreased to absent, microorganisms can be identified.

Imaging Studies

No specific radiographic studies are necessary to make a diagnosis.

As previously discussed, imaging studies are useful in diagnosing infections.

Histologic Findings

The most striking finding in biopsies of infections in patients with all forms of LAD is the absence of neutrophils and other inflammatory cells.

Treatment & Management

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Protein defects.

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Table 1. Complement Receptors

Receptor	Cluster Designation	Ligand	Cell Distribution	Activity
CR1	CD35	C3b/C4b	RBC, polymorphonuclear cell, macrophage, B cell, follicular dendritic cell	Immune adherence, phagocytosis
CR2	CD21	C3dg/C3d	B cell, follicular dendritic cell	Co-receptor for B-cell signaling
CR3	CD11b/CD18	C3bi, ICAM	Myeloid	Phagocytosis, immune adherence
CR4	CD11c/CD18	C3bi, ICAM	Myeloid	Phagocytosis, immune adherence
C1qRP	None	C1q, MBL, surfactant	Polymorphonuclear cell, macrophage	Promotes phagocytosis
C3aR	None	C3a, C4a	Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell	Anaphylatoxin
C4aR	None	C4a	Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell	Anaphylatoxin
C5aR	CD88	C5a	Polymorphonuclear cell, macrophage, epithelial cell, smooth-muscle cell	Anaphylatoxin
ICAM = intercellular adhesion molecule, MBL = mannose-binding lectin

Table 2. Leukocyte Adhesion Defects

Disease	Inheritance	Genetic Defect	Protein Defect	Affected Cells	Affected Function	Manifestations
LAD type 1	Autosomal recessive	INTGB2	CD18	Polymorphonuclear cell, macrophage, lymphocytes, NK cells	Tight adherence, chemotaxis, endocytosis, T-cell/NK-cell cytotoxicity	Delayed cord separation, skin ulcers, periodontitis, leukocytosis, poor pus formation
LAD type 2	Autosomal recessive	FUCT1 encoding for GDP-fucose transporter	Fucosylated proteins, sialyl-Lewis X (sLeX, CD15s)	Polymorphonuclear cell, macrophage	Rolling, chemotaxis, tethering	Same as LAD type 1 plus hh-blood group, mental retardation
LAD type 3	Autosomal recessive	Kindlin 3 (FERMT3), involved in activation of integrin	Kindlin 3	Polymorphonuclear cell, macrophage, lymphocytes, NK cells	Tight adherence	Same as LAD type 1 plus bleeding tendency
Rac 2 deficiency	Possibly autosomal dominant	RAC2	Rac2, involved in regulation of actin cytoskeleton	Polymorphonuclear cell, decreased TRECs	Chemotaxis, O₂^- production	Recurrent infections, poor wound healing, leukocytosis, poor pus formation
E-selectin	Possibly autosomal recessive	Unknown	E-selectin	Endothelial cells	Rolling, tethering	Recurrent infections, poor pus formation, mild neutropenia
NK = Natural killer, TRECs = T-cell receptor excision circles

Table 3. Adhesion Molecules

Molecule	CD Number	Distribution	Ligand	Function
Integrins
LFA-1	CD11a/CD18	All leukocytes	ICAM-1, 2, 3	Adhesion, migration
CR3	CD11b/CD18	Polymorphonuclear cell, macrophage, NK cells, eosinophils	ICAM-1,2; C3bi	Adhesion, migration
CR4	CD11c/CD18	All leukocytes	C3bi, ICAM-1, CD23, fibrinogen	Adhesion
Alpha4-beta7	None	Lymphocytes, NK cells, eosinophils	MadCAM-1, VCAM-1, fibronectin	Adhesion, migration, rolling
VLA-4	CD49d/CD29	Lymphocytes, NK cells, eosinophils, basophils	VCAM-1, fibronectin	Adhesion, migration, rolling
Selectins
E	CD62E	Endothelial cells, platelets	Sialylated, fucosylated molecules (sLeX, CD15s) expressed on PSGL-1 and ESL-1	Rolling
P	CD62P	Endothelial cells, platelets	Sialylated, fucosylated molecules (sLeX) expressed on PSGL-1	No data
L	CD62L	Leukocytes	Sialylated, fucosylated molecules (often sulfated) expressed on CD34, MadCAM-1 and other glycoproteins-1	Rolling
MadCAM = Mucosal addressin cell adhesion molecule; VCAM = Vascular cell adhesion molecule; VLA = Very late activation antigen

Table 4. Subtypes of Leukocyte Adhesion Deficiency Type 1

Subtype	mRNA level	CD18 Expression	Clinical Presentation
1	None	None	Severe
2	Low	Trace	Moderate
3	Reference range	Trace, small protein precursor	Moderate
4	Reference range	Large protein precursor	Severe
5	Reference range	Normal protein precursor	Moderate
mRNA = messenger RNA.