Leukocyte Adhesion Disorders

Leukocyte Adhesion Deficiency Type I

Leukocyte adhesion deficiency (LAD) type I is characterized by a deficiency of glycoprotein CD 11b, which forms the a-subunit of the Mac-1 P2-integrin (CD 11b/CD18) on the cell surface of the neutrophils. Intercellular molecule 1 (ICAM-1) expressed on the vascular endothelium serves as a ligand to Mac-1 for the neutrophil adhesion. Because of the mutation and the absence of Mac-1, neutrophils in LAD type I are not

Table 9-8. Investigations of Patients with Neutropenia"

1. History of drug ingestion, toxin exposure

2. Physical examination—nature of infectious lesions, growth and development, presence of anomalies

3. Familial: absolute granulocyte count in family members

4. Blood count: platelet count, absolute granulocyte count, and reticulocyte count; absolute granulocyte count 3 times per week for 2 months (to exclude cyclic neutropenia)

5. Bone marrow a. Maturation characteristics of myeloid series; ? reduction in mature granulocytes b. Maturation and number of megakaryocytes and erythroid precursors c. Karyotype (to identify myelodysplasia or acute myelocytic leukemia)

d. Electron microscopy (subcellular morphology, congenital dysgranulopoiesis)

6. Presence of leukoagglutinins a. Serum antibodies directed against granulocytes

7. Estimate of marginating granulocyte reserve pool a. Epinephrine stimulation tests (0.1 mL 1:1000 epinephrine SC)

(1) Absolute granulocyte counts at 5, 10, 15, and 30 minutes

(2) Normal: double base count

8. Estimate of bone marrow granulocyte reserve pool a. Cortisone stimulation tests (5 mg/kg IV)

(1) Absolute granulocyte counts hourly for 6 hours

(2) Normal: increase of more than 2000 neutrophils/mm3

b. Typhoid stimulation tests (0.5-mL vaccine SC)

(1) Absolute granulocyte count at 3, 6, 12, and 24 hours

(2) Normal: threefold to fourfold increase

9. Rebuck skin window (to assess leukocyte migration and chemotaxis)

Normal: at 3 hours, neutrophils; at 6 hours, mixed neutrophils and monocytes; at 24 hours, monocytes

10. Immunologic tests:

a. Immune globulins (IgA, IgG, IgM, IgE)

b. Cellular immunity (skin-test activity, purified protein derivative [PPD], T- and B-cell evaluation; suppressor T-cell assay)

c. Antinuclear antibodies, C , C , CH

11. Evidence of metabolic disease a. Plasma and urine amino acid screening b. Serum vitamin B12, folic acid, and copper

12. Evidence of pancreatic disease

Exocrine pancreatic function: stool fat, pancreatic enzyme assays, CT scan of pancreas for pancreatic lipomatosis, serum levels of trypsinogen and isoamylase

13. Chromosomal analysis (Fanconi anemia)

14. Radiographic bone survey (cartilage-hair hypoplasia, Shwachman-Diamond syndrome, Fanconi anemia)

15. Serum muramidase (ineffective myelopoiesis)

16. Colony-forming unit (CFU) assays (adequacy of myeloid-committed stem cell compartment)

17. Colony-stimulating activity (CSA) assay (inhibition of CSA effect or production)

18. Flow cytometric analysis (paroxysmal nocturnal hemoglobinuria)

19. Bone density studies (14% of patients with chronic neutropenia show nonclinical osteoporosis or osteopenia)

20. Neutrophil elastase (ELA-2) mutation gene analysis

"Absolute granulocyte count less than 1500/mm3.

Table 9-9. Management of Neutropenic Patienta

1. Admit to hospital for persistent fever over 101°F.

2. Obtain appropriate cultures (blood, throat, urine, infected area) and sensitivity.

3. Administer parenteral antibiotics (Chapter 26)

a. If an organism is isolated, 10-14 days' intravenous treatment is required.

b. If no organism is isolated, antibiotic is continued until afebrile or neutropenia is resolved.

4. Place on reverse isolation to prevent superinfection with antibiotic-resistant organisms.

5. Observe strict hand-washing procedures.

6. Wash skin carefully with a Povidine-containing solution before all skin puncture procedures.

7. Minimize manipulation of skin, oral mucosa, perineum, and rectum; rectal temperatures and enemas are contraindicated.

8. Treat mouth ulcerations and gingivitis with appropriate systemic antibiotics if secondary bacterial infection is found and 3% hydrogen peroxide-1% alum mouthwash, which usually produces symptomatic relief.

9. Administer recombinant human G-CSF (rHu-GCSF)6 for treatment of Kostmann disease (severe congenital agranulocytosis), Shwachman-Diamond syndrome, other congenital neutropenias, and severe neutropenia following chemotherapy (the starting dose is

5 |rg/kg SC with dose modification according to the patient's absolute neutrophil count).

"Neutrophil count less than 500 cells/mm3.

6G-CSF specifically stimulates myeloid progenitor cells in the bone marrow and enhances neutrophil production and function.

Table 9-10. Classification and Investigation of Diseases of Leukocyte Dysfunction

Function

Disease

Investigations

Motility and migration Chemotaxis

Opsonization

Bacterial killing

Leukocyte adhesion deficiency Lazy-leukocyte syndrome Syndrome of elevated IgE, eczema, and recurrent infection Complement deficiency Specific bacterial antibody deficiency Chediak-Higashi syndrome Myeloperoxidase deficiency Chronic granulomatous disease (CGD) Job's disease Leukocyte glutathione peroxidase deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency

All tests below may be abnormal Rebuck skin window: at 3 hours, neutrophils; at 6 hours, mixed neutrophils and monocytes; at 24 hours, monocytes Serum complement levels Immunoglobulin levels Specific bacterial antibody levels Morphologic tests

Chediak-Higashi giant granules Peroxidase stain Bacterial test

Killing of catalase-positive (Staphylococcus aureus) and catalase-negative (streptococcal) bacteria Metabolic tests

Nitroblue tetrazolium (NBT)

reduction testa Glucose 1-14C oxidation with phagocytosis Oxygen consumption during phagocytosis H2O2-dependent 14C-formate oxidation with phagocytosis Iodine-125 fixation during phagocytosis6

aImpaired in CGD due to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase deficiency, deficiency of glutathione reductase of G6PD. Normal in myeloperoxidase deficiency.

6Impaired in CGD and in myeloperoxidase deficiency.

able to attach to the endothelium and undergo transendothelial migration. Additionally, their ability for chemotaxis, phagocytosis, degranulation, and respiratory burst activity is also impaired. Survival of neutrophils is prolonged in LAD type I.

Clinical Features

• Rare autosomal recessive disorder

• Persistent neutrophilia and lack of pus formation

• Frequent skin and periodontal infection

• Omphalitis, delayed umbilical cord separation (normal mean age of cord separation: 7-15 days)

• Perirectal abscess

• Necrotizing enterocolitis

• Infecting organisms: Staphylococcus aureus, Pseudomonas aeruginosa, Proteus, Escherichia coli, Klebsiella, Candida albicans, and Aspergillus.

Diagnosis

1. Flow cytometry for assessment of expression of CD 11b or CD 18 on neutrophil cell surfaces with the use of specific monoclonal antibodies

2. In vitro functional assays of neutrophil adhesion, chemotaxis, and phagocytosis.

Treatment

For mild and moderate disease: oral hygiene with antimicrobial mouthwash, for example, chlorhexidine gluconate, prophylactic use of trimethoprim/sulfamethoxazole (co-trimoxazole), and aggressive treatment of infections. For severe cases, HSCT is recommended.

Leukocyte Adhesion Deficiency Type II

Extremely rare condition caused by the absence of neutrophil sialyl Lewis X structure. Patients have rare Bombay (hh) red cell phenotype. Compared with LAD type I, these patients suffer from less serious types of infections. They are unable to form pus in spite of leukocytosis of 30,000-150,000/mm3.

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