Leucocyte Adhesion Deficiency

Leucocyte adhesion deficiency is a group of rare inherited disorders in which neutrophils cannot adhere to the vascular endothelium and migrate to sites of infection. This causes recurrent bacterial infections with marked neutrophilia but no pus formation.

Three types are described. Type 1 (ITGB2, defective CD18) is the commonest. Type 2 (SLC35C1, defective fucosylation of selectin ligands) and type 3 (FERMT3, kindlin-3 deficiency, with platelet dysfunction) are rarer. All are autosomal recessive and the incidence is about 1 in 1 million.

Severity in type 1 depends on residual CD18 expression: under 2% gives severe disease, while 2 to 30% gives a moderate form with survival to adulthood.

Pathophysiology.

In type 1, absence of the beta-2 integrin chain (CD18) prevents firm adhesion of leucocytes to endothelium, so neutrophils remain in the circulation and cannot reach tissue.

In type 2, selectin ligand fucosylation is defective, which blocks leucocyte rolling. In type 3, integrin activation in leucocytes and platelets fails.

• Delayed separation of the umbilical cord (over 3 weeks) with omphalitis, in the neonatal period.
• Recurrent infections of the skin, mouth, ears, respiratory tract and bowel (including perianal abscess) with little or no pus, and slow wound healing with dysplastic scars.
• Severe gingivitis and periodontitis with early tooth loss.
• Marked persistent neutrophilia (15 to 100 x 10^9/L, increasing with infection).
• Type 2: severe developmental delay, short stature and Bombay blood group. Type 3: bleeding tendency and osteopetrosis like features.

Red flags.

• Omphalitis with a high neutrophil count, or delayed cord separation.
• Necrotising soft tissue infection, or deep infection without pus.
• Severe periodontitis in a child, or bleeding in a child with infections.

• Full blood count: marked neutrophilia with a normal lymphocyte count.
• Flow cytometry for CD18, CD11a, CD11b and CD11c on neutrophils (absent or reduced in type 1). Type 2: absent CD15s (sialyl Lewis X). Type 3: platelet aggregation studies and integrin activation tests.
• Genetic testing to determine the type and for family counselling.
• Cultures from infected sites, and histology of biopsy showing absence of neutrophils at the infected site.

Differential diagnosis. Chronic granulomatous disease, neutrophil function defects, hyper-IgE syndrome, leukaemoid reactions, severe infection, Wiskott-Aldrich syndrome and congenital neutropenia.

Supportive care.

• Early and aggressive treatment of infection with appropriate systemic antibiotics. Prophylactic co-trimoxazole 5 mg/kg/day of the trimethoprim component once daily is often used.
• Meticulous oral hygiene, regular dental review and chlorhexidine mouthwash, with aggressive treatment of periodontal disease.
• Avoid surgical procedures when possible, because of poor wound healing. Granulocyte transfusions are of limited use.

Definitive therapy.

• Haematopoietic stem cell transplantation is the only cure for severe type 1 and type 3 disease, ideally before infections damage organs. It should be considered early.
• Type 2: oral fucose supplementation (25 to 150 mg/kg/day in divided doses) may reduce infections in some patients. Type 3: platelet transfusions and antifibrinolytic agents for bleeding, and transplantation.
• Gene therapy is under investigation.

Monitoring. Neutrophil count, infections, dental health, growth, development and bleeding.

Referral and escalation. Refer to a paediatric immunology and transplant centre when the diagnosis is suspected, because early transplant improves survival.

Special groups. Affected neonates with omphalitis and neutrophilia need rapid diagnosis and IV antibiotics before any delay for testing.