OVERVIEW
Pediatric leukocyte adhesion deficiency (LAD) type I is a relatively rare primary immunodeficiency disease – a form of leukocyte dysfunction – characterized by delayed umbilical cord detachment, recurrent soft-tissue infections, chronic periodontitis, and significantly higher peripheral blood leukocyte counts. The children often die in the neonatal period.
Etiology
The integrin β2 (CDL8) subunit is a common component of three integrins, namely phagocyte-associated antigen-1 (Mac-1, CDL16), lymphocyte function-associated antigen-1 (LFA-1, CDL1a), and the p150,95 molecule (CDL1c). The gene encoding CDL8, ITBG2, is localized at 21q22.3. Types of mutations in the ITBG2 gene include point mutations, deletions, insertions, and splicing mutations, all of which result in loss of function of CDL8 and are inherited in an autosomal recessive manner. Defects in this gene affect the ability of leukocytes to accumulate at sites of inflammation and exert bactericidal action.
Symptoms
Mainly recurrent bacterial infections of the skin and mucous membranes, characterized by painless necrosis, which may form ulcers that progressively expand or lead to systemic infections. In newborns, umbilical cord shedding is delayed due to cord infection. The most common pathogens are Staphylococcus aureus and enteric gram-negative bacteria, followed by fungal infections; viral infections are uncommon. The absence of pus formation at the site of infection characterizes the disease.
Children with severe defects express less than 1% of normal CDL8 molecules and have severe disease, often dying in infancy from recurrent infections; those with moderate defects have 2.5% to 30% of normal CDL8 and have milder disease, manifesting severe gingivitis and periodontitis, with long-lasting traumatic or surgical wounds, and may survive into adulthood.
Examination
Peripheral blood neutrophils are markedly elevated, especially during infection, and can be as high as 5 to 20 times that of a normal person.The proliferative response of T and B cells is decreased, and serum immunoglobulin levels are in the normal range.Antibody response to the T cell-dependent antigen phage Φx174 is decreased, the cause of which is not known.The cause of the decrease in antibody response to the T cell-dependent antigen Φx174 is not known. Neutrophil chemotaxis is diminished, binding and phagocytosis of ic3b-conditioned particles are impaired, and neutrophil-mediated antibody-dependent cytotoxic effects are absent.
Flow cytometry is used to analyze peripheral blood neutrophils for CDL8 positivity, and ITGB2 gene analysis reveals various mutation types for definitive diagnosis, prenatal diagnosis, and identification of disease carriers.
Chest radiographs and ultrasound are often required and are usually chosen according to clinical need.
Diagnosis
The possibility of the disease should be considered in infants and young children with recurrent soft tissue infections, chronic ulcers of the skin and mucous membranes with peripheral blood neutrophilia. Most have a history of cord infection and delayed cord detachment. Flow cytometric determination of neutrophil CDL8 positivity confirms the diagnosis of the disease.
Treatment.
Routine use of antimicrobials reduces the incidence of bacterial infections, and in the event of an acute bacterial infection, antibiotics should be used aggressively to control the infection. Laboratories have shown that IFN-γ can promote integrin β2 mRNA expression, but clinical application has failed to find a significant effect. Infusion of fresh normal human neutrophils can effectively control the infection, but this treatment is limited by the short duration of action, the difficulty of finding donors and the possibility of secondary infection caused by repeated infusions.
Bone marrow transplantation is currently the most effective treatment, and gene therapy is still in the stage of animal experiments.