OBJECTIVES: Severe LAD-I is a rare life-threatening inborn error of immunity characterized by frequent refractory infections, reduced or defective CD18 and/or CD11a/b neutrophil expression, and significant pediatric mortality. The current definitive treatment is allogeneic hematopoietic stem-cell transplantation (alloHSCT). This review describes transplant-related trends and outcomes in severe LAD-I, globally and in a subset of countries with highly specialized healthcare systems (EU, UK, US, Canada, Japan and Israel).

METHODS: A systematic literature search was conducted using PRISMA guidelines, in PubMed, EMBASE, Cochrane Library and snowballing (1982-2022). Data extracted included CD18 and CD11a/b neutrophil expression; age at first symptoms, diagnosis and alloHSCT; and alloHSCT outcomes. Severe LAD-I patients were identified as those with CD18 and/or CD11a/b expression on <2% neutrophils relative to normal.

RESULTS: 154 studies (85 in the subset cohort) were included, 45% (N=272) of the 593 patients were considered severe. In the global cohort, the mean age at diagnosis was 13.5±10.2 months (m), with only 24.3% of patients undergoing alloHSCT (at 24.1±45.5m), and of whom 30.3% had a matched sibling donor (MSD). In the subset of countries with highly specialized healthcare (N=68), 51.5% underwent alloHSCT, of whom 34.3% had an MSD. First transplant success rates were 53.0% in the global and 54.3% in the subset cohorts. AlloHSCT complications included graft vs host disease (GvHD) observed in 34.3% of transplanted patients in the subset cohort. Most (4/5) post-transplant deaths were attributed to GvHD. In the subset cohort, 25.7% of transplanted patients underwent a second transplant.

CONCLUSIONS: AlloHSCT for the treatment of severe LAD-I may not be readily available, even in countries with specialized healthcare systems. Additionally, MSD transplants are only available for a limited number of patients. Common transplant-related complications include GvHD and second transplant requirements. There remains a high unmet need for well-tolerated, efficacious, and innovative therapies for severe LAD-I.