Leukocyte Adhesion Deficiency-I (LAD-I): A Comprehensive Review of Published Cases

LAD-I is a rare disorder of leukocyte adhesion, resulting from ITGB2 gene mutations encoding for the Beta-2 Integrin component CD18. CD18 deficiencies prevent integrin dimerization and endothelial leukocyte adhesion, essential for extravasation and antimicrobial activity. LAD-I is characterized by delayed separation,of the umbilical cord, omphalitis, poor wound healing and leukocytosis. Severe LAD-I (<2% of normal neutrophil [PMN] CD18 levels) is characterized by recurrent serious infections and early mortality unless treated by allogeneic haematopoietic stem cell transplant (HSCT). Mortality for severe LAD-I was reported as 75% by age 2 in an initial 1988 multicenter retrospective study. Moderate LAD-I (2-30% of PMN CD18 levels) is more indolent; although most pts survive childhood with recurrent skin and mucosal surface infections, mortality by age 40 can exceed 50%.

Reports regarding LAD-I have been published in recent decades but no recent comprehensive prognostic assessments are available. We sought an updated understanding of severe LAD-I with emphasis on prognosis in the absence of HSCT, HSCT outcomes and association of CD18 expression with clinical features. We created a database of all published LAD-I cases via Pubmed searches and review of available references.

Three hundred thirty LAD-I cases were reported between 1975-2017 in 111 publications (89 case-reports; largest series n=36). The nations reporting the most cases were Iran (n=64), USA (n=52), and India (n=45); the highest number of publications were from US centers (26). 113 pts were considered to have severe LAD-I, 63 moderate and 154 were not classified. PMN CD18 expression levels was reported for 270 cases and was <2% in 138 patients (51%) and ≥2% in 132 pts. Four pts with CD18 >2% were considered to have severe LAD-I (CD18% range 2.4 - 17.3). Gender was noted for 289 pts; 153 (53%) were male. Age at presentation was reported for 152 cases. For 65 pts with CD18<2%, median presentation was age 1 m (range 0.03-18m); for 64 pts with CD18 ≥2%, median presentation was age 6m (range 0.03-192m).

We sought to understand whether prognosis for severe LAD-I in the absence of HSCT is similar to the initially-reported 25% survival to age 2. There were 59 severe LAD-I cases (per investigator assessment or CD18 <2%) for whom survival to 2 years was reported, 38 of whom died prior to age 2 (64% mortality). Mortality was similar for the subset of 43 cases reported since 2000 (58%, 25 deaths). Early mortality was substantially lower in patients with CD18 ≥2% and the majority of pts with CD18 >4% survived to adulthood. Outcomes for 119 pts who received HSCT were consistent with recent series; phenotypic correction was reported in 85% of pts with HLA-matched sibling donors. Mortality was 15% overall (8% for HLA-matched sibling recipients). The 27 pts receiving haploidentical HSCT had frequent graft failure (33%) with 16 (59%) receiving ≥1 subsequent HSCT.

Infection details and CD18% were available for 159 (48%) cases. The most frequent infections in pts with CD18 <2% were respiratory tract (39%), sepsis (28%) and otitis media (27%) and for pts with CD18 ≥2% they were periodontal (51%), otitis media (35%) and sepsis (25%). Perianal skin infections and necrotic skin ulcers were noted in >10%. Umbilical complications were more frequent in severe LAD-I (94 of 112 pts with CD18<2% [84%] and 49 of 83 with CD18 ≥2% [59%; p = 0.0001]). For severe LAD-I pts with ≥2 years of follow-up (or death prior to 2y), there was correlation between absence of umbilical complications and survival to 24 m (p < 0.001). WBCs were reported in 149 cases (median 45 x 10⁹/L; range 10 - 150 x 10⁹/L) (normal range 4.5 to 11 × 10⁹/L).There were limited correlations between CD18 expression and WBC (r < 0.1) and between CD18 and CD11 expression (r < 0.5).

Severe LAD-I remains a life-threatening condition with limited 2-year survival in the absence of allogeneic HSCT. Umbilical complications and granulocytosis occur in nearly all pts. Respiratory tract, ear, sepsis, oral and skin infections are common. HSCT is potentially curative; transplant-mortality and other complications are frequent, especially in haploidentical transplants. Rapid identification of pts with potential LAD-I (unusual or severe infections in infancy, granulocytosis and umbilical complications) is essential to enable referral to centers with disease expertise.