Leukocyte adhesion deficiency-I: A comprehensive review of all published cases.

Leukocyte adhesion deficiency-I (LAD-I) is a rare disorder of leukocyte adhesion and migration, resulting from mutations in the ITGB2 gene encoding for the b2-integrin component CD18. Deficiencies in CD18 prevent normal integrin dimerization and leukocyte adhesion to endothelial surfaces, processes essential to extravasation and antimicrobial activity. Severe LAD-I (predominantly classified as <2% of CD18expressing neutrophils) is characterized by recurrent, lifethreatening bacterial and other infections and substantial infant mortality in patients who do not receive allogeneic hematopoietic stem cell transplant (HSCT). Mortality for severe LAD-I was reported as 75% by the age of 2 years in an initial 1988 multicenter retrospective evaluation. Most patients with moderate LAD-I (2%-30% CD18-expressing neutrophils) survive childhood, with recurrent infections of skin and mucosal surfaces; mortality by the age of 40 years reportedly exceeds 50%. LAD-I is also characterized by umbilical cord complications (delayed separation and omphalitis), impaired wound healing, and persistent leukocytosis. Multiple reports have been published in recent decades; however, no comprehensive prognostic assessments are available subsequent to the 1988 report. 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 a review of additional references. Three hundred twenty-three LAD-I cases were reported between 1975 and 2017 in 107 publications (68 of which were single case reports; largest series n 1⁄4 36). The nations with the highest number of cases were Iran (n 1⁄4 65), the United States (n 1⁄4 50), and India (n 1⁄4 45); the highest number of publications originated in the United States (n 1⁄4 25) (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org for a comprehensive listing of publications and patient numbers by country and Table E2 for a comprehensive listing of references). Per investigator assessment, 113 patients were considered to have severe LAD-I, 63 moderate, and 147 not classified. Neutrophil CD18 expression was reported for 265 cases and was less than 2% in 135 patients (51%) and 2% or more in 130 patients (49%). Four patients with CD18 greater than or equal to 2% were considered to have severe LAD-I (CD18% range, 2.4-17.3). Sex information was available for 282 patients, of which 148 (52%) were males. Age at presentation was reported for 146 cases. For 63 patients with CD18 less than 2%, median presentation was at age 1 month (range, 0.03-18 months); for 62 patients with CD18 of 2% or more, median presentation was at age 6 months (range, 0.03-192 months). HSCT was performed for 125 patients; 198 patients did not undergo HSCT. Infections were described for 248 (77%) of the 323 cases; information regarding anatomic site and CD18% was specified in 154 cases (48%). The most frequent infections in 85 cases with CD18 less than 2% were respiratory tract (39%, including pneumonia), sepsis (29%), and otitis media (27%). The most frequent infections in 69 cases with CD18 of 2% or more were periodontal (52%, including gingivitis and oral ulcers), otitis media (36%), and sepsis (25%). Perianal skin infections and necrotic skin ulcers were each reported in more than 10% of the groups. For additional information, see Table E3 in this article’s Online Repository at www.jaci-inpractice.org. Umbilical cord complications (delayed separation or omphalitis) were more frequent in patients with severe LAD-I, reported in 92 of 110 patients with CD18 less than 2% (84%) and 47 of 81 patients with CD18 of 2% or more (58%; P 1⁄4 .0001; c test). For the subset of patients with severe LAD-I with at least 2 years of follow-up (or death before the age of 2 years), there was significant correlation between absence of umbilical cord complications and survival to 24 months (P < .001; Fisher exact test). Tables E4 and E5 in this article’s Online Repository at www.jaci-inpractice.org depict umbilical cord complication incidences and 2-year survival. White blood cell (WBC) counts were reported in 143 cases (median, 45 10/L; range, 10-150 10/L). Although median WBC was higher in the group with CD18 less than 2% (48 vs 30 10/L), there was limited correlation between CD18 expression and WBC (r < 0.1) for the entire cohort and when the groups with CD18 less than 2% and of 2% or more were analyzed independently. Expression of b2-integrin heterodimers CD11a, CD11b, and CD11c was reported in 76, 89, and 69 cases, respectively. Correlations between CD18 and CD11 expressions were also limited (r < 0.5), consistent with a recent report. Figures E1 and E2 in this article’s Online Repository at www.jaci-inpractice.org depict analyses regarding integrin expression and WBC. Mutation analyses were provided for 139 cases; missense (n 1⁄4 34) and frame shift (n 1⁄4 24) mutations were most frequent for the subset (n 1⁄4 100) in which these were characterized. More than 20 locations within the ITGB2 gene were specified (n 1⁄4 120); however, mutations on Exon 6 were most frequent