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

Clinical Implications•Leukocyte adhesion deficiency-I (LAD-I) is a rare, serious disorder with severity determined by defective CD18 expression. LAD-I is characterized by umbilical complications, granulocytosis, and diverse infections. Severe LAD-I is frequently fatal before the age of 2 years without allogeneic transplant. We identified 323 cases published between 1975 and 2017. •Leukocyte adhesion deficiency-I (LAD-I) is a rare, serious disorder with severity determined by defective CD18 expression. LAD-I is characterized by umbilical complications, granulocytosis, and diverse infections. Severe LAD-I is frequently fatal before the age of 2 years without allogeneic transplant. We identified 323 cases published between 1975 and 2017. 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 β2-integrin component CD18. Deficiencies in CD18 prevent normal integrin dimerization and leukocyte adhesion to endothelial surfaces, processes essential to extravasation and antimicrobial activity.1Anderson D.C. Schmalsteig F.C. Finegold M.J. Hughes B.J. Rothlein R. Miller L.J. et al.The severe and moderate phenotypes of heritable Mac01, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features.J Infect Dis. 1985; 152: 668-689Crossref PubMed Scopus (492) Google Scholar, 2Schmidt S. Moser M. Sperandio M. The molecular basis of leukocyte recruitment and its deficiencies.Mol Immunol. 2013; 55: 49-58Crossref PubMed Scopus (141) Google Scholar Severe LAD-I (predominantly classified as <2% of CD18-expressing neutrophils) is characterized by recurrent, life-threatening 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.3Fischer A. Lisowska-Grospierre B. Anderson D.C. Springer T.A. Leukocyte adhesion deficiency: molecular basis and functional consequences.Immunodefic Rev. 1988; 1: 39-54PubMed Google Scholar 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%.3Fischer A. Lisowska-Grospierre B. Anderson D.C. Springer T.A. Leukocyte adhesion deficiency: molecular basis and functional consequences.Immunodefic Rev. 1988; 1: 39-54PubMed Google Scholar LAD-I is also characterized by umbilical cord complications (delayed separation and omphalitis), impaired wound healing, and persistent leukocytosis.4Hanna S. Etzioni A. Leukocyte adhesion deficiencies.Ann NY Acad Sci. 2012; 1250: 50-55Crossref PubMed Scopus (145) Google Scholar, 5Van de Vijver E. Van den Berg T.K. Kuijpers T.W. Leukocyte adhesion deficiencies.Hematol Oncol Clin North Am. 2013; 27: 101-116Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar 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 = 36). The nations with the highest number of cases were Iran (n = 65), the United States (n = 50), and India (n = 45); the highest number of publications originated in the United States (n = 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 = .0001; χ2 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 × 109/L; range, 10-150 × 109/L). Although median WBC was higher in the group with CD18 less than 2% (48 vs 30 × 109/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 β2-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.6Levy-Mendelovich S. Rechavi E. Abuzaitoun O. Vernitsky H. Simon A.J. Lev A. et al.Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1.Immunol Res. 2016; 64: 476-482Crossref PubMed Scopus (13) Google Scholar 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 = 34) and frame shift (n = 24) mutations were most frequent for the subset (n = 100) in which these were characterized. More than 20 locations within the ITGB2 gene were specified (n = 120); however, mutations on Exon 6 were most frequent (24%) and mutations on Exons 5, 6, and 7 accounted for 44% of specified cases. We also identified 18 cases in which CD18 expression was more than 30% (range, 31%-99%). In 8 of 12 cases in which CD18 was more than 30% and CD11 information was available, at least 1 CD11 moiety was reported as less than 2%, consistent with recent descriptions of mutations enabling surface expression of nonfunctional CD18.6Levy-Mendelovich S. Rechavi E. Abuzaitoun O. Vernitsky H. Simon A.J. Lev A. et al.Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1.Immunol Res. 2016; 64: 476-482Crossref PubMed Scopus (13) Google Scholar Clinical and genetic details of these cases are provided in Table E6 of this article's Online Repository at www.jaci-inpractice.org. We sought to understand whether prognosis for severe LAD-I in the absence of HSCT is similar to the initially reported 25% survival to the age of 2 years. There were 66 severe LAD-I cases (per investigator assessment or CD18 less than 2%) for whom survival to 2 years was reported, 40 of whom died before the age of 2 years (61% mortality). As indicated in Table I, survival to the age of 2 years was similar for severe LAD-I subsets defined strictly by CD18 expression, and for severe cases reported since 2000. One patient with severe LAD-I survived beyond the age of 12 years (death at 13.5 years). Because many reports did not provide precise survival durations for severe LAD-I (stating only that mortality occurred before the age of 2 years), it was not possible to generate Kaplan-Meier plots incorporating most of the severe LAD-I cases. Survival to the age of 2 years and throughout early childhood exceeded 90% for patients with more than 4% CD18 expression. Figure 1 shows the survival probability for LAD-I cases on the basis of CD18 expression.Table ISurvival to age of 2 y in absence of HSCT on the basis of clinical and laboratory assessments of LAD-I severityLAD-I severityNSurvival to age 2 yAlive at ≥2 yFollow-up to 2 y or death by 2 y% alive to age 2 ySevere: investigator assessment or CD18 <2%96266639%Severe: CD18 <2%73214844%Severe: CD18 <2% (2000-2017 only)67194344%CD18 2%-4%1791369%CD18 >4%-10%25181995%CD18 >10%362929100%Many reports did not provide precise survival durations (stating only that mortality occurred before the age of 2 y), and hence it was not possible to generate Kaplan-Meier curves incorporating most of the severe LAD-I cases. Several patients were considered to have severe LAD-I despite CD18 expression on >2% neutrophils or unspecified CD18 expression; these cases are included in the top row in addition to those with CD18 expression on <2% neutrophils. Open table in a new tab Many reports did not provide precise survival durations (stating only that mortality occurred before the age of 2 y), and hence it was not possible to generate Kaplan-Meier curves incorporating most of the severe LAD-I cases. Several patients were considered to have severe LAD-I despite CD18 expression on >2% neutrophils or unspecified CD18 expression; these cases are included in the top row in addition to those with CD18 expression on <2% neutrophils. Outcomes for 101 patients receiving HSCT were consistent with recent series.7Qasim W. Cavazzana-Calvo M. Davies E.G. Davis J. Duval M. Eames G. et al.Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency.Pediatrics. 2009; 123: 836-840Crossref PubMed Scopus (89) Google Scholar, 8Hamidieh A.A. Pourpak Z. Hosseinzadeh M. Fazlollahi M.R. Alimoghaddam K. Movahedi M. et al.Reduced-intensity conditioning and hematopoietic SCT for pediatric patients with LAD-1: clinical efficacy and importance of chimerism.Bone Marrow Transplant. 2012; 47: 646-650Crossref PubMed Scopus (27) Google Scholar Phenotypic correction was reported in 83% of HLA-identical sibling allograft recipients. Transplant-related mortality was 19% across all groups (11% for HLA-matched sibling recipients). Seven of 22 (32%) haploidentical recipients had HSCT-related mortality and 12 (55%) received at least 1 subsequent transplant. HSCT outcomes were not markedly different for cases in publications before 2000 (n = 23) versus those from 2000 to 2017 (n = 78), although the more recent interval included matched unrelated donor (n = 24) and cord blood (n = 6) transplants. Additional transplant information is provided in Table E7 in this article's Online Repository at www.jaci-inpractice.org. Our findings indicate that severe LAD-I remains a life-threatening condition with limited 2-year survival in the absence of allogeneic HSCT. Potential publication biases may include predilection for reporting more severe cases and those with favorable treatment outcomes; there is also potential underreporting from regions with higher disease incidence, in which LAD-I management is a component of regular practice. Umbilical cord complications and granulocytosis are frequent early LAD-I manifestations. Respiratory tract, ear, sepsis, oral, and skin infections are common. HSCT is the only available curative therapy; transplant-related mortality and other complications occur frequently, especially in haploidentical transplants. In addition to flow cytometry, genetic evaluation may confer meaningful diagnostic and prognostic information. Rapid identification of patients with potential LAD-I (unusual or severe infections during infancy, granulocytosis, and umbilical cord complications) is essential to enable referral to centers with disease expertise and early implementation of definitive therapy. Figure E2Correlation of neutrophil CD18 expression with highest reported WBC count for (A) all patients for whom information was reported, (B) patients with CD18 <2%, and (C) patients with CD18 ≥2%. Upper limits of normal for WBC counts vary between clinical laboratories, but are generally in the range of 9800/mm3.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Publications and patient numbers by countryCountryNo. of publicationsNo. of patientsUnited States2550Iran1265India1045United Kingdom816The Netherlands59Japan55Italy45Mexico34Canada35France36Taiwan32Israel212Spain22European Union∗Publications with multiple contributing nations.210Saudi Arabia213Turkey22Chile22Jordan22Pakistan23United States/European Union∗Publications with multiple contributing nations.136Germany/France114Switzerland14Tunisia15Argentina11Brazil11Egypt11Norway11Singapore11China11∗ Publications with multiple contributing nations. Open table in a new tab Table E2LAD-I publications evaluated to comprise databaseReferenceNo. of casesAkbari H, Zadeh MM. Leukocyte adhesion deficiency. Indian J Pediatr 2001;68:77-9.1Al-Dhekri H, Al-Mousa H, Ayas M, Al-Muhsen S, Al-Ghonaium A, Al-Ghanam G, et al. Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type 1: a single center experience. Biol Blood Marrow Transplant 2011;17:1245-9.11Alizadeh P, Rahbarimanesh AA, Bahram MG, Salmasian H. Leukocyte adhesion deficiency type 1 presenting as leukemoid reaction. Indian J Pediatr 2007;74:1121-3.1Allende LM, Hernandez M, Corell A, García-Pérez MA, Varela P, Moreno A, et al. CD18 in a patient with severe leukocyte adhesion deficiency: a possible functional association in A, I, M, transplantation for leukocyte adhesion case report. J Schmalsteig Finegold Hughes Rothlein Miller et al. The severe and moderate phenotypes of heritable Mac01, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Springer Leukocyte adhesion deficiency: an in the and the cases were described in more than 1 the of cases in the table is MA, of in a with recurrent bacterial infections. J S, A, M, A, in a patient with adhesion deficiency. Iran J Pediatr Davies A, in a with deficiency of J separation of the umbilical severe and Van et al. Severe recurrent bacterial infections with defective and in patients with neutrophils in a J Pediatr of and in a patient with deficiency. Blood M, et al. Leukocyte adhesion deficiency type 1 with but nonfunctional J Clin A, M, M, et al. of in type leukocyte adhesion deficiency. Blood G, et al. and a in leukocyte adhesion deficiency S, M. Leukocyte adhesion a rare of Indian J Leukocyte adhesion deficiency type 1: an in the clinical of a case and review of the M, et al. of neutrophil its genetic and its association with a J S, A, of leukocyte adhesion deficiency type J E. adhesion deficiency presenting as a and with neutrophil and umbilical cord Clin S, H, H, et al. transplantation in patients with the leukocyte adhesion deficiency. Blood H, rare association between leukocyte adhesion deficiency type and in H. unrelated transplantation with conditioning for leukocyte adhesion deficiency. Marrow Transplant M, Fazlollahi S, et al. of leukocyte adhesion deficiency cases from Iran with new Iran J Duval M, S, et al. transplantation for leukocyte adhesion deficiency. Marrow Transplant M, K. frame recurrent and de mutations in the ITGB2 gene leukocyte adhesion deficiency in a North J M, G, ITGB2 with in a with leukocyte adhesion deficiency. Clin A, I, Lisowska-Grospierre I, et al. transplantation for of with defective and during M, I, et al. adhesion deficiency of a S, P, O. infant with severe adhesion deficiency. AA, Pourpak Alimoghaddam Movahedi M, G, et al. allogeneic stem cell transplantation with a conditioning in a leukocyte adhesion deficiency type Pediatr Transplant AA, Pourpak Hosseinzadeh M, Fazlollahi Alimoghaddam Movahedi M, et al. conditioning and hematopoietic SCT for pediatric patients with LAD-1: clinical efficacy and importance of Marrow Transplant of in J H, S, et al. leukocyte transplantation in a with leukocyte adhesion deficiency Pediatr separation of the umbilical and defective neutrophil Leukocyte adhesion deficiency type 1 presenting with recurrent and Pediatr P, CD18 mutations a in the and a of the in a patient with leukocyte adhesion deficiency type Blood et al. leukocyte adhesion deficiency by but nonfunctional and J Clin 1 leukocyte adhesion deficiency by the of J Leukocyte adhesion deficiency of M, A, S, Pourpak Z. in leukocyte adhesion deficiency type 1 J Infect A, A, G, et al. transplantation from in with fatal severe of to prevent S, P, A, of disease cord blood transplantation for leukocyte adhesion deficiency type Marrow Transplant presentation of type leukocyte adhesion deficiency. J Clin S, J. adhesion Indian Pediatr S, M, S, M. Leukocyte adhesion deficiency: of Iran of neutrophil with neutrophil de M, et al. Leukocyte adhesion deficiency type 1 a characterized by J Clin S, Rechavi Abuzaitoun Vernitsky H, Simon Lev A, et al. the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type in CD18 leukocyte adhesion deficiency in a J M, M, M, M. Clinical of leukocyte adhesion deficiency type Indian Pediatr M, M, S, A, M, et al. of leukocyte adhesion deficiency-I in Indian identification of Blood A, G, Leukocyte adhesion deficiency in a with severe oral de A, and of blood from a patient with leukocyte adhesion normal in via unrelated donor transplantation in leukocyte adhesion deficiency. Marrow Transplant M, M, M, M, et al. treatment in a with disease and manifestations. J Clin in an infant with a rare leukocyte adhesion deficiency. in CD18 the expression of in a patient with leukocyte adhesion deficiency Clin G, M, et al. with and from a patient with recurrent bacterial infections. J M. Leukocyte adhesion deficiency case report. M, M, Fazlollahi et al. of ITGB2 gene in 12 new cases of leukocyte adhesion 1 mutations in Iran M, MA, et al. neutrophil recruitment in leukocyte adhesion deficiency type disease A, H, J. Leukocyte adhesion deficiency in a J Infect Leukocyte adhesion deficiency: a case and J P, and of the in neutrophils with deficiency. J in a A. in impaired and of M. Leukocyte adhesion deficiency: recurrent childhood skin infections. J Acad S, A, et al. of new cases of leukocyte adhesion deficiency type 1 with mutations in the ITGB2 J Clin MA, M. stem cell transplant for a experience. Clin Transplant A, of from an infant with leukocyte adhesion deficiency. Pediatr Infect J Cavazzana-Calvo M, Davies G, Davis Duval M, Eames G, et al. Allogeneic hematopoietic stem cell transplantation for leukocyte adhesion deficiency. A, S, A, Etzioni A. in a with adhesion deficiency an Indian J Pediatr Leukocyte adhesion deficiency J Pediatr with leukocyte adhesion deficiency: a case Pediatr M, S, et al. of patients with leukocyte adhesion deficiency: Clinical and laboratory of patients with an deficiency of neutrophil type and the LFA-1 and J Clin Springer et al. of patients with an to bacterial infections and a genetic deficiency of leukocyte type and the Blood A, et al. of CD18 in adhesion patients with to expression and of the and Clin A, S, P, M. adhesion Indian Pediatr Lev A, et al. The of on a of CD18 leukocyte adhesion deficiency One S, S, and ulcers in a Pediatr Anderson in CD18 in association with the moderate of leukocyte adhesion deficiency. J Biol A, S, A, adhesion deficiency type 1 with to and The association of leukocyte adhesion type and persistent of in a Pediatr Oncol et al. transplantation a in leukocyte adhesion deficiency. Marrow Transplant H, Leukocyte adhesion type 1 presenting with recurrent Indian J Cavazzana-Calvo M, M, S, et al. of allogeneic transplantation in patients with leukocyte adhesion deficiency. Blood of neutrophil with absence of a surface Clin Leukocyte adhesion deficiency type a rare Pediatr A, Leukocyte adhesion J et al. in a patient with leukocyte adhesion deficiency type Blood of leukocyte adhesion deficiency type Iran G, et al. mutations in patients with leukocyte adhesion deficiency Blood in deficiency of J M, et al. CD18 deficiency to case report. Blood Leukocyte adhesion deficiency on the case in and J Leukocyte adhesion deficiency in a patient without umbilical cord J M, treatment in severe adhesion deficiency. J Pediatr of the in a new J Clin G, M, et al. deficiency: and neutrophil Blood G, Davies et al. of leukocyte adhesion deficiency in J M, et al. treatment in patients by leukocyte adhesion deficiency type 1 S, Mutation of the ITGB2 gene in with leukocyte adhesion deficiency type A, H, M, S, H, et al. allogeneic stem cell transplant for leukocyte adhesion deficiency an Pediatr Transplant of 323 LAD-I cases were evaluated and included in the identified in the 107 publications in the Because the cases were described in more than 1 the of cases in the table is Open table in a new tab Table specified LAD-I reported as of specified <2% (n = (n = tract including including gingivitis and oral skin skin reported as of specified infections. Open table in a new tab Table cord complications by neutrophil CD18 expression cord <2% (n = (n = Umbilical cord complications include cord separation and Umbilical cord complication information was available for 110 of 135 patients with CD18 <2% and 81 of 130 patients with CD18 ≥2%. Open table in a new tab Table cord complications and mortality in LAD-I with CD18 cord before 24 at 24 cord complications include cord separation and Table information for patients from whom information regarding umbilical cord complications was available, and for whom follow-up to age 2 y (or death before the age 2 of was Open table in a new tab Table cases with CD18 and at least 1 CD11 moiety of on ITGB2 Open table in a new tab Table haploidentical matched matched sibling matched unrelated not Outcomes were available for 101 of 125 patients reported to have received HSCT, of which LAD-I severity was as n = moderate, n = not n = Phenotypic correction is defined as a of the Open table in a new tab of 323 LAD-I cases were evaluated and included in the identified in the 107 publications in the Umbilical cord complications include cord separation and Umbilical cord complication information was available for 110 of 135 patients with CD18 <2% and 81 of 130 patients with CD18 ≥2%. Umbilical cord complications include cord separation and Table information for patients from whom information regarding umbilical cord complications was available, and for whom follow-up to age 2 y (or death before the age 2 of was on ITGB2 haploidentical matched matched sibling matched unrelated not Outcomes were available for 101 of 125 patients reported to have received HSCT, of which LAD-I severity was as n = moderate, n = not n = Phenotypic correction is defined as a of the

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