Leukocyte Adhesion Deficiency Treatment & Management
- Author: Stephen J Nervi, MD; Chief Editor: Harumi Jyonouchi, MD more...
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- Bone marrow and other stem cell transplantation are the therapies of choice in leukocyte adhesion deficiency (LAD) and have a very high success rate.[10, 11, 12] Thus, bone marrow or other stem cell reconstitution is a first-line treatment for severe leukocyte adhesion deficiency type I, in which less than 1% CD18 expression is detected. Donors may provide human leukocyte antigen (HLA)-matched, related, haploidentical, or unrelated HLA–matched hematopoietic stem cells. The high rate of successful engraftment in patients with leukocyte adhesion deficiency I is thought to be due to absence of CD11a/CD18 expression on lymphocytes; antibodies directed against this integrin also seem to improve engraftment of bone marrow stem cells and prevent graft versus host disease in patients who underwent hematopoietic stem cell transplantation (HSCT) for other disorders. However, not all patients are candidates for early bone marrow transplants.
- Other intervention measures for leukocyte adhesion deficiency I have included prophylactic antibiosis, interferon-gamma, and leukocyte transfusions; none of these has shown significant benefit.
- Gene therapy with insertion of the CD18 subunit is currently under investigation. Because patients with decreased expression of CD18 (1-30%) have a milder disease, partial reconstitution is anticipated to provide clinical benefit.
- Leukocyte adhesion deficiency II does not require prophylactic antibiosis. Fucose replacement administered orally or intravenously has variable effectiveness in improving phagocytic functions.
- The use of granulocyte transfusions has been advocated. Donors must be carefully screened to prevent transmission of infection. In the author's experience, the efficacy of granulocyte transfusions was difficult to prove, and pulmonary sequestration compromise lung severely with marked febrile reactions.
- Interferon-gamma showed no efficacy in one patient (single case report).
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- Surgical procedures for leukocyte adhesion deficiency I are of high risk and require flawless postoperative care because of the delayed wound healing and risk for further infection.
- Complications of surgical procedures in leukocyte adhesion deficiency II have not been reported.
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- Consultations with surgeons, pulmonologists, and intensivists are often mandatory. The clinical immunologist must work closely with these consultants because the lack of inflammation leads to the underestimation of infection by inexperienced medical personnel.
- Bone marrow transplantation teams are mandatory for therapy of severe leukocyte adhesion deficiency I.
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- A normal nutritious diet for age group is appropriate.
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- No restrictions are advised.
- Obviously, care of skin and mucous membranes as portals of entry for infection requires excellent hygiene.
- Injuries are slow to heal and are at high risk for secondary infection.
- Prophylactic antibiotics for injuries are generally used conventionally; the major application is for animal or human bites.
[Guideline] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005 May. 94(5 Suppl 1):S1-63. [Medline].
Hanna S, Etzioni A. Leukocyte adhesion deficiencies. Ann N Y Acad Sci. 2012 Feb. 1250(1):50-5. [Medline].
Cagdas D, Yilmaz M, Kandemir N, Tezcan I, Etzioni A, Sanal O. A Novel Mutation in Leukocyte Adhesion Deficiency Type II/CDGIIc. J Clin Immunol. 2014 Nov. 34(8):1009-14. [Medline].
Anderson DC, Schmalsteig FC, Finegold MJ, et al. The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis. 1985 Oct. 152(4):668-89. [Medline].
Helmus Y, Denecke J, Yakubenia S, et al. Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood. 2006 Feb 2. [Medline].
Alon R, Etzioni A. LAD-III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol. 2003 Oct. 24(10):561-6. [Medline].
Kinashi T, Aker M, Sokolovsky-Eisenberg M, et al. LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood. 2004 Feb 1. 103(3):1033-6. [Medline]. [Full Text].
McDowall A, Svensson L, Stanley P, Patzak I, Chakravarty P, Howarth K, et al. Two mutations in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro. Blood. 2010 Jun 10. 115(23):4834-42. [Medline].
Lorusso F, Kong D, Jalil AK, et al. Preimplantation genetic diagnosis of leukocyte adhesion deficiency type I. Fertil Steril. 2006 Feb. 85(2):494.e15-8. [Medline].
Elhasid R, Rowe JM. Hematopoetic Stem Cell Transplantation in Neutrophil Disorders: Severe Congenital Neutropenia, Leukocyte Adhesion Deficiency and Chronic Granulomatous Disease. Clin Rev Allergy Immunol. 2009 May 19. [Medline].
Stepensky PY, Wolach B, Gavrieli R, Rousso S, Ben Ami T, Goldman V, et al. Leukocyte Adhesion Deficiency Type III: Clinical Features and Treatment With Stem Cell Transplantation. J Pediatr Hematol Oncol. 2014 Jul 28. [Medline].
Moutsopoulos NM, Konkel J, Sarmadi M, Eskan MA, Wild T, Dutzan N, et al. Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med. 2014 Mar 26. 6(229):229ra40. [Medline]. [Full Text].
Alon R, Aker M, Feigelson S, et al. A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow. Blood. 2003 Jun 1. 101(11):4437-45. [Medline]. [Full Text].
Bauer TR Jr, Hickstein DD. Gene therapy for leukocyte adhesion deficiency. Curr Opin Mol Ther. 2000 Aug. 2(4):383-8. [Medline].
Bauer TR, Gu YC, Tuschong LM, et al. Nonmyeloablative hematopoietic stem cell transplantation corrects the disease phenotype in the canine model of leukocyte adhesion deficiency. Exp Hematol. 2005 Jun. 33(6):706-12. [Medline].
Bunting M, Harris ES, McIntyre TM, Prescott SM, Zimmerman GA. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr Opin Hematol. 2002 Jan. 9(1):30-5. [Medline].
DeLisser HM, Christofidou-Solomidou M, Sun J, et al. Loss of endothelial surface expression of E-selectin in a patient with recurrent infections. Blood. 1999 Aug 1. 94(3):884-94. [Medline].
Eklund EA, Freeze HH. The congenital disorders of glycosylation: a multifaceted group of syndromes. NeuroRx. 2006 Apr. 3(2):254-63. [Medline].
Etzioni A. Leukocyte adhesion deficiencies: molecular basis, clinical findings, and therapeutic options. Adv Exp Med Biol. 2007. 601:51-60. [Medline].
Etzioni A, Frydman M, Pollack S, et al. Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med. 1992 Dec 17. 327(25):1789-92. [Medline].
Etzioni A, Harlan JM. Cell adhesion and leukocyte adhesion defects. Ochs HD, Puck JM, Smith CI, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press Inc; 1998. 375-88.
Etzioni A, Sturla L, Antonellis A, et al. Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet. 2002 Jun 15. 110(2):131-5. [Medline].
Farinha NJ, Duval M, Wagner E, et al. Unrelated bone marrow transplantation for leukocyte adhesion deficiency. Bone Marrow Transplant. 2002 Dec. 30(12):979-81. [Medline].
Fiorini M, Vermi W, Facchetti F, et al. Defective migration of monocyte-derived dendritic cells in LAD-1 immunodeficiency. J Leukoc Biol. 2002 Oct. 72(4):650-6. [Medline].
Gu YC, Bauer TR Jr, Ackermann MR, et al. The genetic immunodeficiency disease, leukocyte adhesion deficiency, in humans, dogs, cattle, and mice. Comp Med. 2004 Aug. 54(4):363-72. [Medline].
Harris ES, Shigeoka AO, Li W, et al. A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. Blood. 2001 Feb 1. 97(3):767-76. [Medline]. [Full Text].
Hidalgo A, Ma S, Peired AJ, Weiss LA, et al. Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. Blood. 2003 Mar 1. 101(5):1705-12. [Medline]. [Full Text].
Hixson P, Smith CW, Shurin SB, Tosi MF. Unique CD18 mutations involving a deletion in the extracellular stalk region and a major truncation of the cytoplasmic domain in a patient with leukocyte adhesion deficiency type 1. Blood. 2004 Feb 1. 103(3):1105-13. [Medline]. [Full Text].
Hogg N, Stewart MP, Scarth SL, et al. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest. 1999 Jan. 103(1):97-106. [Medline].
Kurkchubasche AG, Panepinto JA, Tracy TF Jr, et al. Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease. J Pediatr. 2001 Jul. 139(1):141-7. [Medline].
Luhn K, Wild MK, Eckhardt M, Gerardy-Schahn R, Vestweber D. The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat Genet. 2001 May. 28(1):69-72. [Medline].
Malawista SE, de Boisfleury Chevance A, et al. Chemotaxis of non-compressed blood polymorphonuclear leukocytes from an adolescent with severe leukocyte adhesion deficiency. Am J Hematol. 2003 Jun. 73(2):115-20. [Medline].
Mancias C, Infante AJ, Kamani NR. Matched unrelated donor bone marrow transplantation in leukocyte adhesion deficiency. Bone Marrow Transplant. 1999 Dec. 24(11):1261-3. [Medline].
Marquardt T, Brune T, Luhn K, et al. Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism. J Pediatr. 1999 Jun. 134(6):681-8. [Medline].
Marquardt T, Luhn K, Srikrishna G, et al. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood. 1999 Dec 15. 94(12):3976-85. [Medline].
Pasvolsky R, Feigelson SW, Kilic SS, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med. 2007 Jul 9. 204(7):1571-82. [Medline].
Roos D, Meischl C, de Boer M, et al. Genetic analysis of patients with leukocyte adhesion deficiency: genomic sequencing reveals otherwise undetectable mutations. Exp Hematol. 2002 Mar. 30(3):252-61. [Medline].
Shaw JM, Al-Shamkhani A, Boxer LA, et al. Characterization of four CD18 mutants in leucocyte adhesion deficient (LAD) patients with differential capacities to support expression and function of the CD11/CD18 integrins LFA-1, Mac-1 and p150,95. Clin Exp Immunol. 2001 Nov. 126(2):311-8. [Medline].
Sturla L, Fruscione F, Noda K, et al. Core fucosylation of N-linked glycans in leukocyte adhesion deficiency/congenital disorder of glycosylation IIc fibroblasts. Glycobiology. 2005 Oct. 15(10):924-34. [Medline].
Sturla L, Rampal R, Haltiwanger RS, et al. Differential terminal fucosylation of N-linked glycans versus protein O-fucosylation in leukocyte adhesion deficiency type II (CDG IIc). J Biol Chem. 2003 Jul 18. 278(29):26727-33. [Medline]. [Full Text].
Uzel G, Kleiner DE, Kuhns DB, Holland SM. Dysfunctional LAD-1 neutrophils and colitis. Gastroenterology. 2001 Oct. 121(4):958-64. [Medline].
Uzel G, Tng E, Rosenzweig SD, Hsu AP, Shaw JM, Horwitz ME. Reversion mutations in patients with leukocyte adhesion deficiency type I (LAD-I). Blood. 2007 Sep 17. [Medline].
Wild MK, Luhn K, Marquardt T, Vestweber D. Leukocyte adhesion deficiency II: therapy and genetic defect. Cells Tissues Organs. 2002. 172(3):161-73. [Medline].