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ARTICLES: Waseem Qasim, Marina Cavazzana-Calvo, E. Graham Davies, Jeffery Davis, Michel Duval, Gretchen Eames, Nuno Farinha, Alexandra Filopovich, Alain Fischer, Wilhelm Friedrich, Andrew Gennery, Carsten Heilmann, Paul Landais, Mitchell Horwitz, Fulvio Porta, Petr Sedlacek, Reinhard Seger, Mary Slatten, Lochie Teague, Mary Eapen, and Paul Veys Allogeneic Hematopoietic Stem-Cell Transplantation for Leukocyte Adhesion Deficiency Pediatrics 2009; 123: 836-840 [Abstract] [Full text] [PDF]

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HSCT for leukocyte adhesion deficiency

Geoffrey A. Weinberg, MD, Laurie A. Milner MD, Jessica C. Shand MD, MHS   (11 September 2009)

HSCT for leukocyte adhesion deficiency 11 September 2009
Geoffrey A. Weinberg, MD, Professor of Pediatrics & Director, Pediatric HIV Program University of Rochester School of Medicine & Dentistry, Laurie A. Milner MD, Jessica C. Shand MD, MHS Send letter to journal: Re: HSCT for leukocyte adhesion deficiency geoff_weinberg{at}urmc.rochester.edu Geoffrey A. Weinberg, MD, et al.	To the Editor: Qasim et al[1] detail the course of 36 children with a confirmed diagnosis of leukocyte adhesion deficiency (LAD) who underwent hematopoietic stem-cell transplantation (HSCT) between 1993 and 2007. They reported that overall survival was 75%, with apparent trends toward better outcome (survival with at least mixed chimerism) after matched family or unrelated donor transplants, and also after reduced-intensity conditioning. Only a few patients were reported to experience unexplained complications (pneumonitis). We wish to report a 37th child with LAD who underwent 9/10 allele-matched unrelated donor HSCT with reduced intensity conditioning, who died of unexpected thrombocytopenia and neurologic disease despite engraftment with mixed chimerism. Leukocyte adhesion deficiency type 1 was diagnosed at 14 mo of age in a male child of non-consanguineous parents, after an episode of nontypable Haemophilus influenzae sepsis and Pseudomonas aeruginosa urinary tract infection occurred on a background of recurrent otitis media and chronic leukocytosis (20,000 to 30,000 WBC/ėL, increasing to 50,000 to 80,000 WBC/ėL blood when ill). Flow cytometric analysis revealed absence of CD11 molecules, and the diagnosis of LAD type 1 was confirmed by the absence of CD18 on flow cytometric analysis and the presence of compound heterozygote stop mutations in the ITGB2 gene.[2] The child underwent a 9/10 (DRB1 allele mismatched) volunteer unrelated donor peripheral blood HSCT at 25 mo of age, following reduced intensity conditioning3 with melphalan, fludarabine, thiotepa, and rabbit antithymocyte globulin. Graft vs. host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Evidence of neutrophil and platelet engraftment occurred by Days +24 and +28, respectively. Bone marrow analysis on Day +42 showed robust trilineage hematopoiesis. Chimerism studies (both karyotypic and PCR amplification of tandem repeat DNA polymorphisms) on bone marrow and peripheral blood revealed approximately 35-40% donor cells. He had only minimal grade 1 skin GVHD and an otherwise uneventful recovery until at Day +42 when he experienced acute thrombocytopenia (platelet count decrease from 50,000 to 3,000 cells/ėL blood) and within 48 hr developed progressive, ascending, symmetric, flaccid paralysis with evidence of T2-signal enhancement and diffuse swelling of the cervical and upper thoracic spinal cord on magnetic resonance imaging. Over the next 10 days, swelling and microinfarcts of the entire spinal cord and medulla were documented by repeated magnetic resonance imaging, and despite treatment with high dose corticosteroids, intravenous immune globulin, ganciclovir, and empiric antibiotics, he died on Day +55. Numerous bacterial and viral cultures of blood, urine, and cerebrospinal fluid (CSF) were negative, as were nucleic acid amplification tests for adenoviruses, BK and JC polyomaviruses, cytomegalovirus, enteroviruses, Epstein Barr virus, herpes simplex viruses types 1 & 2, and varicella zoster virus. Low copy numbers of uncertain significance of human herpes virus type 6 [HHV-6] DNA were detected in the blood and from a sample of bloody CSF after traumatic lumbar puncture (11,500 copies/mL and 3,100 DNA copies/mL, respectively). Antibodies for neuromyelitis optica were negative. Permission for post- mortem examination was not granted. We cannot clearly ascribe this child’s death either to infection or an immune-mediated process. HHV-6 may have played a causative role,[4,5] or simply reactivated coincidentally;[6] post-infectious transverse myelitis, or GVHD could also have caused his illness. However, we are concerned that a rare immunologic or infectious complication of SCT for LAD type 1 may have occurred,[7,8] and thus wish to alert practitioners accordingly. Reference List 1. Qasim W, Cavazzana-Calvo M, Davies EG, et al. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency. Pediatrics 2009;123:836-40. Erratum in: Pediatrics 2009;123:1436. 2. Malech HL, Hickstein DD. Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency. Curr Opin Hematol 2007;14:29-36. 3. Rao K, Amrolia PJ, Jones A, et al. Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Blood 2005;105:879-85. 4. Zerr DM. Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation. J Clin Virol 2006;37(suppl 1):S52- S56. 5. Mori T, Mihara A, Yamazaki R, et al. Myelitis associated with human herpes virus 6 (HHV-6) after allogeneic cord blood transplantation. Scand J Infect Dis 2007;39:276-278. 6. Caserta MT, McDermott MP, Dewhurst S, et al. Human herpesvirus 6 (HHV6) DNA persistence and reactivation in healthy children. J Pediatr 2004;145:478-484. 7. Richard S, Fruchtman S, Scigliano E, et al. An immunological syndrome featuring transverse myelitis, Evans syndrome and pulmonary infiltrates after unrelated bone marrow transplant in a patient with severe aplastic anemia. Bone Marrow Transplant 2000;26:1225-1228. 8. Greter M, Heppner FL, Lemos MP, et al.. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Medicine 2005;11:328-334. Conflict of Interest: None declared