Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome
2019; Elsevier BV; Volume: 143; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2018.12.1013
ISSN1097-6825
AutoresGiorgia Bucciol, Sarah K. Nicholas, Pier Luigi Calvo, Andrew J. Cant, David Edgar, Teresa Español, Francesca Ferrua, Miguel Galicchio, Andrew R. Gennery, Nedim Hadžić, I. Celine Hanson, Gustavo Kusminsky, Andrzej Lange, Fanny Lanternier, Nizar Mahlaoui, Despina Moshous, Zohreh Nademi, Bénédicte Neven, Matías Oleastro, Fulvio Porta, Paola Quarello, Marcelo Silva, Mary Slatter, Elena Soncini, Marek Stefanowicz, Francesco Tandoi, M Teisseyre, Troy R. Torgerson, Paul Veys, Katja G. Weinacht, Beata Wolska‐Kuśnierz, Jacques Pirenne, M. Teresa de la Morena, Isabelle Meyts,
Tópico(s)Pneumocystis jirovecii pneumonia detection and treatment
ResumoX-linked hyper-IgM syndrome (XHIGM [or HIGM1]) is a combined immunodeficiency caused by mutations in the gene encoding CD40 ligand (CD40LG), leading to an impairment of both cellular and humoral immunity.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar Lack of CD40 ligand (CD40L) and hence of interaction between CD40L and CD40 results in defective T-cell function and costimulation, with ensuing impaired class-switch recombination and somatic hypermutation in B cells, hindering an effective secondary antibody response. Moreover, activation of natural killer cells, dendritic cells, and monocytes is impaired, which results in an impaired inflammatory response.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar Around 40% of patients present with Pneumocystis jirovecii interstitial pneumonia, and recurrent respiratory tract infections are present in 80% of cases. Other pathogens include mainly bacteria; mycobacteria; fungi, such as Histoplasma, Cryptococcus, and Candida species; and viruses, especially cytomegalovirus (CMV).1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 2de la Morena M.T. Clinical phenotypes of hyper-IgM syndromes.J Allergy Clin Immunol Pract. 2016; 4: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar Gastrointestinal manifestations are described in 40% of patients and include diarrhea with failure to thrive, inflammatory bowel disease, and oral ulcers; neuroendocrine tumors of the gastrointestinal tract have been reported.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 2de la Morena M.T. Clinical phenotypes of hyper-IgM syndromes.J Allergy Clin Immunol Pract. 2016; 4: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373Crossref PubMed Scopus (403) Google Scholar, 5Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar Liver involvement can manifest as an increase in levels of liver enzymes, infectious hepatitis, and sclerosing cholangitis. Cryptosporidium species infection has been reported in as many as half of the cases of sclerosing cholangitis, often leading to cirrhosis and liver failure.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 2de la Morena M.T. Clinical phenotypes of hyper-IgM syndromes.J Allergy Clin Immunol Pract. 2016; 4: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373Crossref PubMed Scopus (403) Google Scholar, 5Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar Central nervous system disease can be present in up to 11% of patients at presentation in the form of central nervous system infections or neurodegenerative disease.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 2de la Morena M.T. Clinical phenotypes of hyper-IgM syndromes.J Allergy Clin Immunol Pract. 2016; 4: 1023-1036Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373Crossref PubMed Scopus (403) Google Scholar, 5Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar Hematologic abnormalities, such as neutropenia and anemia, are described in more than 60% and 15% to 20% of patients, respectively.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373Crossref PubMed Scopus (403) Google Scholar, 5Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar Despite immunoglobulin substitution and antimicrobial prophylaxis, the overall prognosis is poor, with a median survival time from diagnosis of 25 years.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Both European and US registries report mortality of 10% to 20% before the age of 30 years in their patient cohorts.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373Crossref PubMed Scopus (403) Google Scholar, 5Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar, 6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar A recent retrospective observational study analyzed the survival rate of 176 patients with a diagnosis of XHIGM between 1964 and 2013 and compared outcomes for those patients treated with or without hematopoietic stem cell transplantation (HSCT).6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Liver or biliary involvement at diagnosis represented the only significant predictor of mortality, and survival was not influenced by HSCT.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar However, a survival benefit for patients undergoing transplantation was noted starting from 1987, suggesting improvements in transplantation practice over the last 4 decades. Also, patients treated with HSCT demonstrated improvement on scales of daily living (Lansky or Karnofsky) when compared with the group not undergoing transplantation.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar A recent retrospective study from the United Kingdom of 24 patients with XHIGM reported a crude mortality of 38% in patients with liver disease compared with 6% in patients without liver disease.7Azzu V. Kennard L. Morillo-Gutierrez B. Slatter M. Edgar J.D.M. Kumararatne D.S. et al.Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2018; 141: 405-408.e7Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Mortality as high as 80% was reported for patients with XHIGM with liver disease treated with HSCT compared with 10% for those treated with HSCT without liver pathology.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Therefore it is generally recommended that patients with XHIGM patients receive HSCT upfront and before the onset of liver disease.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Azzu V. Kennard L. Morillo-Gutierrez B. Slatter M. Edgar J.D.M. Kumararatne D.S. et al.Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2018; 141: 405-408.e7Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Liver transplantation (LT) has been performed in small numbers of patients with XHIGM who have end-stage liver disease with or without concomitant HSCT. Mortality in patients with XHIGM only receiving LT is high. This is likely because the underlying immune defect is not corrected and could be aggravated further by the immunosuppression needed for LT, as previously reported.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 8Lanternier F. Amazzough K. Favennec L. Mamzer-Bruneel M.-F. Abdoul H. Tourret J. et al.Cryptosporidium spp. infection in solid organ transplantation: the nationwide "TRANSCRYPTO" study.Transplantation. 2017; 101: 826Crossref PubMed Scopus (33) Google Scholar Improved outcome is noted when both LT and HSCT are performed.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Azzu V. Kennard L. Morillo-Gutierrez B. Slatter M. Edgar J.D.M. Kumararatne D.S. et al.Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2018; 141: 405-408.e7Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The aim of this study was to systematically report and compile the data on published and unpublished patients with XHIGM who received LT with or without HSCT. Patients were included from the previous study by de la Morena et al,6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar as well as through contacting corresponding authors of previously reported cases (the relevant bibliographic references can be found in this article's Online Repository at www.jacionline.org). Additionally, a query was sent to the Primary Immune Deficiency Treatment Consortium, the Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation, and the Stem Cell Transplant for primary Immune Deficiencies in Europe registry. For review of the questionnaire used, please see this article's online repository at www.jacionline.org. We report the clinical manifestations, clinical course, and outcome of 13 patients with XHIGM from 3 continents and 8 countries who underwent LT for sclerosing cholangitis. Five of these patients (P1, P4, P5, P7, and P11) were previously reported as cases in the literature (the relevant bibliographic references can be found in this article's online repository at www.jacionline.org), 3 patients (P1, P2, and P8) were included from the previous study, and 1 patient (P7) was included in the study by Azzu et al.7Azzu V. Kennard L. Morillo-Gutierrez B. Slatter M. Edgar J.D.M. Kumararatne D.S. et al.Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2018; 141: 405-408.e7Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar LT and HSCT characteristics are summarized in Table I. Except for 1 patient (P8, who received a diagnosis in adulthood after onset of sclerosing cholangitis), all patients received diagnoses of XHIGM in infancy or childhood, with a median age at diagnosis of 3.5 years (range, 5 months to 36 years).Table ITransplantation characteristics of 13 patients with XHIGM who underwent LT with or without HSCTPatient no.AgeAge at diagnosis of liver diseaseSCCryptosporidium species infectionOrder of transplantationTime elapsed between HSCT/LTYear of and age at LTISYear of and age at HSCTType of HSCTConditioningGvHDRxComplicationsDonor chimerism at last FUSurvival after LTOutcomeP127 y9.5 yYesYesLT - HSCTHSCT - LT2 mo7 wk2009, 17 y2010, 19 yCSTacroMMFCSTacroMMFBasilix2009, 17 y2010, 19 yMUDMUDNMFluATGRICFluTreoATGNoAcute, gut—CSHSC graft failure, relapse of cryptosporidiosis and sclerosing cholangitis after LT—LostFull8 yA/WP225 y10 yYesYesHSCT - LT2 y2009, 16 yCSTacro2007, 14 yMatched cord from siblingRICFluMelAlemNo——NA9 yA/WP313 y7 yNoYesHSCT - LT3 y2015, 10 yCSTacro2012, 7 yMismatched MUDRICFluTreoAlemAcute, gut and liver (grade IV)CSInflixATGECPCatheter-related sepsis, Klebsiella species UTI, adenovirus infection after HSCTMixed2 yA/WP418 y5 yYesYesHSCT - LT1 y2008, 8 yCSTacroMMF2007, 7 yMUDMBuCyATGAcute and chronic; skin, gut, and liver (grade III)CSTacroMMFEtanerceptHHV-6 infection, hypertension after HSCTTransient renal and hepatic insufficiency after LTFull10 yA/WP511 y3 yYesYesLT - HSCT4 wk2015, 8 yTacroCSA Basilix2015, 8 yMUDRICFluTreoThioAcute, skin and liver (grade II)CSMMFMild/moderate acute LT rejection, CMV reactivation, bilateral optic neuritisFull3 yA/WP623 y18 yYesYesLT - HSCT4 wk2016, 21 yCSTacro2016, 21 yMatched siblingRICFluMelNo——Full2 yAlive, relapse of Cryptosporidium species infection (asymptomatic)P738 y5 yYesNoLT - HSCT5 wk1998, 18 yCSTacro1998, 18 yMUDRICFluMelATGAcute, skin and gut (mild)CS—NA20 yA/WP838 y∗Deceased.33 yYesNoLT—1995, 38 yNA—————NA—Deceased soon after LTCause of death: LT-related complicationsP916 y∗Deceased.11 yYesYesHSCT - LT2 mo1999, 16 yTacro1999, 16 yMismatched MUDMCyAlemTBIAcute, skinNAHSC graft failure and liver failure after HSCTPulmonary hemorrhage and renal failure after emergency LTLostDeceased soon after LTCause of death: disseminated cryptosporidiosis and HLHP1012 y∗Deceased.7 yYesYesLT - HSCT2 mo2005, 12 yNA2005, 12 yMismatched MUDRICFluMelThioATGAcute, gut and liver (grade II)—Pleuric effusion, renal failure, relapse of cryptosporidiosis and sclerosing cholangitis after LTFullDeceased 4 mo after LTCause of death: relapse of Cryptosporidium species infection and sclerosing cholangitis, renal failureP1113 y∗Deceased.6 yYesYesLT—1993, 10 yCSCSA———————Deceased 3 y after LTCause of death: relapse of Cryptosporidium species infection and sclerosing cholangitisP1215 y∗Deceased.13 yYesYesLT—2016, 14 yTacro—————Hepatic artery stenosis, relapse of cryptosporidiosis, chronic rejection—Deceased 1 y after LTCause of death: relapse of Cryptosporidium species infection, fulminant liver failureP1325 y∗Deceased.NAYesYesLT—2008, 24 yCSTacroMMF—————Hemorrhagic shock during biopsy,Enterococcus species bacteremia, CMV reactivation, pericarditis, relapse of cryptosporidiosis—Deceased 1 y after LTCause of death: relapse of Cryptosporidium species infection, sepsisAlem, Alemtuzumab; A/W, alive and well; Basilix, basiliximab; Bu, busulfan; CS, corticosteroids; CSA, cyclosporine; Cy, cyclophosphamide; ECP, extracorporeal photopheresis; Flu, fludarabine; FU, follow-up; HHV-6, human herpesvirus 6; HLH, hemophagocytic lymphohistiocytosis; Inflix, infliximab; M, myeloablative; Mel, melphalan; NA, not available; NM, nonmyeloablative; RIC, reduced-intensity conditioning; Rx, therapy; SC, sclerosing cholangitis; Tacro, tacrolimus; TBI, total-body irradiation; Thio, thiotepa; Treo, treosulfan; UTI, urinary tract infection.∗ Deceased. Open table in a new tab Alem, Alemtuzumab; A/W, alive and well; Basilix, basiliximab; Bu, busulfan; CS, corticosteroids; CSA, cyclosporine; Cy, cyclophosphamide; ECP, extracorporeal photopheresis; Flu, fludarabine; FU, follow-up; HHV-6, human herpesvirus 6; HLH, hemophagocytic lymphohistiocytosis; Inflix, infliximab; M, myeloablative; Mel, melphalan; NA, not available; NM, nonmyeloablative; RIC, reduced-intensity conditioning; Rx, therapy; SC, sclerosing cholangitis; Tacro, tacrolimus; TBI, total-body irradiation; Thio, thiotepa; Treo, treosulfan; UTI, urinary tract infection. Additional clinical and genetic data are summarized in Table E1 in this article's online repository at www.jacionline.org. A genetic diagnosis of XHIGM was confirmed in 10 of the 13 patients; in 3 patients diagnosis was based on clinical and immunologic criteria (hyper-IgM and absent CD40L expression). Of the 9 reported mutations, 1 is a missense in the promoter region of CD40L, 1 is a splice-site missense mutation downstream of exon 1, 1 is a nonsense mutation in exon 5, 5 are frameshift mutations (1 in exon 1, 1 in exon 2, and 3 in exon 5), and 1 is a partial deletion of the CD40L gene. Familial cases were found in 5 patients. Six patients had recurrent respiratory tract infections, and 4 patients had chronic lung disease, but only 2 presented with confirmed P jirovecii pneumonia. One patient had pulmonary Mycobacterium avium infection and aspergillosis. One patient had tuberculosis of the shoulder and knee and septic arthritis of the hip, and another patient had an episode of cryptococcal meningitis. Seven patients manifested neutropenia, and 1 had pancytopenia caused by hypersplenism. Eight patients had gastrointestinal manifestations, such as chronic diarrhea, and 6 patients had failure to thrive. In all but 1 patient (P3), liver disease was diagnosed as sclerosing cholangitis, and Cryptosporidium species infection was reported in 11 cases. P3 manifested liver disease after HSCT; his liver histology was compatible with chronic graft-versus-host disease (GvHD), but he also had Cryptosporidium species infection since before HSCT (microscopically identified) that did not respond to antimicrobial treatment. All patients were receiving immunoglobulin substitution treatment at the time of LT; P jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole was used in 11 of 13 patients. Azithromycin, nitazoxanide, and paromomycin were used alone or in combination as prophylaxis or treatment of Cryptosporidium species infection in 7 patients. Two patients were receiving ursodeoxycholic acid for sclerosing cholangitis. A total of 14 LTs and 10 HSCTs were performed in 13 patients (P1 received 2 LTs and 2 HSCTs, Table I). The median age at LT was 14 years (range, 8-38 years). The average time gap between XHIGM diagnosis and onset of liver disease in this cohort was 4.5 years (range, 0.1-17.5 years). Nine patients underwent LT and HSCT. Four patients received LT alone. Among those patients treated with both LT and HSCT, in 5 patients the LT followed HSCT by an average of 15 months (range, 1.6 months to 3 years), whereas in 4 patients LT preceded HSCT by an average of 1 month (range, 1-2 months). All patients received liver allografts from deceased unrelated donors. Living related donor LT was not used for patients in whom a family member was the HSCT donor. One LT was performed as emergency transplantation in the context of liver failure after HSCT (P9). In the patients for whom information is available, standard ABO matching was used for the LT. Immunosuppression regimens for LT consisted of standard therapies according to the center performing the LT. These included tacrolimus for 11 patients (P1-P7, P9, P12, and P13), which was combined with steroids in 8 patients. Two patients (P5 and P11) received cyclosporine, and mycophenolate mofetil (MMF) was added to dual calcineurin inhibitor and steroids in 3 patients (P1, P4, and P13). Basiliximab was added as induction in 2 patients (P1 and P5). Nine patients received 10 HSCTs. In 5 patients the HSCT preceded the LT. Donor characteristics included 5 patients treated with matched unrelated donors (MUDs; 3 bone marrow and 2 unknown), 3 patients had mismatched unrelated donors (mMUDs; bone marrow), and 2 patients had matched sibling donors (bone marrow). Conditioning was myeloablative in 2 cases and reduced intensity in 7 cases. The conditioning regimen used in the patients who received HSCT first was not limited due to liver dysfunction in any of the cases. Of 10 HSCTs performed, 5 resulted in full donor chimerism, 1 in mixed chimerism (64% on granulocytes and 80% on lymphocytes), and 2 in HSC graft failure (P1 and P9). Both patients who lost donor chimerism manifested a recurrence of cryptosporidiosis and liver failure. P1 showed loss of chimerism 6 months after an MUD HSCT with nonmyeloablative conditioning, followed by relapse of Cryptosporidium species infection, sclerosing cholangitis, and cirrhosis of the previously transplanted liver (LT was performed 2 months before HSCT). He was rescued by a second HSCT from a different unrelated donor after reduced-intensity conditioning, closely followed by a second LT, both of which were successful. P9 had early loss of donor chimerism after an mMUD HSCT with myeloablative conditioning. He experienced acute liver failure and died from disseminated Cryptosporidium species infection and hemophagocytic lymphohistiocytosis after emergency LT. It is possible that the graft failure in P1 was facilitated by the presence of allogeneic T cells from the recently transplanted liver. Seven patients experienced GvHD. Two of those who received HSCT after LT manifested grade II acute liver GvHD (P5 and P10). We can speculate that the occurrence of GvHD in the transplanted liver was more likely to happen because of the HLA mismatch between the liver donor and the HSC donor, although 2 patients treated with HSCT before LT manifested acute GvHD on the native liver (P3 and P4). Six of 13 patients died, 4 of whom received LT alone without HSCT (4/4), 1 in whom LT preceded HSCT (1/4), and 1 in whom LT occurred after HSCT (1/5, Fig 1). In patients who received HSCT, survival was better if HSCT was performed in more recent years, probably because of improved transplantation practices (see Fig E1 in this article's Online Repository at www.jacionline.org). In 5 of the 6 patients who died, Cryptosporidium species infection was present before LT/HSCT, and a persistence/relapse of cryptosporidiosis with or without liver disease was considered the cause of death. The sixth patient died of early LT-related complications. Only 1 patient (P6) who received LT followed by HSCT had a relapse of Cryptosporidium species infection without signs of liver disease 2 years after LT. Except in 1 case, in which HSC engraftment failed (P9), Cryptosporidium species was not identified after LT in those patients who had received successful HSCT before LT. This case series describes the current published data available on LT in patients with XHIGM. Liver involvement in patients with XHIGM is commonly described as sclerosing cholangitis, which is reported in 6% to 20% of patients and is frequently associated with Cryptosporidium species infection.3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar, 5Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar, 6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Azzu V. Kennard L. Morillo-Gutierrez B. Slatter M. Edgar J.D.M. Kumararatne D.S. et al.Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2018; 141: 405-408.e7Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Sclerosing cholangitis is responsible for one third of the cases of cirrhosis and liver failure in patients with XHIGM, although it represents only 4% of cases of LT in the general population. It has also been reported in association with liver carcinoma and cholangiocarcinoma.1Qamar N. Fuleihan R.L. The hyper IgM syndromes.Clin Rev Allergy Immunol. 2014; 46: 120-130Crossref PubMed Scopus (93) Google Scholar, 3Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar The mortality noted herein (6/13 [46%] patients) is in line with previously published data showing how liver disease represents a significant negative predictor of survival for patients with XHIGM, who otherwise have better survival if not affected by hepatic dysfunction.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Azzu V. Kennard L. Morillo-Gutierrez B. Slatter M. Edgar J.D.M. Kumararatne D.S. et al.Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2018; 141: 405-408.e7Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 9Mitsui-Sekinaka K. Imai K. Sato H. Tomizawa D. Kajiwara M. Nagasawa M. et al.Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan.J Allergy Clin Immunol. 2015; 136: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Moreover, the survival rate of pediatric LT recipients has increased over the last few decades and is set now between 70% and 80% at 20 years after transplantation,E7Venick R.S. Farmer D.G. Soto J.R. Vargas J. Yersiz H. Kaldas F.M. et al.One thousand pediatric liver transplants during thirty years: lessons learned.J Am Coll Surg. 2018; 226: 355-366Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar whereas in our cohort overall crude survival was noted to be less than 55%, with an average follow-up of 6.8 years. However, s
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