Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency
2018; Elsevier BV; Volume: 143; Issue: 3 Linguagem: Inglês
10.1016/j.jaci.2018.08.024
ISSN1097-6825
AutoresDonald B. Kohn, Michael S. Hershfield, Jennifer M. Puck, Alessandro Aiuti, Annaliesse Blincoe, H. Bobby Gaspar, Luigi D. Notarangelo, Eyal Grunebaum,
Tópico(s)Virus-based gene therapy research
ResumoInherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in “real-life” conditions to further inform these management guidelines. Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in “real-life” conditions to further inform these management guidelines. Inherited deficiency of adenosine deaminase (ADA; now often referred to as ADA1) causes a subtype of severe combined immunodeficiency (SCID) characterized by unique effects on lymphoid and nonlymphoid cells. The pathogenesis of ADA deficiency has been studied extensively in human subjects and in a highly representative murine model, as reviewed recently.1Bradford K.L. Moretti F.A. Carbonaro-Sarracino D.A. Gaspar H.B. Kohn D.B. Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID): molecular pathogenesis and clinical manifestations.J Clin Immunol. 2017; 37: 626-637Crossref PubMed Scopus (58) Google Scholar The absence of functional ADA leads to increased concentrations of its substrates adenosine and 2′-deoxyadenosine and their phosphorylated derivatives (total deoxyadenosine nucleotides [dAXP]) and inactivation of S-adenosylhomocysteine hydrolase (SAHase) in cells.2Flinn A.M. Gennery A.R. Adenosine deaminase deficiency: a review.Orphanet J Rare Dis. 2018; 13: 65Crossref PubMed Scopus (88) Google Scholar Excessive levels of deoxyadenosine triphosphate can block DNA synthesis by inhibiting ribonucleotide reductase, and inactivation of SAHase can interfere with processes dependent on transmethylation. ADA deficiency has been associated preferentially with abnormalities in lymphoid development and function.3Joachims M.L. Marble P.A. Laurent A.B. Pastuszko P. Paliotta M. Blackburn M.R. et al.Restoration of adenosine deaminase-deficient human thymocyte development in vitro by inhibition of deoxynucleoside kinases.J Immunol. 2008; 181: 8153-8161Crossref PubMed Scopus (13) Google Scholar, 4Gangi-Peterson L. Sorscher D.H. Reynolds J.W. Kepler T.B. Mitchell B.S. Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination.J Clin Invest. 1999; 103: 833-841Crossref PubMed Scopus (45) Google Scholar, 5Sauer A.V. Brigida I. Carriglio N. Hernandez R.J. Scaramuzza S. Clavenna D. et al.Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID.Blood. 2012; 119: 1428-1439Crossref PubMed Scopus (81) Google Scholar, 6Marciano B.E. Huang C.Y. Joshi G. Rezaei N. Carvalho B.C. Allwood Z. et al.BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies.J Allergy Clin Immunol. 2014; 133: 1134-1141Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 7Patel N.C. Hertel P.M. Estes M.K. de la Morena M. Petru A.M. Noroski L.M. et al.Vaccine-acquired rotavirus in infants with severe combined immunodeficiency.N Engl J Med. 2010; 362: 314-319Crossref PubMed Scopus (166) Google Scholar, 8Roifman C.M. Zhang J. Atkinson A. Grunebaum E. Mandel K. Adenosine deaminase deficiency can present with features of Omenn syndrome.J Allergy Clin Immunol. 2008; 121: 1056-1058Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 9Dalal I. Tasher D. Somech R. Etzioni A. Garti B.Z. Lev D. et al.Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome.Clin Immunol. 2011; 140: 284-290Crossref PubMed Scopus (26) Google Scholar, 10Sauer A.V. Brigida I. Carriglio N. Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency.Front Immunol. 2012; 27: 265Google Scholar Additional defects with varied clinical significance and attributed to diverse mechanisms have been observed in myeloid cells11Kim V. Pham-Huy A. Grunebaum E. Neutropenia among patients with adenosine deaminase deficiency.J Allergy Clin Immunol. 2019; 143: 403-405Abstract Full Text Full Text PDF Scopus (14) Google Scholar, 12Sokolic R. Maric I. Kesserwan C. e Garabedian E. Hanson I.C. Dodds M. et al.Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency.Blood. 2011; 118: 2688-2694Crossref PubMed Scopus (39) Google Scholar, 13Nomura K. Hoshino A. Miyawaki T. Hama A. Kojima S. Kanegane H. Neutropenia and myeloid dysplasia in a patient with delayed-onset adenosine deaminase deficiency.Pediatr Blood Cancer. 2013; 60: 885-886Crossref PubMed Scopus (8) Google Scholar and the lungs,14Booth C. Algar V.E. Xu-Bayford J. Fairbanks L. Owens C. Gaspar H.B. Non-infectious lung disease in patients with adenosine deaminase deficient severe combined immunodeficiency.J Clin Immunol. 2012; 32: 449-453Crossref PubMed Scopus (34) Google Scholar, 15Grunebaum E. Cutz E. Roifman C.M. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency.J Allergy Clin Immunol. 2012; 129: 1588-1593Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16Komarow H.D. Sokolic R. Hershfield M.S. Kohn D.B. Young M. Metcalfe D.D. et al.Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency.Orphanet J Rare Dis. 2015; 10: 159Google Scholar, 17Scott O. Kim V.H. Reid B. Pham-Huy A. Atkinson A.R. Aiuti A. et al.Long-term outcome of adenosine deaminase-deficient patients—a single-center experience.J Clin Immunol. 2017; 37: 582-591Crossref PubMed Scopus (19) Google Scholar brain,18Rogers M.H. Lwin R. Fairbanks L. Gerritsen B. Gaspar H.B. Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency.J Pediatr. 2001; 139: 44-50Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 19Titman P. Pink E. Skucek E. O'Hanlon K. Cole T.J. Gaspar J. et al.Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies.Blood. 2008; 112: 3907-3913Crossref PubMed Scopus (87) Google Scholar, 20Nofech-Mozes Y. Blaser S.I. Kobayashi J. Grunebaum E. Roifman C.M. Neurologic abnormalities in patients with adenosine deaminase deficiency.Pediatr Neurol. 2007; 37: 218-221Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 21Sauer A.V. Hernandez R.J. Fumagalli F. Bianchi V. Poliani P.L. Dallatomasina C. et al.Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.Sci Rep. 2017; 7: 40136Crossref PubMed Scopus (24) Google Scholar, 22Tanaka C. Hara T. Suzaki I. Maegaki Y. Takeshita K. Sensorineural deafness in siblings with adenosine deaminase deficiency.Brain Dev. 1996; 18: 304-306Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 23Albuquerque W. Gaspar H.B. Bilateral sensorineural deafness in adenosine deaminase-deficient severe combined immunodeficiency.J Pediatr. 2004; 144: 278-280Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar skeleton,24Cederbaum S.D. Kaitila I. Rimoin D.L. Stiehm E.R. The chondro-osseous dysplasia of adenosine deaminase deficiency with severe combined immunodeficiency.J Pediatr. 1976; 89: 737-742Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 25Chakravarti V.S. Borns P. Lobell J. Douglas S.D. Chondroosseous dysplasia in severe combined immunodeficiency due to adenosine deaminase deficiency (chondroosseous dysplasia in ADA deficiency SCID).Pediatr Radiol. 1991; 21: 447-448Crossref PubMed Scopus (26) Google Scholar, 26Manson D. Diamond L. Oudjhane K. Hussain F.B. Roifman C. Grunebaum E. Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency SCIDS in the first year of life.Pediatr Radiol. 2013; 43: 589-592Crossref PubMed Scopus (33) Google Scholar liver,27Bollinger M.E. Arredondo-Vega F.X. Santisteban I. Schwarz K. Hershfield M.S. Lederman H.M. Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency.N Engl J Med. 1996; 334: 1367-1371Crossref PubMed Scopus (96) Google Scholar, 28Somech R. Lai Y.H. Grunebaum E. Le Saux N. Cutz E. Roifman C.M. Polyethylene glycol-modified adenosine deaminase improved lung disease but not liver disease in partial adenosine deaminase deficiency.J Allergy Clin Immunol. 2009; 124: 848-850Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 29Kühl J.S. Schwarz K. Münch A. eSchmugge M. Pekrun A. Meisel C. et al.Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID).Klin Padiatr. 2011; 223: 85-89Google Scholar and kidneys,30Pham-Huy A. Kim Vy Nizalik E. Weiler G. Vethamuthu J. Grunebaum E. Atypical hemolytic-uremic syndrome in a patient with adenosine deaminase deficiency.LymphoSign J. 2015; 2: 195-199Google Scholar, 31Ratech H. Greco M.A. Gallo G. Rimoin D.L. Kamino H. Hirschhorn R. Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations.Am J Pathol. 1985; 120: 157-169PubMed Google Scholar, 32Nikolajeva O. Worth A. Hague R. Martinez-Alier N. Smart J. Adams S. et al.Adenosine deaminase deficient severe combined immunodeficiency presenting as atypical haemolytic uraemic syndrome.J Clin Immunol. 2015; 35: 366-372Crossref PubMed Scopus (7) Google Scholar as has increased risk for tumor development (Table I).33Kapoor N. Jung L.K. Engelhard D. Filler J. Shalit I. Landreth K.S. et al.Lymphoma in a patient with severe combined immunodeficiency with adenosine deaminase deficiency, following unsustained engraftment of histoincompatible T cell-depleted bone marrow.J Pediatr. 1986; 108: 435-438Abstract Full Text PDF PubMed Scopus (17) Google Scholar, 34Kaufman D.A. Hershfield M.S. Bocchini J.A. Moissidis I.J. Jeroudi M. Bahna S.L. Cerebral lymphoma in an adenosine deaminase-deficient patient with severe combined immunodeficiency receiving polyethylene glycol-conjugated adenosine deaminase.Pediatrics. 2005; 116: e876-e879Crossref PubMed Scopus (31) Google Scholar, 35Husain M. Grunebaum E. Naqvi A. Atkinson A. Ngan B.Y. Aiuti A. et al.Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase.J Pediatr. 2007; 151: 93-95Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 36Kesserwan C. Sokolic R. Cowen E.W. Garabedian E. Heselmeyer-Haddad K. Lee C.C. et al.Multicentric dermatofibrosarcoma protuberans in patients with adenosine deaminase-deficient severe combined immune deficiency.J Allergy Clin Immunol. 2012; 129: 762-769Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 37Migliavacca M. Assanelli A. Ponzoni M. Pajno R. Barzaghi F. Giglio F. et al.First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature.Front Immunol. 2018; 9: 113-115Crossref PubMed Scopus (15) Google Scholar ADA-associated abnormalities have been reviewed previously1Bradford K.L. Moretti F.A. Carbonaro-Sarracino D.A. Gaspar H.B. Kohn D.B. Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID): molecular pathogenesis and clinical manifestations.J Clin Immunol. 2017; 37: 626-637Crossref PubMed Scopus (58) Google Scholar, 38Grunebaum E. Cohen A. Roifman C.M. Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies.Curr Opin Allergy Clin Immunol. 2013; 13: 630-638Crossref PubMed Scopus (73) Google Scholar, 39Whitmore K.V. Gaspar H.B. Adenosine deaminase deficiency—more than just an immunodeficiency.Front Immunol. 2016; 7: 314-316Crossref PubMed Scopus (73) Google Scholar and will not be detailed here.Table IAbnormalities associated with ADA deficiencyAffected cells/tissuesMechanismClinical significanceReferencesLymphoid cellsDecreased numbers and function of T, B, and NK lymphocytesIncreased susceptibility to infections and autoimmunity, Omenn syndrome3Joachims M.L. Marble P.A. Laurent A.B. Pastuszko P. Paliotta M. Blackburn M.R. et al.Restoration of adenosine deaminase-deficient human thymocyte development in vitro by inhibition of deoxynucleoside kinases.J Immunol. 2008; 181: 8153-8161Crossref PubMed Scopus (13) Google Scholar, 4Gangi-Peterson L. Sorscher D.H. Reynolds J.W. Kepler T.B. Mitchell B.S. Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination.J Clin Invest. 1999; 103: 833-841Crossref PubMed Scopus (45) Google Scholar, 5Sauer A.V. Brigida I. Carriglio N. Hernandez R.J. Scaramuzza S. Clavenna D. et al.Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID.Blood. 2012; 119: 1428-1439Crossref PubMed Scopus (81) Google Scholar, 6Marciano B.E. Huang C.Y. Joshi G. Rezaei N. Carvalho B.C. Allwood Z. et al.BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies.J Allergy Clin Immunol. 2014; 133: 1134-1141Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 7Patel N.C. Hertel P.M. Estes M.K. de la Morena M. Petru A.M. Noroski L.M. et al.Vaccine-acquired rotavirus in infants with severe combined immunodeficiency.N Engl J Med. 2010; 362: 314-319Crossref PubMed Scopus (166) Google Scholar, 8Roifman C.M. Zhang J. Atkinson A. Grunebaum E. Mandel K. Adenosine deaminase deficiency can present with features of Omenn syndrome.J Allergy Clin Immunol. 2008; 121: 1056-1058Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 9Dalal I. Tasher D. Somech R. Etzioni A. Garti B.Z. Lev D. et al.Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome.Clin Immunol. 2011; 140: 284-290Crossref PubMed Scopus (26) Google Scholar, 10Sauer A.V. Brigida I. Carriglio N. Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency.Front Immunol. 2012; 27: 265Google ScholarMyeloid cellsNeutropenia and myeloid dysplasiaNot known11Kim V. Pham-Huy A. Grunebaum E. Neutropenia among patients with adenosine deaminase deficiency.J Allergy Clin Immunol. 2019; 143: 403-405Abstract Full Text Full Text PDF Scopus (14) Google Scholar, 12Sokolic R. Maric I. Kesserwan C. e Garabedian E. Hanson I.C. Dodds M. et al.Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency.Blood. 2011; 118: 2688-2694Crossref PubMed Scopus (39) Google Scholar, 13Nomura K. Hoshino A. Miyawaki T. Hama A. Kojima S. Kanegane H. Neutropenia and myeloid dysplasia in a patient with delayed-onset adenosine deaminase deficiency.Pediatr Blood Cancer. 2013; 60: 885-886Crossref PubMed Scopus (8) Google ScholarLungsAlveolar proteinosis, increased airway resistanceRespiratory distress, bronchiectasis14Booth C. Algar V.E. Xu-Bayford J. Fairbanks L. Owens C. Gaspar H.B. Non-infectious lung disease in patients with adenosine deaminase deficient severe combined immunodeficiency.J Clin Immunol. 2012; 32: 449-453Crossref PubMed Scopus (34) Google Scholar, 15Grunebaum E. Cutz E. Roifman C.M. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency.J Allergy Clin Immunol. 2012; 129: 1588-1593Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16Komarow H.D. Sokolic R. Hershfield M.S. Kohn D.B. Young M. Metcalfe D.D. et al.Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency.Orphanet J Rare Dis. 2015; 10: 159Google Scholar, 17Scott O. Kim V.H. Reid B. Pham-Huy A. Atkinson A.R. Aiuti A. et al.Long-term outcome of adenosine deaminase-deficient patients—a single-center experience.J Clin Immunol. 2017; 37: 582-591Crossref PubMed Scopus (19) Google ScholarBrainNot knownNeurodevelopment, cognitive, behavior seizures, hearing defects18Rogers M.H. Lwin R. Fairbanks L. Gerritsen B. Gaspar H.B. Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency.J Pediatr. 2001; 139: 44-50Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 19Titman P. Pink E. Skucek E. O'Hanlon K. Cole T.J. Gaspar J. et al.Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies.Blood. 2008; 112: 3907-3913Crossref PubMed Scopus (87) Google Scholar, 20Nofech-Mozes Y. Blaser S.I. Kobayashi J. Grunebaum E. Roifman C.M. Neurologic abnormalities in patients with adenosine deaminase deficiency.Pediatr Neurol. 2007; 37: 218-221Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 21Sauer A.V. Hernandez R.J. Fumagalli F. Bianchi V. Poliani P.L. Dallatomasina C. et al.Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.Sci Rep. 2017; 7: 40136Crossref PubMed Scopus (24) Google Scholar, 22Tanaka C. Hara T. Suzaki I. Maegaki Y. Takeshita K. Sensorineural deafness in siblings with adenosine deaminase deficiency.Brain Dev. 1996; 18: 304-306Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 23Albuquerque W. Gaspar H.B. Bilateral sensorineural deafness in adenosine deaminase-deficient severe combined immunodeficiency.J Pediatr. 2004; 144: 278-280Abstract Full Text Full Text PDF PubMed Scopus (53) Google ScholarSkeletalOsteoblast insufficiencySkeletal dysplasia24Cederbaum S.D. Kaitila I. Rimoin D.L. Stiehm E.R. The chondro-osseous dysplasia of adenosine deaminase deficiency with severe combined immunodeficiency.J Pediatr. 1976; 89: 737-742Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 25Chakravarti V.S. Borns P. Lobell J. Douglas S.D. Chondroosseous dysplasia in severe combined immunodeficiency due to adenosine deaminase deficiency (chondroosseous dysplasia in ADA deficiency SCID).Pediatr Radiol. 1991; 21: 447-448Crossref PubMed Scopus (26) Google Scholar, 26Manson D. Diamond L. Oudjhane K. Hussain F.B. Roifman C. Grunebaum E. Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency SCIDS in the first year of life.Pediatr Radiol. 2013; 43: 589-592Crossref PubMed Scopus (33) Google ScholarLiverNot knownHepatic dysfunction27Bollinger M.E. Arredondo-Vega F.X. Santisteban I. Schwarz K. Hershfield M.S. Lederman H.M. Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency.N Engl J Med. 1996; 334: 1367-1371Crossref PubMed Scopus (96) Google Scholar, 28Somech R. Lai Y.H. Grunebaum E. Le Saux N. Cutz E. Roifman C.M. Polyethylene glycol-modified adenosine deaminase improved lung disease but not liver disease in partial adenosine deaminase deficiency.J Allergy Clin Immunol. 2009; 124: 848-850Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 29Kühl J.S. Schwarz K. Münch A. eSchmugge M. Pekrun A. Meisel C. et al.Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID).Klin Padiatr. 2011; 223: 85-89Google ScholarRenalNot knownAtypical hemolytic uremic syndrome30Pham-Huy A. Kim Vy Nizalik E. Weiler G. Vethamuthu J. Grunebaum E. Atypical hemolytic-uremic syndrome in a patient with adenosine deaminase deficiency.LymphoSign J. 2015; 2: 195-199Google Scholar, 31Ratech H. Greco M.A. Gallo G. Rimoin D.L. Kamino H. Hirschhorn R. Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations.Am J Pathol. 1985; 120: 157-169PubMed Google Scholar, 32Nikolajeva O. Worth A. Hague R. Martinez-Alier N. Smart J. Adams S. et al.Adenosine deaminase deficient severe combined immunodeficiency presenting as atypical haemolytic uraemic syndrome.J Clin Immunol. 2015; 35: 366-372Crossref PubMed Scopus (7) Google ScholarTumorsImpaired DNA repair, defective immune surveillanceDermatofibrosarcoma protuberans, lymphoma, liver cancer33Kapoor N. Jung L.K. Engelhard D. Filler J. Shalit I. Landreth K.S. et al.Lymphoma in a patient with severe combined immunodeficiency with adenosine deaminase deficiency, following unsustained engraftment of histoincompatible T cell-depleted bone marrow.J Pediatr. 1986; 108: 435-438Abstract Full Text PDF PubMed Scopus (17) Google Scholar, 34Kaufman D.A. Hershfield M.S. Bocchini J.A. Moissidis I.J. Jeroudi M. Bahna S.L. Cerebral lymphoma in an adenosine deaminase-deficient patient with severe combined immunodeficiency receiving polyethylene glycol-conjugated adenosine deaminase.Pediatrics. 2005; 116: e876-e879Crossref PubMed Scopus (31) Google Scholar, 35Husain M. Grunebaum E. Naqvi A. Atkinson A. Ngan B.Y. Aiuti A. et al.Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase.J Pediatr. 2007; 151: 93-95Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 36Kesserwan C. Sokolic R. Cowen E.W. Garabedian E. Heselmeyer-Haddad K. Lee C.C. et al.Multicentric dermatofibrosarcoma protuberans in patients with adenosine deaminase-deficient severe combined immune deficiency.J Allergy Clin Immunol. 2012; 129: 762-769Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 37Migliavacca M. Assanelli A. Ponzoni M. Pajno R. Barzaghi F. Giglio F. et al.First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature.Front Immunol. 2018; 9: 113-115Crossref PubMed Scopus (15) Google ScholarNK, Natural killer. Open table in a new tab NK, Natural killer. Since the original description of the condition in 1972,40Giblett E.R. Anderson J.E. Cohen F. Pollara B. Meuwissen H.J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity.Lancet. 1972; 2: 1067-1069Abstract PubMed Scopus (1168) Google Scholar more treatment options have been developed for ADA than for other genetic forms of SCID (Fig 1). Current treatments include enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), ex vivo–corrected autologous hematopoietic stem cell gene therapy (HSC-GT), or combinations of these options. Almost a decade ago, experts in ADA-deficient SCID reviewed the pathogenesis of this condition and provided guidelines for its management.41Gaspar H.B. Aiuti A. Porta F. Candotti F. Hershfield M.S. Notarangelo L.D. How I treat ADA deficiency.Blood. 2009; 114: 3524-3532Crossref PubMed Scopus (173) Google Scholar Since then, there have been significant advances in the management of ADA deficiency. Long-term outcomes for ADA-deficient patients receiving different therapies have been reported from single-center17Scott O. Kim V.H. Reid B. Pham-Huy A. Atkinson A.R. Aiuti A. et al.Long-term outcome of adenosine deaminase-deficient patients—a single-center experience.J Clin Immunol. 2017; 37: 582-591Crossref PubMed Scopus (19) Google Scholar, 42Baffelli R. Notarangelo L.D. Imberti L. Hershfield M.S. Serana F. Santisteban I. et al.Diagnosis, treatment and long-term follow up of patients with ADA deficiency: a single-center experience.J Clin Immunol. 2015; 35: 624-637Crossref PubMed Scopus (19) Google Scholar, 43Cagdas D. Gur Cetinkaya P. Karaatmaca B. Esenboga S. Tan C. Yılmaz T. et al.ADA deficiency: evaluation of the clinical and laboratory features and the outcome.J Clin Immunol. 2018; 38: 484-493Crossref PubMed Scopus (16) Google Scholar (H. B. Gaspar, unpublished data; June 17, 2018) and multicenter44Hassan A. Booth C. Brightwell A. Allwood Z. Veys P. Rao K. et al.Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency.Blood. 2012; 120: 3615-3624Crossref PubMed Scopus (136) Google Scholar, 45Pai S.Y. Logan B.R. Griffith L.M. Buckley R.H. Parrott R.E. Dvorak C.C. et al.Transplantation outcomes for severe combined immunodeficiency, 2000-2009.N Engl J Med. 2014; 371: 434-446Crossref PubMed Scopus (495) Google Scholar studies. HSC-GT has been approved for clinical use in the European Union,46Aiuti A. Roncarolo M.G. Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products.EMBO Mol Med. 2017; 9: 737-740Crossref PubMed Scopus (159) Google Scholar and promising results from lentivirus vector–based HSC-GT studies are emerging.47Kohn D.B. Gaspar H.B. How we manage adenosine deaminase-deficient severe combined immune deficiency (ADA SCID).J Clin Immunol. 2017; 37: 351-356Google Scholar Therefore, it is timely to review the new information and provide updated guidance for management of affected patients. The authors, together with clinicians and scientists, patient advocacy groups, the pharmaceutical industry, and US government representatives interested in ADA deficiency, convened in Toronto, Ontario, Canada, on April 29, 2018. The group reached a consensus regarding new treatment guidelines and a treatment algorithm that are described here. Newborn screening for SCID uses DNA from infants' dried blood spots to detect T-cell receptor excision circles as a surrogate marker for new T-cell production. The introduction of newborn screening in all but 3 states in the United States and in an increasing number of countries worldwide has led to significant changes in the diagnosis of SCID and ADA deficiency.48Kwan A. Abraham R.S. Currier R. Brower A. Andruszewski K. Abbott J.K. et al.Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.JAMA. 2014; 312: 729-738Crossref PubMed Scopus (468) Google Scholar Currently, where newborn screening for SCID or a positive family history are available, ADA-deficient patients might be asymptomatic when initially evaluated (J. Puck et al, manuscript submitted).49Heimall J. Logan B.R. Cowan M.J. Notarangelo L.D. Griffith L.M. Puck J.M. et al.Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.Blood. 2017; 130: 2718-2727Crossref PubMed Scopus (149) Google Scholar Clues to the diagnosis of ADA deficiency include an associated neutropenia, characteristic bone abnormalities, and in some cases increased liver enzyme levels. Diagnosis of ADA deficiency is usually established by demonstrating absent or very low (<1% of normal) ADA activity in RBCs, which is accompanied by increased levels of adenosine and 2′-deoxyadenosine in plasma, urine, or dried blood spots. An increased level of deoxyadenosine triphosphate (also measured as dAXP) in RBCs is pathognomonic for ADA deficiency. Demonstrating biallelic mutations in the ADA gene should also be done to further confirm ADA deficiency, permit genetic counseling for the family, and possibly help predict the phenotype.50Arredondo-Vega F.X. Sa
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