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Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with Identical Mutations

Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with... Journal of Clinical Immunology (2019) 39:523–526 https://doi.org/10.1007/s10875-019-00649-w LETTER TO EDITOR Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with Identical Mutations 1 2 3 1 1 1 Zohreh Nademi & Nesrine Radwan & Kanchan Rao & Kimberly Gilmour & Austen Worth & Claire Booth Received: 11 March 2019 /Accepted: 20 May 2019 / Published online: 29 May 2019 Springer Science+Business Media, LLC, part of Springer Nature 2019 . . . . Keywords X-linked lymphoproliferative hemophagocytic lymphohistiocytosis lymphoma EBV infection hematopoietic stem cell transplant To the Editor, of Yemeni origin with hemizygous deletions of exon 2 X-linked lymphoproliferative disease (XLP1) was first of the SH2D1A gene who manifested different pheno- described in the 1970s [1]and is arareprimary immuno- types at different ages (Table 1). deficiency (PID) caused by mutations in the SH2D1A Patient one was well until 21 months of age when he gene. This gene encodes the SLAM-associated protein developed bilateral bronchopneumonia and pleural effu- (SAP) which is a key regulator of immune function in T, sion requiring hospital admission. Further investigation NK, and NKT cells and defects in this protein may lead to confirmed severe hypogammaglobulinemia, marked lym- the cellular and humoral immune defects characterized in phocytosis, and subsequently, hemizygous deletion of ex- patients [2]. Clinical manifestations vary and include on 2 of the SH2D1A gene. He commenced immunoglob- hemophagocytic lymphohistiocytosis (HLH), lymphoma, ulin replacement therapy and was monitored regularly. and dysgammaglobulinemia [2, 3] but patients can expe- Lung function and chest imaging showed chronic chang- rience a wide range of phenotypes associated with im- es. A donor search for hematopoietic stem cell transplant mune dysregulation, even independent of Epstein-Barr vi- (HSCT) identified the best available donor was a rus (EBV) infection [3, 4]. Although historically associat- haploidentical donor therefore HSCT was not undertaken ed with EBV infection, a recent study showed 35% of at an early age. He first developed EBV viremia at patients with XLP1 had no evidence of previous EBV six years old and received three courses of rituximab over infection and patients are often diagnosed based on posi- the next five years. On depletion of B cells, EBV viremia tive family history alone [4]. No clear genotype- persisted and further analysis confirmed the presence of phenotype correlation has been identified [4]. Here, we EBV in T and NK cells. Recently, he developed fevers, report three siblings from a non-consanguineous family weight loss, and increased cough. Investigations revealed autoimmune hemolytic anemia (AIHA) requiring rituxi- mab and high-dose intravenous immunoglobulin (IVIG) Capsule Summary XLP1 can present in many different ways with no alongside lower lobe lung collapse associated with genotype-phenotype correlation. Therefore, close monitoring is extreme- Haemophilus influenza treated with a prolonged course ly important especially in those with a family history. of antibiotics. At this time, B cells had returned (CD19+ 660/μl) but were depleted upon rituximab administration. * Zohreh Nademi zohreh.nademi@nuth.nhs.uk He remains on immunoglobulin therapy and prophylactic antibiotics awaiting HSCT. 1 Patient two was diagnosed at birth based on the posi- Department of Pediatric Immunology, Great Ormond Street Hospital, London WC1N 3JH, UK tive family history. He remained well until three years of 2 age when he developed intermittent abdominal pain. This Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Cairo, Egypt was not associated with fever, night sweats, or diarrhea/ constipation. Further investigation confirmed raised LDH, Bone Marrow Transplant Unit, Great Ormond Street Hospital, London, UK anemia, and negative EBV PCR. EBV is negative in 25% 524 J Clin Immunol (2019) 39:523–526 Table 1 Patients’ characteristic Age at Age at SAP Presentation Immunoglobulin Vaccine Lymphocyte Pre-transplant Pre- Dx presentation expression (g/L) responses subsets prophylaxis transplant (× 10^9/L) infections P1 2 years 21 months Absent Chest infections, IgG 4.3 NA CD3 6.13 IVIG EBV bronchiectasis, IgA < 0.06 CD19 2 hypogammaglobulinemia IgM 0.05 CD56 0.35 CD4 3.4 CD8 2.6 Naïve T normal P2 Birth 3 years Absent Non-Hodgkin lymphoma in IgG 4.5 Low then CD3 5.4 Nil before Nil ileum IgA 0.52 normal CD19 0.36 presenta- IgM 0.66 after CD56 0.64 tion booster CD4 4.5 then IVIG vaccine CD8 0.86 Naïve T normal P3 4 months 11 months Absent Uncontrollable seizures IgG 2.76 Normal CD3 6.7 Nil before RSV CNS HLH IgA 0.36 CD19 1.25 presenta- Adenovirus Chest infection IgM 0.58 CD56 1.54 tion then HHV6 CD4 5.66 IVIG/ABx CD8 0.96 Naïve T normal Dx,diagnosis; P, patient; CNS, central nerve system; HLH, hemophagocytic lymphohistiocytosis; EBV, Epstein-Barr virus; RSV, respiratory syncytial virus; HHV6, human herpes virus type 6; IVIG, intravenous immunoglobulin; ABx,antibiotic; NA, not available Naïve T: CD4+CD45RA+CD27+/CD4−CD45RA+CD27+ of lymphoma cases in XLP patients [4]. Abdominal CT unrelated cord blood transplant (Table 2). He successfully scan demonstrated marked thickening of the distal ileum engrafted with 100% donor engraftment at last follow-up with pathological mesenteric and right iliac fossa enlarged two years post-HSCT. He developed grade II gut and skin lymph nodes. A biopsy was consistent with non-Hodgkin graft versus host disease (GvHD) with complete resolu- lymphoma and he received two cycles of R-GRAB (cy- tion. He also developed AIHA post-HSCT requiring ste- clophosphamide, doxorubicin, vincristine, prednisolone, roid, rituximab, high-dose IVIG, and cyclosporine (which methotrexate, folinic acid, etoposide, tioguanine, was stopped following the development of posterior re- cytarabine, intrathecal methotrexate, and rituximab) che- versible encephalopathy syndrome (PRES). Currently, he motherapy before proceeding to a mismatched (8/10) is fit and well. Table 2 Hematopoietic stem cell transplant characteristic Donor Conditioning GVHD CD34+ Donor Infection Complication Outcome prophylaxis engraftment post-HSCT post-HSCT P2 MMUD Treosulfan 14 g/m CSA 4.6 × 10^5/kg 100% CMV Engraftment Alive and Cord Fludarabin MMF Adenovirus syndrome well 1A mm 150 mg/m EBV 1DQ Thiotipa 10 mg/kg mm P3 MMUD Treosulfan 14 g/m TMA Died CSA 10 × 10^6/kg 100% Coronavirus PBSC Fludarabin Mycobacteria Skin GVHD 1A mm 160 mg/m Stenotrophomonas ATM lung infection 1DQ Thiotipa 10 mg/kg MOF mm ATG 15 mg/kg TCRα/β Rituximab depleted 200 mg/m P, patient; MMURD, mismatched unrelated donor; mm, mismatched; TCR ab, T cell receptor alpha/beta; CSA, cyclosporine A; MMF, mycophenolate mofetil; CMV, cytomegalovirus; EBV, Epstein-Barr virus; TMA, thrombotic microangiopathy; GvHD, graft versus host disease; ATM, atypical mycobacteria; MOF, multi-organ failure J Clin Immunol (2019) 39:523–526 525 Fig. 1 Brain imagings. a Brain MRI at the time of diagnosis of CNS is also noted. b Brain MRI post-HLH 94 protocol therapy. The multiple HLH. There are multifocal enhancing lesions involving white matter brain lesions appear more extensive in keeping with disease progression. and area of cortical and deep gray matter. Leptomeningeal enhancement Diagnosis was confirmed in patient three at four months of failure progressing to multi-organ failure and sadly died age. He thrived and developed normally until 11 months of nine months post-transplant. age when he presented with generalized seizures. Brain CT XLP1 is a disorder of severe immune dysregulation, with and MRI scans showed multiple areas of signal abnormality in HLH, lymphoma, and humoral abnormalities among its the cerebral hemispheres, internal capsules, and cerebellum spectrum of manifestations [2, 4]. It is associated with an but no hydrocephalus or hemorrhage (Fig. 1). He required increased susceptibility to severe EBV infection, however, PICU admission and ventilation to control his seizures. A 35% of patients are EBV negative at diagnosis and may lumbar puncture showed a raised protein in CSF with no cells already display a clinical phenotype. There appears to be present. There was no evidence of hemophagocytosis on bone no significant difference in mortality seen between EBV- marrow aspirate and trephine. He never developed any sys- positive and EBV-negative patients [4]. This family illus- temic features of HLH; ferritin was modestly raised to a peak trates that when XLP is managed conservatively, physicians of around 2000 μg/L, triglycerides of 3 mmol/L, and soluble need to maintain a high index of suspicion for complications CD25 of 10,000 pg/ml. There was no evidence of EBV infec- of immune dysregulation, which may present indolently or tion. He was commenced on the HLH 94 protocol; however, with an isolated organ presentation. Considering the high he received only two doses of etoposide due to developing morbidity and mortality rate, it is strongly recommended that mucositis. A repeat brain MRI showed progression of the genetic screening and counseling be carried out in families focal lesions and evolving brainstem herniation. An external with history of XLP1. However, patients diagnosed at birth ventricular device was inserted to decompress the ventricles due to positive family history still carry a significant risk of and relieve the edema. Brain biopsy confirmed a lymphocytic mortality despite monitoring as demonstrated here; infiltrate and features of immune dysregulation but no defin- highlighting the severity of this disorder. Considering the itive hemophagocytosis on histopathology. As salvage thera- lack of genotype-phenotype correlation and unpredictable py for progressive CNS HLH, he was treated with course of XLP1 [4], close monitoring remains critical to al- alemtuzumab (0.3 mg/kg in total) which led to modest CNS low the prevention of infections, organ damage such as bron- improvement. He developed a right lower zone consolidation chiectasis, and to permit early treatment of EBV infection which impaired his ventilation. His nasopharyngeal secretion and other serious complications. Active disease at HSCT, was positive for respiratory syncytial virus and treatment with pre-transplant organ damage and use of a mismatched donor zanamivir and ribavirin was initiated. A lung biopsy per- reduces post-HSCT survival to almost 50% [4]. With the formed pre-transplant showed scarring with significant fibro- improved outcomes associated with haploidentical HSCT sis and macrophage infiltrates with negative cultures and in primary immunodeficiency [5], pre-emptive early HSCT PCRs. He underwent a TCR alpha/beta CD19-depleted could be considered for patients with XLP once stabilized HSCT from a MMUD (8/10) (details in Table 2)with100% after initial presentation even if a fully HLA-matched donor donor engraftment on whole blood. However, he developed is not available. numerous complications post-transplant including thrombotic Author Contribution ZN and NR equally contributed to writing the microangiopathy (TMA), grade III skin GvHD, manuscript. Mycobacterium abscessus,and Stenotrophomonas lung infec- tion and widespread skin breakdown. After several months, Compliance with Ethical Standards abdominal distention and discomfort were noted with raised lactate and an abdominal CT scan demonstrated fatty infiltra- Conflict of Interest The authors declare that they have no conflict of tion of a grossly distended liver. He rapidly developed liver interest. 526 J Clin Immunol (2019) 39:523–526 4. Booth C. X-linked lymphoproliferative disease due to SAP/SH2D1A References deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011;117(1):53–62. 1. Purtilo DT. X-linked recessive progressive combined variable immu- + + 5. Shah R. T-cell receptor αβ and CD19 cell–depleted haploidentical nodeficiency (Duncan’s disease). Lancet. 1975;1(7913):935–40. and mismatched hematopoietic stem cell transplantation in primary 2. Worth AJ. Severe Epstein–Barr virus infection in primary immuno- immune deficiency. J Allerg Clin Immunol. 2018;141(4):1417–26. deficiency and the normal host. Br J Haematol. 2016;175(4):559–76. 3. Panchal N. X-linked lymphoproliferative disease type 1: a clinical Publisher’sNote Springer Nature remains neutral with regard to and molecular perspective. Front Immunol. 2018;9:666. jurisdictional claims in published maps and institutional affiliations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Immunology Pubmed Central

Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with Identical Mutations

Journal of Clinical Immunology , Volume 39 (5) – May 29, 2019

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Abstract

Journal of Clinical Immunology (2019) 39:523–526 https://doi.org/10.1007/s10875-019-00649-w LETTER TO EDITOR Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with Identical Mutations 1 2 3 1 1 1 Zohreh Nademi & Nesrine Radwan & Kanchan Rao & Kimberly Gilmour & Austen Worth & Claire Booth Received: 11 March 2019 /Accepted: 20 May 2019 / Published online: 29 May 2019 Springer Science+Business Media, LLC, part of Springer Nature 2019 . . . . Keywords X-linked lymphoproliferative hemophagocytic lymphohistiocytosis lymphoma EBV infection hematopoietic stem cell transplant To the Editor, of Yemeni origin with hemizygous deletions of exon 2 X-linked lymphoproliferative disease (XLP1) was first of the SH2D1A gene who manifested different pheno- described in the 1970s [1]and is arareprimary immuno- types at different ages (Table 1). deficiency (PID) caused by mutations in the SH2D1A Patient one was well until 21 months of age when he gene. This gene encodes the SLAM-associated protein developed bilateral bronchopneumonia and pleural effu- (SAP) which is a key regulator of immune function in T, sion requiring hospital admission. Further investigation NK, and NKT cells and defects in this protein may lead to confirmed severe hypogammaglobulinemia, marked lym- the cellular and humoral immune defects characterized in phocytosis, and subsequently, hemizygous deletion of ex- patients [2]. Clinical manifestations vary and include on 2 of the SH2D1A gene. He commenced immunoglob- hemophagocytic lymphohistiocytosis (HLH), lymphoma, ulin replacement therapy and was monitored regularly. and dysgammaglobulinemia [2, 3] but patients can expe- Lung function and chest imaging showed chronic chang- rience a wide range of phenotypes associated with im- es. A donor search for hematopoietic stem cell transplant mune dysregulation, even independent of Epstein-Barr vi- (HSCT) identified the best available donor was a rus (EBV) infection [3, 4]. Although historically associat- haploidentical donor therefore HSCT was not undertaken ed with EBV infection, a recent study showed 35% of at an early age. He first developed EBV viremia at patients with XLP1 had no evidence of previous EBV six years old and received three courses of rituximab over infection and patients are often diagnosed based on posi- the next five years. On depletion of B cells, EBV viremia tive family history alone [4]. No clear genotype- persisted and further analysis confirmed the presence of phenotype correlation has been identified [4]. Here, we EBV in T and NK cells. Recently, he developed fevers, report three siblings from a non-consanguineous family weight loss, and increased cough. Investigations revealed autoimmune hemolytic anemia (AIHA) requiring rituxi- mab and high-dose intravenous immunoglobulin (IVIG) Capsule Summary XLP1 can present in many different ways with no alongside lower lobe lung collapse associated with genotype-phenotype correlation. Therefore, close monitoring is extreme- Haemophilus influenza treated with a prolonged course ly important especially in those with a family history. of antibiotics. At this time, B cells had returned (CD19+ 660/μl) but were depleted upon rituximab administration. * Zohreh Nademi zohreh.nademi@nuth.nhs.uk He remains on immunoglobulin therapy and prophylactic antibiotics awaiting HSCT. 1 Patient two was diagnosed at birth based on the posi- Department of Pediatric Immunology, Great Ormond Street Hospital, London WC1N 3JH, UK tive family history. He remained well until three years of 2 age when he developed intermittent abdominal pain. This Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Cairo, Egypt was not associated with fever, night sweats, or diarrhea/ constipation. Further investigation confirmed raised LDH, Bone Marrow Transplant Unit, Great Ormond Street Hospital, London, UK anemia, and negative EBV PCR. EBV is negative in 25% 524 J Clin Immunol (2019) 39:523–526 Table 1 Patients’ characteristic Age at Age at SAP Presentation Immunoglobulin Vaccine Lymphocyte Pre-transplant Pre- Dx presentation expression (g/L) responses subsets prophylaxis transplant (× 10^9/L) infections P1 2 years 21 months Absent Chest infections, IgG 4.3 NA CD3 6.13 IVIG EBV bronchiectasis, IgA < 0.06 CD19 2 hypogammaglobulinemia IgM 0.05 CD56 0.35 CD4 3.4 CD8 2.6 Naïve T normal P2 Birth 3 years Absent Non-Hodgkin lymphoma in IgG 4.5 Low then CD3 5.4 Nil before Nil ileum IgA 0.52 normal CD19 0.36 presenta- IgM 0.66 after CD56 0.64 tion booster CD4 4.5 then IVIG vaccine CD8 0.86 Naïve T normal P3 4 months 11 months Absent Uncontrollable seizures IgG 2.76 Normal CD3 6.7 Nil before RSV CNS HLH IgA 0.36 CD19 1.25 presenta- Adenovirus Chest infection IgM 0.58 CD56 1.54 tion then HHV6 CD4 5.66 IVIG/ABx CD8 0.96 Naïve T normal Dx,diagnosis; P, patient; CNS, central nerve system; HLH, hemophagocytic lymphohistiocytosis; EBV, Epstein-Barr virus; RSV, respiratory syncytial virus; HHV6, human herpes virus type 6; IVIG, intravenous immunoglobulin; ABx,antibiotic; NA, not available Naïve T: CD4+CD45RA+CD27+/CD4−CD45RA+CD27+ of lymphoma cases in XLP patients [4]. Abdominal CT unrelated cord blood transplant (Table 2). He successfully scan demonstrated marked thickening of the distal ileum engrafted with 100% donor engraftment at last follow-up with pathological mesenteric and right iliac fossa enlarged two years post-HSCT. He developed grade II gut and skin lymph nodes. A biopsy was consistent with non-Hodgkin graft versus host disease (GvHD) with complete resolu- lymphoma and he received two cycles of R-GRAB (cy- tion. He also developed AIHA post-HSCT requiring ste- clophosphamide, doxorubicin, vincristine, prednisolone, roid, rituximab, high-dose IVIG, and cyclosporine (which methotrexate, folinic acid, etoposide, tioguanine, was stopped following the development of posterior re- cytarabine, intrathecal methotrexate, and rituximab) che- versible encephalopathy syndrome (PRES). Currently, he motherapy before proceeding to a mismatched (8/10) is fit and well. Table 2 Hematopoietic stem cell transplant characteristic Donor Conditioning GVHD CD34+ Donor Infection Complication Outcome prophylaxis engraftment post-HSCT post-HSCT P2 MMUD Treosulfan 14 g/m CSA 4.6 × 10^5/kg 100% CMV Engraftment Alive and Cord Fludarabin MMF Adenovirus syndrome well 1A mm 150 mg/m EBV 1DQ Thiotipa 10 mg/kg mm P3 MMUD Treosulfan 14 g/m TMA Died CSA 10 × 10^6/kg 100% Coronavirus PBSC Fludarabin Mycobacteria Skin GVHD 1A mm 160 mg/m Stenotrophomonas ATM lung infection 1DQ Thiotipa 10 mg/kg MOF mm ATG 15 mg/kg TCRα/β Rituximab depleted 200 mg/m P, patient; MMURD, mismatched unrelated donor; mm, mismatched; TCR ab, T cell receptor alpha/beta; CSA, cyclosporine A; MMF, mycophenolate mofetil; CMV, cytomegalovirus; EBV, Epstein-Barr virus; TMA, thrombotic microangiopathy; GvHD, graft versus host disease; ATM, atypical mycobacteria; MOF, multi-organ failure J Clin Immunol (2019) 39:523–526 525 Fig. 1 Brain imagings. a Brain MRI at the time of diagnosis of CNS is also noted. b Brain MRI post-HLH 94 protocol therapy. The multiple HLH. There are multifocal enhancing lesions involving white matter brain lesions appear more extensive in keeping with disease progression. and area of cortical and deep gray matter. Leptomeningeal enhancement Diagnosis was confirmed in patient three at four months of failure progressing to multi-organ failure and sadly died age. He thrived and developed normally until 11 months of nine months post-transplant. age when he presented with generalized seizures. Brain CT XLP1 is a disorder of severe immune dysregulation, with and MRI scans showed multiple areas of signal abnormality in HLH, lymphoma, and humoral abnormalities among its the cerebral hemispheres, internal capsules, and cerebellum spectrum of manifestations [2, 4]. It is associated with an but no hydrocephalus or hemorrhage (Fig. 1). He required increased susceptibility to severe EBV infection, however, PICU admission and ventilation to control his seizures. A 35% of patients are EBV negative at diagnosis and may lumbar puncture showed a raised protein in CSF with no cells already display a clinical phenotype. There appears to be present. There was no evidence of hemophagocytosis on bone no significant difference in mortality seen between EBV- marrow aspirate and trephine. He never developed any sys- positive and EBV-negative patients [4]. This family illus- temic features of HLH; ferritin was modestly raised to a peak trates that when XLP is managed conservatively, physicians of around 2000 μg/L, triglycerides of 3 mmol/L, and soluble need to maintain a high index of suspicion for complications CD25 of 10,000 pg/ml. There was no evidence of EBV infec- of immune dysregulation, which may present indolently or tion. He was commenced on the HLH 94 protocol; however, with an isolated organ presentation. Considering the high he received only two doses of etoposide due to developing morbidity and mortality rate, it is strongly recommended that mucositis. A repeat brain MRI showed progression of the genetic screening and counseling be carried out in families focal lesions and evolving brainstem herniation. An external with history of XLP1. However, patients diagnosed at birth ventricular device was inserted to decompress the ventricles due to positive family history still carry a significant risk of and relieve the edema. Brain biopsy confirmed a lymphocytic mortality despite monitoring as demonstrated here; infiltrate and features of immune dysregulation but no defin- highlighting the severity of this disorder. Considering the itive hemophagocytosis on histopathology. As salvage thera- lack of genotype-phenotype correlation and unpredictable py for progressive CNS HLH, he was treated with course of XLP1 [4], close monitoring remains critical to al- alemtuzumab (0.3 mg/kg in total) which led to modest CNS low the prevention of infections, organ damage such as bron- improvement. He developed a right lower zone consolidation chiectasis, and to permit early treatment of EBV infection which impaired his ventilation. His nasopharyngeal secretion and other serious complications. Active disease at HSCT, was positive for respiratory syncytial virus and treatment with pre-transplant organ damage and use of a mismatched donor zanamivir and ribavirin was initiated. A lung biopsy per- reduces post-HSCT survival to almost 50% [4]. With the formed pre-transplant showed scarring with significant fibro- improved outcomes associated with haploidentical HSCT sis and macrophage infiltrates with negative cultures and in primary immunodeficiency [5], pre-emptive early HSCT PCRs. He underwent a TCR alpha/beta CD19-depleted could be considered for patients with XLP once stabilized HSCT from a MMUD (8/10) (details in Table 2)with100% after initial presentation even if a fully HLA-matched donor donor engraftment on whole blood. However, he developed is not available. numerous complications post-transplant including thrombotic Author Contribution ZN and NR equally contributed to writing the microangiopathy (TMA), grade III skin GvHD, manuscript. Mycobacterium abscessus,and Stenotrophomonas lung infec- tion and widespread skin breakdown. After several months, Compliance with Ethical Standards abdominal distention and discomfort were noted with raised lactate and an abdominal CT scan demonstrated fatty infiltra- Conflict of Interest The authors declare that they have no conflict of tion of a grossly distended liver. He rapidly developed liver interest. 526 J Clin Immunol (2019) 39:523–526 4. Booth C. X-linked lymphoproliferative disease due to SAP/SH2D1A References deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood. 2011;117(1):53–62. 1. Purtilo DT. X-linked recessive progressive combined variable immu- + + 5. Shah R. T-cell receptor αβ and CD19 cell–depleted haploidentical nodeficiency (Duncan’s disease). Lancet. 1975;1(7913):935–40. and mismatched hematopoietic stem cell transplantation in primary 2. Worth AJ. Severe Epstein–Barr virus infection in primary immuno- immune deficiency. J Allerg Clin Immunol. 2018;141(4):1417–26. deficiency and the normal host. Br J Haematol. 2016;175(4):559–76. 3. Panchal N. X-linked lymphoproliferative disease type 1: a clinical Publisher’sNote Springer Nature remains neutral with regard to and molecular perspective. Front Immunol. 2018;9:666. jurisdictional claims in published maps and institutional affiliations.

Journal

Journal of Clinical ImmunologyPubmed Central

Published: May 29, 2019

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