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Successful engraftment of donor marrow after allogeneic hematopoietic cell transplantation in autosomal-recessive hyper-IgE syndrome caused by dedicator of cytokinesis 8 deficiency

2010; Elsevier BV; Volume: 126; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2010.07.034

1097-6825

Douglas R. McDonald, Michel J. Massaad, Alicia Johnston, Sevgi Keleş, Talal A. Chatila, Raif S. Geha, Sung‐Yun Pai,

Immune Cell Function and Interaction

To the Editor:The hyper-IgE syndromes are rare combined immune deficiencies associated with marked elevations in plasma IgE levels and eosinophilia. An autosomal-dominant form of hyper-IgE syndrome caused by mutations in signal transducer and activator of transcription 3 is characterized by elevated IgE, eosinophilia, eczema, recurrent skin and pulmonary infections, and skeletal abnormalities.1Freeman A.F. Holland S.M. The hyper-IgE syndromes.Immunol Allergy Clin North Am. 2008; 28 (viii): 277-291Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Recently, an autosomal recessive form of hyper-IgE syndrome caused by mutations in the dedicator of cytokinesis 8 (DOCK8) gene has been identified and is characterized by elevated IgE levels, eosinophilia, atopic dermatitis, asthma, food allergies, recurrent upper and lower respiratory tract infections, and unusual susceptibility to infections with herpesvirus family members (herpes simplex virus, human papilloma virus) and molluscum contagiosum.2Zhang Q. Davis J.C. Lamborn I.T. Freeman A.F. Jing H. Favreau A.J. et al.Combined immunodeficiency associated with DOCK8 mutations.N Engl J Med. 2009; 361: 2046-2055Crossref PubMed Scopus (530) Google Scholar, 3Engelhardt K.R. McGhee S. Winkler S. Sassi A. Woellner C. Lopez-Herrera G. et al.Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.J Allergy Clin Immunol. 2009; 124 (e4): 1289-1302Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar Cutaneous infections with human papilloma virus have progressed to squamous cell carcinomas in some cases. Immunologic evaluation of DOCK8-deficient patients has revealed T-cell lymphopenia with impaired proliferative responses of both CD4+ and CD8+ T cells as well as impaired differentiation of TH17 T cells.2Zhang Q. Davis J.C. Lamborn I.T. Freeman A.F. Jing H. Favreau A.J. et al.Combined immunodeficiency associated with DOCK8 mutations.N Engl J Med. 2009; 361: 2046-2055Crossref PubMed Scopus (530) Google Scholar, 3Engelhardt K.R. McGhee S. Winkler S. Sassi A. Woellner C. Lopez-Herrera G. et al.Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.J Allergy Clin Immunol. 2009; 124 (e4): 1289-1302Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, 4Al Khatib S. Keles S. Garcia-Lloret M. Karakoc-Aydiner E. Reisli I. Artac H. et al.Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.J Allergy Clin Immunol. 2009; 124 (8 e1-5): 342-348Abstract Full Text Full Text PDF PubMed Scopus (90) Google ScholarWe report a case of an 8-year-old girl, born to first-degree cousins, who initially presented with pneumococcal meningitis at 11 months of age, complicated by chorda tendineae rupture and flail mitral valve. Isolated asplenia was noted during imaging. She later began to have recurrent episodes of upper and lower respiratory tract infections, pneumococcal bacteremia, giardiasis, and cutaneous infections with herpes simplex virus and Staphylococcus aureus. She also developed flat warts thought to be a result of human papilloma virus infection. Complete blood count revealed hypereosinophilia that ranged from 11,020 to 49,700 cells/μL (Table I) for which she was treated with corticosteroids because of concerns of possible cardiac involvement. Bone marrow examination ruled out a leukemic process. The patient developed moderate persistent asthma and mild eczema. She had multiple food allergies, elevated total IgE (Table I), and positive specific IgE to milk, egg, fish, peanuts, and tree nuts. The patient had received immunization with tetanus toxoid and 23-valent pneumococcal polysaccharide vaccine (Pneumovax, Merck, Whitehouse Station, NJ) and had protective antibody titers to tetanus toxoid and to 6 of 14 pneumococcal serotypes tested. However, titers waned by age 5 years 6 months, and she failed to respond to Pneumovax booster given at age 6 years (see this article's Table E1 in the Online Repository at www.jacionline.org). Her T-cell numbers decreased over time, whereas her B-cell numbers were elevated (see this article's Table E2 in the Online Repository at www.jacionline.org). T-cell proliferation to mitogens and antigens was mildly diminished (see this article's Table E3 in the Online Repository at www.jacionline.org). Serum IgG levels fell over time, and the patient was started on intravenous immunoglobulin replacement therapy at age 7 years. Her clinical presentation prompted an evaluation for DOCK8 deficiency. Western blot of lysates from PBMCs and an EBV-immortalized B-cell line revealed absence of DOCK8 protein (Fig 1, A). PCR amplifying genomic DNA revealed a deletion of exons 28 to 35 of the DOCK8 gene (Fig 1, B).Table IEosinophil counts and IgE levelsAgeAbsolute eosinophil count (cells/μL)IgE (U/mL)10 mo1,020ND2 y 7 mo49,700ND3 y 8 mo22,390ND4 y21,7109306 y 8 mo22,4501,3407 y 1 mo13,3405747 y 10 mo20,7301,287ND, Not determined. Open table in a new tab Although experience with DOCK8 deficiency is limited, its long-term prognosis is poor. Many DOCK8-deficient patients have disfiguring molluscum or human papilloma virus infections or die from fatal infections, squamous cell cancers, or lymphoma.2Zhang Q. Davis J.C. Lamborn I.T. Freeman A.F. Jing H. Favreau A.J. et al.Combined immunodeficiency associated with DOCK8 mutations.N Engl J Med. 2009; 361: 2046-2055Crossref PubMed Scopus (530) Google Scholar Therefore, the decision was made to perform allogeneic hematopoietic cell transplantation (HCT) for definitive correction of her combined immune deficiency. The patient was conditioned with 16 doses of busulfan intravenously adjusted to achieve levels of 800 to 1200 μmol/min on days –9 to –6 and 4 doses of cyclophosphamide 50 mg/kg intravenously on days –4 to –1 without incident. She received unmanipulated bone marrow containing 10 × 106/kg CD34+ cells from her fully matched unaffected younger brother. Cyclosporine A and short-course methotrexate were given for graft-versus-host disease prophylaxis, and she received standard antiviral and antifungal prophylaxis. Neutrophil engraftment occurred on day +16 followed by a rapid rise in lymphocyte count to 4490 cells/μL on day +21. She was febrile and tachypneic with evidence of pulmonary edema with no organisms recovered from nasal secretions or sputum. Cell type–specific chimerism studies on day +21 post-HCT revealed that 100% of CD3+ cells (3536 cells/μL) and 100% of CD15+ cells (6210 cells/μL) were of donor origin. Elevated numbers of lymphocytes were attributed to the response of normal donor cells to occult infection present before the transplant. Fevers and tachypnea resolved, and she was discharged on day +35 post-HCT on cyclosporine A with no signs of acute graft-versus-host disease. Repeat analysis of T and B lymphocyte subsets on day +37 post-HCT revealed continued T-cell engraftment and evidence of emerging naive CD4+ and CD8+ T cells (Table II). T-cell proliferation was not evaluated because the patient continued to receive immune suppression with cyclosporine A. She had neither bacterial nor viral skin infections post-HCT. She presented day +58 post-HCT to the emergency department of her local hospital with high fever, and blood cultures were taken. She was started on antibiotics of appropriate coverage and referred to our institution, where she was found to have septic shock. She died 6 hours later of overwhelming Klebsiella pneumoniae bacteremia. Congenital asplenia may have contributed to the patient's susceptibility to Klebsiella, as has been previously reported.5Waldman J.D. Rosenthal A. Smith A.L. Shurin S. Nadas A.S. Sepsis and congenital aplenia.J Pediatr. 1977; 90: 555-559Abstract Full Text PDF PubMed Scopus (125) Google ScholarTable IIPosttransplant T-cell and B-cell subsetsPosttransplant dayDay +37CD3+ absolute706CD3+/CD4+ absolute520CD3+/CD8+ absolute142CD56+ absolute175CD19+ absolute2CD3+/CD4+/CD45RA+ %4.4CD3+/CD4+/CD45RO+ %95.6CD3+/CD8+/CD45RA+ %29.9CD3+/CD8+/CD45RO+ %70.1 Open table in a new tab In summary, we report a child with DOCK8 deficiency who underwent allogeneic HCT after myeloablative conditioning and demonstrated full donor chimerism early after transplant. These results suggest that HCT may be a viable option to treat DOCK8 deficiency. Unfortunately, the death of the patient precluded further follow-up of immune function and clinical status.This experience demonstrates that HCT with conventional myeloablative conditioning may be potentially curative in DOCK8 deficiency, although more experience is clearly required to assess clinical outcomes. Furthermore, early diagnosis of this newly discovered immune deficiency before repeated infectious injury will likely optimize clinical outcomes after HCT. Because DOCK8 is expressed in both hematopoietic and nonhematopoietic tissues, further experience and long-term follow-up will be needed to determine whether correction of the hematopoietic compartment is sufficient to protect DOCK8-deficient patients from infection and cancer. As this letter was being prepared, Gatz et al reported successful HCT on two patients with autosomal recessive hyper-IgE syndrome found to be due to DOCK8 deficiency after transplant.6Gatz S.A. Benninghoff U. Schutz C. Honig M. Pannicke U. et al.Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation.Bone Marrow Transplantation. 2010; ([in press])PubMed Google Scholar To the Editor: The hyper-IgE syndromes are rare combined immune deficiencies associated with marked elevations in plasma IgE levels and eosinophilia. An autosomal-dominant form of hyper-IgE syndrome caused by mutations in signal transducer and activator of transcription 3 is characterized by elevated IgE, eosinophilia, eczema, recurrent skin and pulmonary infections, and skeletal abnormalities.1Freeman A.F. Holland S.M. The hyper-IgE syndromes.Immunol Allergy Clin North Am. 2008; 28 (viii): 277-291Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Recently, an autosomal recessive form of hyper-IgE syndrome caused by mutations in the dedicator of cytokinesis 8 (DOCK8) gene has been identified and is characterized by elevated IgE levels, eosinophilia, atopic dermatitis, asthma, food allergies, recurrent upper and lower respiratory tract infections, and unusual susceptibility to infections with herpesvirus family members (herpes simplex virus, human papilloma virus) and molluscum contagiosum.2Zhang Q. Davis J.C. Lamborn I.T. Freeman A.F. Jing H. Favreau A.J. et al.Combined immunodeficiency associated with DOCK8 mutations.N Engl J Med. 2009; 361: 2046-2055Crossref PubMed Scopus (530) Google Scholar, 3Engelhardt K.R. McGhee S. Winkler S. Sassi A. Woellner C. Lopez-Herrera G. et al.Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.J Allergy Clin Immunol. 2009; 124 (e4): 1289-1302Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar Cutaneous infections with human papilloma virus have progressed to squamous cell carcinomas in some cases. Immunologic evaluation of DOCK8-deficient patients has revealed T-cell lymphopenia with impaired proliferative responses of both CD4+ and CD8+ T cells as well as impaired differentiation of TH17 T cells.2Zhang Q. Davis J.C. Lamborn I.T. Freeman A.F. Jing H. Favreau A.J. et al.Combined immunodeficiency associated with DOCK8 mutations.N Engl J Med. 2009; 361: 2046-2055Crossref PubMed Scopus (530) Google Scholar, 3Engelhardt K.R. McGhee S. Winkler S. Sassi A. Woellner C. Lopez-Herrera G. et al.Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.J Allergy Clin Immunol. 2009; 124 (e4): 1289-1302Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, 4Al Khatib S. Keles S. Garcia-Lloret M. Karakoc-Aydiner E. Reisli I. Artac H. et al.Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.J Allergy Clin Immunol. 2009; 124 (8 e1-5): 342-348Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar We report a case of an 8-year-old girl, born to first-degree cousins, who initially presented with pneumococcal meningitis at 11 months of age, complicated by chorda tendineae rupture and flail mitral valve. Isolated asplenia was noted during imaging. She later began to have recurrent episodes of upper and lower respiratory tract infections, pneumococcal bacteremia, giardiasis, and cutaneous infections with herpes simplex virus and Staphylococcus aureus. She also developed flat warts thought to be a result of human papilloma virus infection. Complete blood count revealed hypereosinophilia that ranged from 11,020 to 49,700 cells/μL (Table I) for which she was treated with corticosteroids because of concerns of possible cardiac involvement. Bone marrow examination ruled out a leukemic process. The patient developed moderate persistent asthma and mild eczema. She had multiple food allergies, elevated total IgE (Table I), and positive specific IgE to milk, egg, fish, peanuts, and tree nuts. The patient had received immunization with tetanus toxoid and 23-valent pneumococcal polysaccharide vaccine (Pneumovax, Merck, Whitehouse Station, NJ) and had protective antibody titers to tetanus toxoid and to 6 of 14 pneumococcal serotypes tested. However, titers waned by age 5 years 6 months, and she failed to respond to Pneumovax booster given at age 6 years (see this article's Table E1 in the Online Repository at www.jacionline.org). Her T-cell numbers decreased over time, whereas her B-cell numbers were elevated (see this article's Table E2 in the Online Repository at www.jacionline.org). T-cell proliferation to mitogens and antigens was mildly diminished (see this article's Table E3 in the Online Repository at www.jacionline.org). Serum IgG levels fell over time, and the patient was started on intravenous immunoglobulin replacement therapy at age 7 years. Her clinical presentation prompted an evaluation for DOCK8 deficiency. Western blot of lysates from PBMCs and an EBV-immortalized B-cell line revealed absence of DOCK8 protein (Fig 1, A). PCR amplifying genomic DNA revealed a deletion of exons 28 to 35 of the DOCK8 gene (Fig 1, B). ND, Not determined. Although experience with DOCK8 deficiency is limited, its long-term prognosis is poor. Many DOCK8-deficient patients have disfiguring molluscum or human papilloma virus infections or die from fatal infections, squamous cell cancers, or lymphoma.2Zhang Q. Davis J.C. Lamborn I.T. Freeman A.F. Jing H. Favreau A.J. et al.Combined immunodeficiency associated with DOCK8 mutations.N Engl J Med. 2009; 361: 2046-2055Crossref PubMed Scopus (530) Google Scholar Therefore, the decision was made to perform allogeneic hematopoietic cell transplantation (HCT) for definitive correction of her combined immune deficiency. The patient was conditioned with 16 doses of busulfan intravenously adjusted to achieve levels of 800 to 1200 μmol/min on days –9 to –6 and 4 doses of cyclophosphamide 50 mg/kg intravenously on days –4 to –1 without incident. She received unmanipulated bone marrow containing 10 × 106/kg CD34+ cells from her fully matched unaffected younger brother. Cyclosporine A and short-course methotrexate were given for graft-versus-host disease prophylaxis, and she received standard antiviral and antifungal prophylaxis. Neutrophil engraftment occurred on day +16 followed by a rapid rise in lymphocyte count to 4490 cells/μL on day +21. She was febrile and tachypneic with evidence of pulmonary edema with no organisms recovered from nasal secretions or sputum. Cell type–specific chimerism studies on day +21 post-HCT revealed that 100% of CD3+ cells (3536 cells/μL) and 100% of CD15+ cells (6210 cells/μL) were of donor origin. Elevated numbers of lymphocytes were attributed to the response of normal donor cells to occult infection present before the transplant. Fevers and tachypnea resolved, and she was discharged on day +35 post-HCT on cyclosporine A with no signs of acute graft-versus-host disease. Repeat analysis of T and B lymphocyte subsets on day +37 post-HCT revealed continued T-cell engraftment and evidence of emerging naive CD4+ and CD8+ T cells (Table II). T-cell proliferation was not evaluated because the patient continued to receive immune suppression with cyclosporine A. She had neither bacterial nor viral skin infections post-HCT. She presented day +58 post-HCT to the emergency department of her local hospital with high fever, and blood cultures were taken. She was started on antibiotics of appropriate coverage and referred to our institution, where she was found to have septic shock. She died 6 hours later of overwhelming Klebsiella pneumoniae bacteremia. Congenital asplenia may have contributed to the patient's susceptibility to Klebsiella, as has been previously reported.5Waldman J.D. Rosenthal A. Smith A.L. Shurin S. Nadas A.S. Sepsis and congenital aplenia.J Pediatr. 1977; 90: 555-559Abstract Full Text PDF PubMed Scopus (125) Google Scholar In summary, we report a child with DOCK8 deficiency who underwent allogeneic HCT after myeloablative conditioning and demonstrated full donor chimerism early after transplant. These results suggest that HCT may be a viable option to treat DOCK8 deficiency. Unfortunately, the death of the patient precluded further follow-up of immune function and clinical status. This experience demonstrates that HCT with conventional myeloablative conditioning may be potentially curative in DOCK8 deficiency, although more experience is clearly required to assess clinical outcomes. Furthermore, early diagnosis of this newly discovered immune deficiency before repeated infectious injury will likely optimize clinical outcomes after HCT. Because DOCK8 is expressed in both hematopoietic and nonhematopoietic tissues, further experience and long-term follow-up will be needed to determine whether correction of the hematopoietic compartment is sufficient to protect DOCK8-deficient patients from infection and cancer. As this letter was being prepared, Gatz et al reported successful HCT on two patients with autosomal recessive hyper-IgE syndrome found to be due to DOCK8 deficiency after transplant.6Gatz S.A. Benninghoff U. Schutz C. Honig M. Pannicke U. et al.Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation.Bone Marrow Transplantation. 2010; ([in press])PubMed Google Scholar We thank Ms Katrin Eurich for technical assistance. Table E1. Tabled 1Antigen-specific antibody titers to vaccinesAntibody titerAntigenSerotype4 y∗More than 1 month after booster of 23-valent pneumococcal vaccine.5 y6 mo6 y∗More than 1 month after booster of 23-valent pneumococcal vaccine.Tetanus (IU/mL)ND2.9Pneumococcus (μg/mL)11.090.030.11324.751.310.2345.380.940.4150.570.020.016B48.485.711.817F4.170.140.14811.480.490.119N0.260.010.09V9.370.270.3212F0.180.030.011477.532.322.8718C19.191.660.819F27.7811.653.3723F28.791.451.03ND, Not determined.∗ More than 1 month after booster of 23-valent pneumococcal vaccine. Open table in a new tab ND, Not determined. Table E2. Tabled 1Lymphocyte countsAge at testingLymphocyte subset4 y7 y8 y8 y7 moNormal valueLymphocyte counts (cells/μL)CD3+ cells11729246937501000-2600CD4+ cells824409408530530-1500CD8+ cells173408278191330-1100CD56+ cells3471761988370-480CD19+ cells2560130915702798270-860 Open table in a new tab Table E3. Tabled 1Proliferation of PBMCs to mitogens and antigens (cpm of 3H-thymidine incorporation into DNA)StimulusPatientControlMedium day 3885566Concavalin A33,75367,764Phytohemagglutinin19,52733,148Pokeweed mitogen106,93567,937Medium day 6818534Tetanus toxoid4,1899,310Diphtheria toxoid4,35211,920Assay was performed on the same day using PBMCs from the patient and a healthy control. Open table in a new tab Assay was performed on the same day using PBMCs from the patient and a healthy control.