Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy

Immunosuppressive treatment (IST) and hematopoietic cell transplant (HCT) are standard therapies for severe aplastic anemia (SAA). We report on conditional survival and standardized mortality ratios (SMR), which compare the mortality risk with the general population adjusted for age, gender, and race/ethnicity, in patients with SAA alive for at least 12 months after treatment with IST or HCT between 2000 and 2018. Given changes to treatment regimens and differences in length of follow-up, two treatment periods were defined a priori: 2000-2010 and 2011-2018. The SMR of patients treated during the period 2000-2010 and who survived one year were 3.50 (95% confidence interval [CI]: 2.62-4.58), 4.12 (95% CI: 3.20-5.21), and 8.62 (95% CI: 6.88-10.67) after IST, matched related donor HCT, and alternative donor HCT, respectively. For the period 2011-2018, the corresponding SMR were 2.89 (95% CI: 1.54-4.94), 3.12 (95% CI: 1.90-4.82), and 4.75 (95% CI: 3.45-6.38), respectively. For IST patients, their mortality risk decreased over time, and became comparable to the general population by five years. For patients who underwent HCT during 2000-2010 and 2011-2018, their mortality risk became comparable to the general population after ten years and after five years, respectively. Thus, 1-year survivors after IST or HCT can expect their longevity beyond five years to be comparable to that of the general US population

Related and unrelated donor transplantation for β-thalassemia major: results of an international survey.

We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively (P < .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% (P < .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection

Diversity and Complexity of the Large Surface Protein Family in the Compacted Genomes of Multiple Pneumocystis Species

Pneumocystis, a major opportunistic pathogen in patients with a broad range of immunodeficiencies, contains abundant surface proteins encoded by a multicopy gene family, termed the major surface glycoprotein (Msg) gene superfamily. This superfamily has been identified in all Pneumocystis species characterized to date, highlighting its important role in Pneumocystis biology. In this report, through a comprehensive and in-depth characterization of 459 msg genes from 7 Pneurnocystis species, we demonstrate, for the first time, the phylogeny and evolution of conserved domains in Msg proteins and provide a detailed description of the classification, unique characteristics, and phylogenetic relatedness of five Msg families. We further describe, for the first time, the relative expression levels of individual msg families in two rodent Pneumocystis species, the substantial variability of the msg repertoires in P. coda from laboratory and wild rats, and the distinct features of the expression site for the classic msg genes in Pneumocystis from 8 mammalian host species. Our analysis suggests multiple functions for this superfamily rather than just conferring antigenic variation to allow immune evasion as previously believed. This study provides a rich source of information that lays the foundation for the continued experimental exploration of the functions of the Msg superfamily in Pneumocystis biology. IMPORTANCE Pneumocystis continues to be a major cause of disease in humans with immunodeficiency, especially those with HIV/AIDS and organ transplants, and is being seen with increasing frequency worldwide in patients treated with immunode-pleting monoclonal antibodies. Annual health care associated with Pneumocystis pneumonia costs similar to$475 million dollars in the United States alone. In addition to causing overt disease in immunodeficient individuals, Pneumocystis can cause subclinical infection or colonization in healthy individuals, which may play an important role in species preservation and disease transmission. Our work sheds new light on the diversity and complexity of the msg superfamily and strongly suggests that the versatility of this superfamily reflects multiple functions, including antigenic variation to allow immune evasion and optimal adaptation to host environmental conditions to promote efficient infection and transmission. These findings are essential to consider in developing new diagnostic and therapeutic strategies.Peer reviewe

Practice pattern changes and improvements in hematopoietic cell transplantation for primary immunodeficiencies

Allogeneic HCT practice patterns for PID changed between 1974–2016. Three-year survival improved to >70% for SCID and non-SCID patients after 1999, and further increased to 94% for SCID patients transplanted 2010–2016 following newborn screening diagnosis

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection

Risk of Zika microcephaly correlates with features of maternal antibodies

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2019-10-10T12:26:15Z No. of bitstreams: 1 Robbiani F D ...Risk.pdf: 2296966 bytes, checksum: 5e47aca9208f3f35c969fd82960279f4 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2019-10-10T13:32:42Z (GMT) No. of bitstreams: 1 Robbiani F D ...Risk.pdf: 2296966 bytes, checksum: 5e47aca9208f3f35c969fd82960279f4 (MD5)Made available in DSpace on 2019-10-10T13:32:42Z (GMT). No. of bitstreams: 1 Robbiani F D ...Risk.pdf: 2296966 bytes, checksum: 5e47aca9208f3f35c969fd82960279f4 (MD5) Previous issue date: 2019-01-07National Institutes of Health grants 5R01AI121207, R01TW009504, and R25TW009338 to A.I. Ko; National Institutes of Health pilot awards U19AI111825 and UL1TR001866 to D.F. Robbiani; National Institutes of Health grants R01AI037526, UM1AI100663, U19AI111825, UL1TR001866, and P01AI138938 to M.C. Nussenzweig; National Institutes of Health grants R01AI124690 and U19AI057229 (Cooperative Center for Human Immunology pilot project); The Rockefeller University Development Office and anonymous donors (to C.M. Rice); Fundação de Amparo `a Pesquisa do Estado da Bahia grant PET0021/2016 (to M.G. Reis); National Institutes of Health grant R21AI129479-Supplement (to K.K.A. Van Rompay) and the National Institutes of Health Office of Research Infrastructure Programs/OD (P51OD011107 to the CNPRC); the United States Food and Drug Administration contract HHSF223201610542P (to L.L. Coffey); National Institutes of Health grants R01AI100989 and R01AI133976 (to L. Rajagopal and K.M. Adams Waldorf); and National Institutes of Health grants AI083019 and AI104002 (to M. Gale Jr.) and grant P51OD010425 to the WaNPRC (to K.M. Adams Waldorf, J. Tisoncik-Go, and M. Gale Jr.). Studies at WNPRC were supported by DHHS/PHS/National Institutes of Health grant R01Al116382-01A1 (to D.H. O’Connor), in part by the National Institutes of Health Office of Research Infrastructure Programs/OD (grant P51OD011106) awarded toWNPRC, at a facility constructed in part with support from Research Facilities Improvement Programgrants RR15459-01 and RR020141-01; and National Institutes of Health core and pilot grant P51 OD011092 and grants R21-HD091032 and R01-HD08633 (to ONPRC). P.F.C. Vasconcelos was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (projects 303999/2016-0, 439971/20016-0, and 440405/2016-5) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Zika fast-track).The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA / Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven / Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.Fudan University. School of Basic Medical Sciences. Shanghai Medical College. Key Laboratory of Medical Molecular Virology. Shanghai, China.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil / Universidade Federal de São Paulo. São Paulo, SP, Brasil.Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Secretaria de Saúde do Estado da Bahia. Hospital Geral Roberto Santos. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA.Universidade Federal de São Paulo. São Paulo, SP, Brasil.Hospital Santo Amaro. Salvador, BA, Brasil.Hospital Santo Amaro. Salvador, BA, Brasil.Hospital Santo Amaro. Salvador, BA, Brasil.Hospital Aliança. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven / Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.University of California. California National Primate Research Center. Davis, Davis, CA, USA.University of California. School of Veterinary Medicine. Department of Pathology, Microbiology, and Immunology. Davis, Davis, CA, USA.Washington National Primate Research Center. Seattle, WA, USA / University of Washington. Center for Innate Immunity and Immune Disease. Seattle, WA, USA / University of Washington. Department of Immunology. Seattle, WA, USA.Washington National Primate Research Center. Seattle, WA / University of Washington. Center for Innate Immunity and Immune Disease. Seattle, WA, USA / University of Washington. Department of Immunology. Seattle, WA, USA / University of Washington. Department of Global Health. Seattle, WA, USA.University of Washington. Department of Global Health. Seattle, WA, USA / University of Washington. Department of Pediatrics. Seattle, WA, USA / Seattle Children’s Research Institute. Center for Global Infectious Disease Research. Seattle, WA, USA.Washington National Primate Research Center. Seattle, WA, USA / University of Washington. Center for Innate Immunity and Immune Disease. Seattle, WA, USA / University of Washington. Department of Global Health. Seattle, WA, USA / University of Washington. Department of Obstetrics and Gynecology. Seattle, WA, USA.University of Wisconsin-Madison. Department of Pathology and Laboratory Medicine. Madison, WI, USA.University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.University of Wisconsin-Madison. Wisconsin National Primate Research Center. Madison, WI, USA.University of Wisconsin-Madison. Department of Pathology and Laboratory Medicine. Madison, WI, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA / Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Oregon National Primate Research Center. Pathology Services Unit, Division of Comparative Medicine. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA / Oregon Health and Science University. Department of Obstetrics and Gynecology. Portland, OR, USA.Oregon National Primate Research Center. Division of Reproductive and Developmental Sciences. Beaverton, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA / Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Oregon National Primate Research Center. Division of Pathobiology and Immunology. Beaverton, OR, USA / Oregon Health and Science University. Vaccine and Gene Therapy Institute. Portland, OR, USA.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.Universidade Federal da Bahia. Faculdade de Medicina. Instituto da Saúde Coletiva. Salvador, BA, Brasil.University of California. California National Primate Research Center. Davis, Davis, CA, USA / University of California. School of Veterinary Medicine. Department of Pathology, Microbiology, and Immunology. Davis, Davis, CA, USA.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Yale School of Public Health. Department of Epidemiology of Microbial Diseases. New Haven, USA.The Rockefeller University. Laboratory of Molecular Immunology. New York, NY, USA / The Rockefeller University. Howard Hughes Medical Institute. New York, NY, USA.Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015-2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly